Lecture 12: Mechanisms Of Pathogenecity

Lecture 12: MECHANISMS OF PATHOGENECITY Define pathogenicity and ● Pathogenicity: ability to cause disease by evading or overcoming the host defenses virulence ● Virulence: the extent to which the microorganism is pathogenic Distinguish between primary and opportunistic pathogens Primary pathogens: always cause disease even in healthy immuno- competent individuals e.g. Bacillus anthracis Opportunistic pathogen: a microorganism that may cause disease if given the right circumstances e.g. Candida albicans – immunosuppression Mucor species – diabetics Pseudomonas aeruginosa – burns, CF, HIV, and neutropenic cancer patients Define virulence factor ● molecules/structures produced by pathogens that contribute to their “pathogenicity “or ability to cause disease e.g. Streptococcus pneumoniae is a pathogen, but only when it produces a capsule - a virulence factor Describe at least 3 virulence factors used by bacteria to evade the immune system 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Capsules Cell Wall Components Biofilms Enzymes Invasins Superantigens Toxins Secretion systems Antigenic variation Intra/extracellular growth Capsules ❖ Glycocalyx (= capsule, slime layer etc) -initially prevents the phagocyte from recognizing and ingesting the bacteria • many bacteria can produce capsules in the right environmental conditions Cell wall components M protein ● Streptococcus pyogenes o Heat and acid resistant protein in the cell wall that allows attachment o the bacteria to epithelial cells and inhibits phagocytosis Mycolic acids ● Mycobacterium tuberculosis o Waxy substances in cell walls make the bacterium resistant to digestion inside the phagocyte Biofilms “united we stand” for bacteria o Community of bacteria (single or mixed species), often surrounded by shared glycocalyx o Reduces antibiotic effectiveness, WBC penetration o e.g. Porphyromonas gingivalis in oral cavity, Pseudomonas aeruginosa in lungs, on medical implants . Exoenzymes: released from bacterial cells ● ● ● ● Some bacteria especially G- have genes encoded on their chromosome that code for pathogenic characteristics e.g. coding for a type 3 secretion apparatus Chromosomal region is where the genes are clustered (pathogenicity island) o E.g. Type 3 secretion apparatus enables a bacterial cell to inject proteins into a host cell killing or altering it Kinase: ( e.g. Streptococcus pyogenes) o break down fibrin and dissolve clots formed by the body to isolate the infection (important for spread) ● Hemolysin (Staph, Strep, Listeria, Clostridium) o Break down red blood cells, (Streptolysin S and O in S. pyogenes) ● Coagulase: Clots: converts fibrinogen to fibrin (protein strands), clot can wall the bacteria off from the host defenses Secretion systems ● Leucocidin ● destroys WBC e.g. produced by S. aureus, Actinobacillus species) **** Staphylococcus aureus (not epidermidis) ● Collagenase: breaks down collagen (connective tissue) ● e.g. Clostridium perfringens ● Lecithinase: destroy plasma membranes o e.g. Clostridium perfringens o Proteases: inactivate antibodies and other body proteins, like IgA protease o e.g. Neisseria gonorrhoeae Coagulase test Invasins • surface proteins on some bacteria which activate actin , the cytoskeleton of eukaryotic cells • rearranges and facilitates bacterial engulfment into the host cell • e.g. pedestal formation with Salmonella and pathogenic E. coli, Listeria rearrangement of actin to use as propellent ● ● Describe at least 3 virulence factors used to enter host cells ● ● ● ● Antigenic Variation ● Escaping the immune system o Pathogens have antigens on their surface to which B cells produce antibodies ● Some pathogens can change their makeup of their antigens as they replicate (mutate) ● The immune system will then see them as new pathogens o E.g. Neisseria gonorrhoeae and Trypanosoma species Intracellular growth ● Obligate intracellular growth: can only grow inside of host cells often in protected vacuole o E.g. Chlamydia, Rickettsia ● Facultative intracellular bacteria: bacteria that can multiply outside of host cells, but often use intracellular growth as a means of evading the host defenses o Bordetella, Mycobacterium, Salmonella Some bacteria use their invasins to move from one host cell to another e.g. Shigella and Listeria These bacteria infect intestinal epithelial cells laterally as well as from the outside in Mucous membranes Skin Parenteral route via the mouth Surgical sites and implants can provide a route to bypass these o Some microorganisms have preferred portal of entry and are only capable of causing disease via a specific route Tropism 🡪 the ability of a specific pathogen to infect a particular area ● Determinants of tropism o Distribution of cell receptors for microbes o Accessibility of correct host cell types o Other competing microbes o Appropriate nutrients for growth o Physical and innate defenses at the site of infection o Age, etc plays into this! o Permissive environmental condition – e.g. pH ❑ ❑ Define superantigens and provide an example Also called Type 1 exotoxins Protein antigens that stimulate a very large immune response o Normally <1% of Th cells are activated by an infection, but with a superantigen as activator, then the response can be measured in up to 20% of all Th lymphocytes o Unspecific binding to MHC II and TCR ❑ Results in excessive release of cytokines o This will result in nausea, fever, diarrhea, shock, death e.g. Staphylococcus aureus TSST-1 toxin which causes toxic shock syndrome Define toxins and provide at least 2 examples Some pathogens can remain at the site of infection and do not have to spread through the system to cause disease ● These pathogens may produce toxins that get into cells and cause the disease process o Examples of exotoxin producing bacteria ▪ Corynebacterium diphtheriae ▪ Vibrio cholerae ▪ Clostridium tetani, botulinum, perfringens ▪ Bordetella pertussis Toxins ● ● ● Often primary virulence factor Usually proteins that can produce fever, cause hear failure, diarrhea, edema or shock Can destroy cells 🡪 some inhibit protein synthesis leading to cell death 2 major types 1. Endotoxin like LPS, Lipid A portion a. Molecule that contributes to the structure of the bacteria 2. Exotoxins including superantigens a. An extra protein that is made by bacterium to affect cells other than itself Exotoxin Endotoxin ❑ outer cell wall Gram-neg bacteria - lipopolysaccharide (LPS) ❑ LPS is made of polysaccharide and a lipid A portion ❑ the lipid A is the endotoxin, heat stable ❑ causes chills, fever, weakness, aches, even shock and death ❑ activates the blood clotting system (DIC) (disseminated intravascular coagulation) ❑ Shock: life-threatening loss of blood pressure (if caused by bacteria called septic shock and if caused by Gram negatives called endotoxic shock) ❑ produced by certain types of bacteria and released into the tissues (can be G+ or G- bacteria) ❑ genes for exotoxins are carried by bacteriophages or plasmids -e.g. diphtheria toxin, tetanus toxin 3 types of exotoxins 1. Cytotoxins – affect the cell 2. Neurotoxins – affect brain and nervous system 3. Enterotoxins – affect guts / intestines ❑ ❑ ❑ Describe multiple ways bacteria use to share virulence factors between them very potent proteins, but most are heat labile (sensitive) body produces antibodies called antitoxins for neutralization common structure is A-B toxins where A is toxic part and B binds to cells Bacteria can share or acquire new DNA. Three methods of horizontal gene transmission: ❑ conjugation: transferral of plasmids containing genes for virulence attributes or antibiotic resistance ❑ transduction: acquisition of genes for toxin production e.g. C. diphtheriae bacteria via transferral by a bacteriophage ❑ transformation: acquiring gene for toxin, capsule production, etc by absorbing naked DNA from the environment around the bacterium Plasmids ● Small circular DNA molecules separated from the main bacterial chromosome ● Plasmids may encode antimicrobial resistance or virulence factors e.g. toxins, like tetanus toxin, staphylococcal enterotoxin and heat liable oximes of E.coli Bacteriophage ● Viruses which infect specific bacteria 🡪 transfer of genes by transduction ● E.g. Corynebacterium diphteriae List some effects viruses can exert on host cells to cause disease Not pathogenic unless it is lysogenized by a phage and then produces toxin Cytopathic effects (CPE) : ❑ Killing or damaging of the host cell ❑ Different strains of virus cause different CPE Syncytium formation ● Infected cells fuse to form a giant cell with many nuclei ● This giant cell dies when viruses use up all building material and cause necrosis of tissue ● Permits viral multiplication without exposing virus to antibodies o RSV, measles Lecture 13 : FLORA Describe the differences between normal and transient flora Normal flora 🡪 microbiota ● Animals and humans are free of microbes in utero, in healthy situation acquire bacteria at and after birth ● Newborns first contact with bacteria is usually lactobacilli from mother’s vagina ● With breast feeding and exposure to the environment, foods and other people these type of organisms are able to colonize their skin and intestinal tracts Normal flora in terms of region 1. Respiratory – streptococcus species (mainly alpha hemolysis) 2. GI – Bacteroides fragilis 3. Vagina – Lactobacilli 4. Skin – staphylococcus epidermidis Transient flora ● Microorganisms that may be present on body surfaces ● temporarily (days, weeks or months), then disappear ● Removed by handwashing (soap and mechanical scrubbing) ● Can be either pathogenic (disease causing) or nonpathogenic ● Do not necessarily cause disease unless special conditions prevail Anthrax caused by Bacillus anthracis (Primary pathogen) Treatment 🡪 must be started early Penicillin is he drug of choice but ciprofloxacin used if resistance suspected Susceptible to many antibiotics ● Pen, cipro, tetra, macrolides, clinda, chloro ● ● ● ● ● ● ● principle pathogen of Bacillus species large aerobic Gram positive bacillus with spores disease of herbivores found in soil and on vegetation spores very hardy - >50 yrs NO human to human 3 routes of infection for humans Inoculation (most common) Usually acquired by contact with animals or animal hides Inhalation (e.g bioterror event in US 2002) Not common in present time, historically wool sorters disease Ingestion Common in carnivorous animals, also found in outbreaks in Africa usually due to ingestion of contaminated meat ● ● ● ● ● ● ● ● ● Plasmids responsible for acquisition of virulence factors: o pX01 for toxins and pX02 for capsule polypeptide capsule (glutamic acid) - antiphagocytic Inert nonmetabolizing spores germinate to growing “vegetative”bacteria when conditions are right growth of bacteria leads to production of toxin 3 components of toxin: PA (protective antigen) LF (lethal factor) EF(edema factor) must have PA and either LF or EF for toxicity Immunity and vaccines ● Some animal species are naturally resistant to anthrax ● Vaccines are based on the capsule, poor antigenicity (no good vaccination for humans) ● Animal vaccines good for controlling disease in animals Smallpox (Poxviridae) Ortho poxvirus, variola virus 🡪 small ● Enveloped DNA virus ● Other members of the orthopoxvirus family are: o Vaccinia, Monkeypox, Cowpox… ● Vaccinia and Variola virus differ in only one antigen and ● cross react. ● Immunity to smallpox = immunity to monkeypox ● Vaccinia used in smallpox vaccines (safe) ● ● ● Define terms used to describe disease Smallpox: two forms o Variola major ~30% mortality o Variola minor ~1% mortality Variola major presents in different ways: o Ordinary (discrete, semi-confluent, confluent) o Modified/mild o Flat and hemorrhagic Infectious, but not nearly as infectious as flu Zoonosis ● Disease transmitted to humans from an animal ● Animal may be healthy carrier or may be diseased ● Human 🡪 accidental host o Anthrax, Rabies, Tularemia, Chylamydia psittaci, west nile virus ● ● ● ● ● ● Describe how diseases are transmitted Incubation period 🡪 slight increase in organisms Prodrome phase 🡪 where we start to see slight symptoms (runny nose, sore throat, feel stuffy) Illness 🡪 most busy phase of bacterial replication (exponential) Death 🡪 if there is no immune response Period of decline 🡪 organisms decrease and immune system starts to get activated Convalescence 🡪 at the very end, recovering but still able to make other sick ❑ Horizontal transmission: o Transmission from one person to another through contact, ingestion, vectors, etc e.g. Chickenpox, Strep throat ❑ Vertical transmission: o transfer of a pathogen from a pregnant woman to her fetus e.g. Streptococcus group B or rubella virus Contact transmission 1. Direct contact 🡪 person to person (kissing, touching, sexual intercourse 2. Indirect contact 🡪 agent transferred from reservoir to susceptible host by a non-living object (fomites, towels, cups and etc) 3. Droplet transmission 🡪 microbes spread in droplet nuclei Vehicle transmission ● Transmission of infection by a medium 🡪 food, water, air, blood, IV fluids e.g. Hepatitis B by blood transfusion, M. tuberculosis by airborne route Vectors 🡪 arthropods (bugs) ● Mechanical transmission 🡪 passive transport on the vector’s body e.g spread of shigella infection on house fly-feet ● Biological transmission 🡪 part of the life cycle of the microorganism is in the arthropods body e.g. Malaria and Anopheles mosquitoes Define epidemiological terms Describe different types of infections including nosocomial infections Study 🡪 when and where disease occur Purpose 🡪 to control disease transmission Notifiable diseases 🡪 disease which physicians and laboratories are required to report to Public Health Incidence 🡪 number of diseases occurring within a specified time period Prevalence 🡪 number of diseases in a population at the particular point in time Morbidity 🡪 incidence of specific diseases Mortality 🡪 number of deaths from diseases ● Local infection: infection limited to one site ● Systemic infection: disseminated or generalized infection spread through body ● Focal infection: after spread of a systemic infection through the body, the organisms stay in specific areas (e.g. the liver for hepatitis) ● Primary infection: acute initial infection ● Secondary infection: appears as a complication of a primary infection Consequences of hospital infection ● ● ● ● Serious illness or death Prolonged hospital stay Expensive antimicrobials may be needed Patient may become a carrier or source and spread the infection in the community Spread of multi-resistant organisms ● Growing problem in health care institutions ● MRSA (methicillin resistant Staphylococcus aureus), VRE (vancomycin resistant enterococci), MRTB (multi-resistant M. tuberculosis), etc. ● Hand washing and adherence to hygienic routines is the only way to curb the epidemic List hazards you face as a health care professional ● ● ● Diseases: infectious, pose a risk for healthcare workers involved in the primary care of patients some of the more serious of these diseases are: o HIV o Hepatitis A,B,C Norovirus o TB and other respiratory pathogens (incl. N. meningitidis) Hemorrhagic fever viruses (e.g. Lassa fever, Ebola) Tularemia, Plague o SARS Sources of infection for healthcare workers ● infected patients ● soiled bedding, towels, dressings, other fomites ● contaminated needles ● surgical equipment How to avoid getting infected Acute vs Chronic Disease ● ● ● ● Hand washing: the number one preventative measure gloves, gowns, masks, goggles proper handling of used needles disinfection of the environment ● ● ● Acute disease: characterized by acute inflammatory responses where the neutrophil is the predominant cell type in the infiltrate o Pus production e.g. Boil caused by Staphylococcus aureus ● ● ● ● Chronic disease: characterized by chronic inflammatory responses where the predominant cell responders are mononuclear cells Slower type of infection Characterized by development of granulomas e.g. tuberculosis ● Sub-acute disease: intermediate between acute and chronic, usually a disease process that takes a long time to develop fully o e.g. BSE or vCJD in humans o Latent disease: causative organism may lie dormant for long periods of time before “reactivating” o e.g Herpes simplex or varicella ● ● Lecture 14 : SKIN AND EYE INFECTIONS Describe why the skin is a good barrier to infection ● ● ● ● ● Poor environment for microbial growth o Dry, high salt, sebum o Lysozyme, antimicrobial peptides Microbial inhabitants often Gram positive Washing reduces numbers but does not eliminate normal flora o Quickly re-establishes from hair follicles, sweat glands etc High moisture areas have larger microbial populations Identify the normal flora of the skin and give reasons why they survive on skin ● Identify common eye infections, their causes and the results of disease (i.e. styes, blepharitis, conjunctivitis, keratitis, trachoma, inclusion conjunctivitis, ophthalmia neonatorum etc) ● ● ● ● ● ● outer surface of eye is exposed to the external environment and infectious organisms eyelid serves as a mechanical barrier to organisms tears with lysozyme and IgA: chemical barrier conjunctiva: especially susceptible to infection -vulnerable epithelial surface -covered by eyelid, creates warm, moist conditions ● Viral conjunctivitis Conjunctiva ● Both aerobic and some anaerobic bacteria grow on the skin o Staphylococcus epidermidis (dominant flora in skin) Mucous membranes o Line the body cavities o Internal skin o Sheets of epithelial cells attached to a basement membrane o Goblet cells in skin secrete mucus to protect mucosal surface o Cilia on some cells o Acidic pH, normal flora must like to live at lower pHs ▪ E.g. respiratory tract: alpha streptococci ▪ Vaginal canal 🡪 lactobacillus Thin layer of mucous membrane lining the eyelids and covering the surface of the eye Bacterial conjunctivitis Keratitis Inflammation of the cornea 1. 2. Staphylococcus aureus eye infections Bacterial keratitis a. Characterized by pus Viral keratitis a. Less pus Blepharitis 🡪 inflammation of lid margins (infection) Stye 🡪 involvement of eyelid glands and follicles C.trachomatis Ocular ● Types A-C Genital ● Types D-K, LGV Define terms used to describe rash lesions (i.e. macular, vesicular…) Identify characteristics of Staphylococcus aureus and Streptococcus pyogenes that make them major skin pathogens ● ● Staphlycoccus sp. o Gram positive cocci in clusters o Non-motile, non spore forming, can and cannot have capsules 3 main species to know o S. aureus (primary pathogen) o S. epidermidis (opportunistic) o S. saphrophyticus (primary pathogen in the urinary tract, young women) S.aureus ● ● ● ● ● ● produce coagulase (differentiating characteristic from other staph species) - converts fibrinogen (sol) to fibrin (insol): 🡪 “coagulase positive staphylococci” -often yellowish colonies on BAP “yellow or golden staphylococci” MSSA (methicillin susceptible S. aureus) MRSA (methicillin resistant S. aureus) S.aureus virulence factors ● ● ● ● ● ● ● Coagulase Adhesion molecules Exotoxins and superantigens DNase Membrane damaging toxins (e.g. leucocidin) Capsule (sometimes) Protein A (Fc receptor) Impetigo ● ● ● ● Often in newborns and young children caused by staphylococci and streptococci Infection of epidermal layer Treatment 🡪 remove crusts, wash lesions and apply topical antibiotics Oral antibiotics if the infection spreads Toxic Shock Syndrome life threatening, multi-system effects -fever, vomiting, sunburn-like rash -effect of a “superantigen” -often the exotoxin causing this is TSST-1 (toxic shock syndrome toxin-1) in S. aureus -first identified in association with tampon use, now most common in patients following surgery, and intravenous drug abusers -most often caused by S. aureus, but can also be caused by GAS (group A streptococcus = S. pyogenes Treatment: IV antibiotic (usually semisynthetic penicillin like oxacillin) Scalded skin syndrome neonatal or 2° to toxic shock syndrome - due to S. aureus exfoliative toxin -often begins as skin lesion -exfoliative toxin affects the junctions of epidermal cells and causes loosening of cells Treatment: IV antibiotic Streptococcus sp facultative Gram positive cocci in chains -divided into three groups on the basis of their hemolytic reactions on blood agar: Beta hemolysis ● Group A 🡪 S. pyogenes ● Group B 🡪 S. agalaciate Streptococcus pyogenes ● Beta-hemolytic Important pathogen in skin infections, M protein 🡪 important “Group A”or “GAS” -pharyngitis, tonsillitis -impetigo -cellulitis, erysipelas -”childbed fever” -necrotizing fasciitis Post-infectious disease: acute glomerulonephritis rheumatic fever Streptococcal toxins and enzymes ● ● ● ● ● ● ● Describe common skin diseases and their causes -streptokinase (dissolves blood clots - fibrin) -hyaluronidase (breaks down connective tissue) -deoxyribonucleases (degrade DNA) -proteases (e.g. IgA protease) -erythrogenic toxin (rash of Scarlet Fever) (superantigen) -Spe toxins (superantigens sometimes present in NF strains, are exotoxins that cause massive tissue damage and inflammation, like Flesh Eating Disease) ETC. Erysipelas ● Infection of the dermal layer of skin ● Can progress to septicemia and fatal outcome ● Can begin as pharyngitis ● Treatment 🡪 antibiotics Streptococcal impetigo ● Treatment 🡪 removal of crusts, gentle washing and topical antibiotics Necrotizing fasciitis (flesh eating disease) 🡪 S.pyogenes or GAS ● Massive tissue damage found, cultures and Gram smears done, finding of ● Gram positive cocci in chains and growth of beta- hemolytic streptococci on blood agar plates. ● SpeA toxin detected in bacterial isolate. (superAg) Diagnostic symptom is disproportionate pain to injury!!!! Herpesviruses (DNA viruses) ● ● ● ● ● Extremely rapid progressive infection Streptococci invade deep and destroy the fascia (muscle sheath) liquifying the tissues as it progresses Mortality >40% even with timely treatment Very important with quick diagnosis, debridement of necrotic tissue and antibiotics ● HSV-1 o Causes cold sores very common, > 90% infected, most in childhood transmitted by oral route or direct contact causes “cold sores” remains latent in nerve endings (trigeminal nerve ganglia) and flares up with stress ● ● ● ● ● Herpes glaitortium 🡪 wrestlers on body Herpes whitlow 🡪 occupational hazard of healthcare workers Describe the diseases caused by measles virus and 5th disease (B-19) Measles (Rubeola ) ● Maculopapular viral disease caused by rubeola virus, an enveloped paramyxovirus (RNA) ● Extremely infectious (airborne) ● 90% attack rate in susceptible households ● Systemic disease with rash ● Other closely related viruses are canine distemper and rinderpest ● One serotype, humans only natural host ● No latent or persistent infection ● ● ● Often complicated by secondary bacterial infections like Staphylococcus aureus pneumonia and ear infections Blindness in children with vitamin A deficiency Rare fatal complication 🡪 subacute sclerosing panencephalitis (SSPE several years later) Classic measles ● Rarely subclinical ● Symptoms are respiratory: fever, malaise, anorexia, conjunctivitis, photophobia, myalgia ● Koplik’s spots (appear on buccal mucosa: red white and ● blue spots diagnostic of measles prior to rash) ● Maculopapular rash, starts behind ears, and spreads to face, upper arms and trunk, then legs ● Intense inflammation of lymphoid tissue and mucosa of the ● respiratory tract ● Tracheobronchitis and pneumonia common Measles causes immunosuppression ● Dendritic cells and monocytes are infected, antigen presenting activity compromised ● Circulating T lymphocytes are decreased by 50% ● Abberrant cytokine responses o IL-4 and IL-10 increased, skews TH1 (cell) to Th2 (AB) o Reduced macrophage activity Lecture 15 : UPPER RESPIRATORY TRACT INFECTIONS ▪ ▪ Bacterial infection ▪ Strep throat & complications ▪ Diphtheria ▪ Otitis Media ▪ Whooping cough (borderline URT/LRT) Viral infection ▪ Common cold ▪ Infectious mononucleosis (kissing disease) Identify some common causes of pharyngitis including the common cold The common cold ● >100-200 different viruses can cause a cold, so immunity ● not usually protective factor, no vaccines ● ● ~30-50% of colds caused by rhinoviruses (hosts are primates) 15-20% caused by coronaviruses o Infection easily spreads to sinuses, lower respiratory tract and middle ear Rhinovirus ● >50% of common colds caused by rhinovirus ● Small virus, RNA genome, non-enveloped ● > 100 subtypes, classed into 3 classes based on the receptor they bind to o 90% bind to ICAM-1 ● Transmitted mostly by direct contact (e.g shaking hands very efficient transmission), some by droplet ● ● ● Does not grow at 37°C, optimal at 33°C; therefore grows only in upper respiratory tract 10-12 hours incubation period Self-limiting infection: no antivirals, no vaccine Identify the cause and discuss the disease “Infectious Mononucleosis” Major cause: ● EBV: Epstein Barr virus (HHV 4) DNA, Herpesviridae, enveloped, latent in B cells ● ● ● ● ● Infectious Mononucleosis (IM) (“kissing disease”) Most people have the infection when very young and have mild or sub-clinical infection More severe disease when older (teenagers, college students) Systemic effects on cardiovascular and lymphatic systems Virus shed intermittently from saliva through life Symptoms of IM: ● -fever, sore throat, swollen lymph glands in neck, general weakness, fatigue, enlarged spleen ● ● Production of heterophile antibodies (weird antibodies that agglutinate other mammals RBC) -no function known for these antibodies but they are used for lab tests (e.g. Monospot) ● Ampicillin rash a complication (not just a rash!) if you have mono and are given beta-lactams. This is like a superantigen effect! EBV related cancer EBV related cancer ● Associated with Burkitt’’s lymphoma and other B cell lymphomas ● Most common type of childhood cancer in Africa ● Association with malaria endemic areas Discuss S. pyogenes pathogenicity in the respiratory tract Streptococcal pharyngitis (Strep throat) ● Streptococcus pyogenes (Strep group A) - beta hemolytic streptococci ● on inspection, strep throat cannot be differentiated from ● any other type of infection - laboratory tests necessary!!! ● ● rapid tests are available but if the test is negative and the suspicion continues send a swab to the lab! Need to treat all cases of Streptococcus pyogenes pharyngitis with antibiotics to prevent sequalae (complications coming after an infection) Scarlet fever ● S. pyogenes can produce an erythrogenic toxin o Rheumatic Fever Explain how C. diphtheriae causes disease ● ● The first time you get strep throat with one of these strains producing this superantigen toxin you can get scarlet fever ▪ Pinkish-red sandpaper like skin rash ▪ High fever ▪ Strawberry tongue (loses upper membrane and becomes inflamed) ▪ Scarlet fever varies in severity, may progress to glomerulonephritis or rheumatic fever ● Non-infectious complication of a S.pyogenes infection occurring after an infection has disappeare Cross reactivity of bacterial antigens with tissue antigens. o Some evidence of T lymphocyte invasion in addition to neutrophil damage Most often mitral valve damage ● ● caused by Corynebacterium diphtheriae, an aerobic Gram positive bacillus (non- spore forming) bacteria do not invade tissues - they produce an exotoxin (inhibits protein synthesis in host cells - tropism for nerve cells) ● ● once leading cause of mortality in children (9,000 cases in children 1-5 yrs in the early 1920’s ● ● ● Toxoid vaccine introduced in 1924 Vaccination has drastically reduced the incidence of disease in North America and Europe – now it is a rare disease here o Symptoms: ▪ sore throat, fever, malaise ▪ neck swelling (“bull neck”) ▪ nerve paralysis ▪ white-gray membrane across back of throat (fibrin, dead tissue, bacterial cells, toxin and neutrophils) Pathogenic strains of C. diphtheriae produce exotoxins that diffuse through tissues, cause death of epithelial cells in the throat and affect nerves (e.g. in heart and face). Typical thick gray membrane (pseudomembrane): -covers back of throat – very hard to remove, grows out of the tissue and bleeds if you try to dislodge it can prevent breathing, obstructs air passage ● ● Identify the causes of otitis media C.diptheriae 🡪 apathogenic unless transduction occurs by a bacteriophage which transfers the exotoxin gene o All isolates of this bacteria have to be tested for the toxin first ▪ Effects of toxin: myocarditis, cardiac failure, polyneuritis, death (toxin has an affinity for nerve cells) ▪ bacteria do not invade tissues, just expel exotoxin which can diffuse into other areas Treatment: antibiotics and antitoxin o effective, but older people in population may only have effective protection in 20% of cases due to lack of boosters o -tetanus toxoid is usually combined with diphtheria toxoid and pertussis DTaP Discuss pathogenic mechanisms of Bordetella pertussis causing whooping cough Bordetella pertussis ● Small aerobic Gram neg coccobacillus ● Produces many exotoxins ● Does not invade tissues, colonizes ciliated respiratory epithelium and kills cells with tracheal cytotoxin ● Transmission: droplet ● ● Three stages of disease: o Catarrhal: cold like o Paroxysmal: gasping cough o Convalescence: healing Infants most at risk for: o Broken ribs o Pertussis pneumonia o Oxygen deprivation to brain Pathogenicity ● FTA filamentous hemagglutinin (for adherence) ● Pertussis toxin 🡪 systemic effects ● Tracheal cytotoxin 🡪 damages ciliated cells ● Lethal toxin 🡪 tissue necrosis ● Adenylate cyclase 🡪 reduces phagocytic activity ● LPS Treatment ● Treatment usually not effective for disease but reduces infectivity o Erythromycin Vaccine ● ● New acellular vaccine (against toxins) Combined with tetanus and diphtheria DTaP o 5 doses, new recommendations for re-vaccinating in early teens Lecture 16 : LOWER RESPIRATORY TRACT INFECTIONS Describe M. tuberculosis pathogenicity, Tuberculosis (Mycobacterium tuberculosis) latent infection and active disease • Leading cause of death world wide from bacterial disease • Capable of intracellular survival & growth in macrophages (facultatively intracellular) • No toxin produced. Inflammation- major pathogenic mechanism • Transmission: airborne • Bacillus, non-motile, acid fast Strict aerobe • • • • Mycolic acid forms an impermeable barrier to entry of molecules into the bacillus. Survive long period on dry surfaces. Not visible in Gram stain (mycolic acid prevents Gram stain from entering the cell wall) Stained with Ziehl-Neelsen (acid fast) stain. • Production of cord factor (causes bacteria to clump together and inhibits phagocytosis): this chemical is also toxic to host cells. After TB exposure Three things could happen: 1. Latent infection where few TB organisms enter macrophages and remain latent there 2. Primary tubercle forms but the immune system – can stop replication 3. Spread of active infection – this happens in immunocompromised individuals Primary infection: often in lung ● Host walls off the infection in a tubercule (a granuloma) o Tubercule ▪ Macrophage B and T cell collection with central caseation, TB cannot replicate because of low Ph and low oxygen concentration ● Disseminated infection 🡪 occurs if tubercule does not even form for bursts allowing bacteria to spread o This is then disseminated infection called miliary tuberculosis Ghon complex ● A calcified granuloma that shows on an x-ray Second dtage infection ● Miliary infecton ● Directly spread from first infection or a reactivation of a latent infection ● Characterized by spread of tubercles (granulomas ) ● You can get TB anywhere In the body ● Symptoms o weight loss, fever, night sweats, chronic cough, coughing up blood, lethargia (consumption) Mantoux Test 🡪 quantitative tuberculin test Tuberculosis Vaccine ● BCG: Bacillus Calmette-Guerin ● Live culture of Mycobacterium bovis ● In North America only given to children at high risk ● Effectivity of the vaccine is not very good and it doesn’t last ● very long! Therefore…. ● Adults – almost no effect, children some effect Treatment and antibiotic resistance ▪ Multiple drug regimens used to prevent development of drug resistance ▪ Treatment 6 mo – 1 yr because of slow growth of the bacterium ▪ MDR-TB and XDR-TB is a growing problem ▪ MDR-TB resistant to isoniazid and rifampicin (first line drugs) ▪ XDR-TB resistant to first and second line drugs Isolation and Quarantine Describe pneumonia caused by S. pneumoniae and the major virulence factor for the organism Typical: classically caused by S. pneumoniae, responds to penicillin treatment Atypical: caused by other organisms, penicillin resistant, includes virus, bacteria and fungi - most common cause of infection-related death globally - causes of pneumonia in adults and children different: Adults: Mainly bacterial Children: Mainly viral Pneumococcal (Pneumonia (Typical) • Encapsulated facultatively anaerobic Gram positive diplococci – Streptococcus pneumoniae (nickname: pneumococcus) • Most common cause of pneumonia, involves alveoli and bronchi • Symptoms: fever, rust coloured sputum (blood), breathing problems and chest pain • Often spreads to the blood • (bacteremia - septicemia - sepsis) • Vaccines • polysaccharide (23 types) Conjugate (13 types) S. pneumoniae Pathogenicity Many virulence factors • Capsule: >90 antigenic types - main virulence factor • Cell wall: lipoteichoic acids and peptidoglycan • Choline binding proteins for host cell attachment. • Autolysins : self-destruction, release other chemicals. • Pneumolysins: damage pneumocytes in lungs. Production of hydrogen peroxide, neuraminidase and IgA protease Pneumonia Risk Factors ● Asthma ● Cystic Fibrosis ● Chronic Obstructive Pulmonary Disease (COPD) ● Weakened immune system (HIV, cancer…) ● Young children and elderly Identify and discuss characteristics of some viral causes of LRTI: RSV, Parainfluenza, Influenza Bronchiolitis in infants • Usually after an upper respiratory tract infection • Disease restricted to children usually < 2 years • Bronchioles of children very small (diameter) - if the cells lining them are inflamed and swollen the passage of air to and from alveoli is reduced • Necrosis of epithelial cells (spread to the lung →interstitial pneumonia) RSV **RSV (Respiratory Syncytial Virus) • Enveloped, RNA, spread mainly by direct contact and occasionally droplet • Infants and children < 5 yrs ; elderly in nursing homes • Epidemics and seasonal : late winter and early spring • Life-threatening pneumonia and bronchiolitis in infants • Symptoms : coughing and wheezing • Premature babies highest risk for serious disease Treatment –no effective antiviral , new mRNA vaccine Prophylaxis: Synagis monoclonal antibody, (passive immunization), given only to premature babies with other risk factors (very expensive! 15mg/kg,, $260 US $/kg monthly) Croup (children): • Parainfluenza virus (PIV) (enveloped RNA) is a common cause of “croup”in small children • Swelling of mucous membranes in the respiratory tract • Larynx and trachea have non-expandable rings of cartilage and since children have narrow tubes, obstruction can occur Typical seal-like barking cough Influenza A • Influenza A,B,C are enveloped orthomyxoviridae, segmented RNA viruses • Influenza A + B have 8 RNA segments, C has 7 Only Influenza A has subtypes ● ● ● Symptoms ● ● ● ● ● ● Hemagglutinin 🡪 glycoprotein used for attachment to the host cell Neuraminidase 🡪 helps newly formed viruses in the host cell to escape o Need these 2 for a disease to happen M2 ion channel 🡪 allows for acidification of the vacuole that the virus will be enclosed in Malaise Fever Headache Myalgia Cough Sore throat Incubation period and infectious dose ● Small infectious dose ● Incubation 1-5 days ● Virus viable on hard surfaces 24-48 hours ● Droplet transmission Identify the major cause of epiglottis, a life-threatening infection ● ● ● Most often seen in young children,usually due to H. influenzae type b Typical sign → children lean forward to breathe and drool Bacteria spread from nasopharynx to epiglottis, cause severe inflammation, and the epiglottis will swell shut → closing airways ● Define antigenic shift and antigenic drift for Influenza A virus Life threatening, call for help to intubate! Antigenic Drift: ▪ Point mutations in the viral genome encoding for H or N antigens ▪ These strains cause the yearly infections (some cross- immunity from year before) Antigenic Shift: ▪ Recombination of the viral RNA segments with those from another human or an animal ▪ Significant changes in the H and N surface antigens ▪ Leads to pandemics, no immunity to “new” viruses Describe Covid-19 and mechanism of pathogenicity Covid-19 • • • • New enveloped RNA virus belonging to the coronavirus family emerges in China late 2019, probably from a bat reservoir Able to establish infection in humans globally Four subtypes: alpha, beta, (human pathogens) gamma and theta (animal) ß : SARS-CoV, Mers-CoV &“Covid-19 (Sars- CoV2)” • Heterogeneous: symptoms may vary and include: – Fever, conjunctivitis, pharyngitis, coryza, headache, dizziness, generalized weakness, vomiting, diarrhea, dry cough, shortness of breath – Lack of taste and smell, fatigue Severe disease usually presents after 9 days of infection How does this corona virus affect humans? • Glycoprotein spikes: responsible for tropism and attachment to host cell • Spikes have two functional units: S1 (used to bind to receptors on host cells) and S2 (used to fuse host cell and virus envelope) • Main receptor for Covid-19: Angiotensin converting enzyme 2 (ACE2) • ACE2 is highly expressed in lung, heart, ileum, kidney and bladder, on epithelial cells and some endothelial cells. New vaccines developed, antivirals are being developed • Vaccine development is a major push around the world • Few antiviral substances found that can shorten the duration of disease (not prevent) • A common cortisone derivative dexamethazone has been found to improve survival What does ACE2 do? • • • Risk factors for severe disease (ARDS or acute respiratory disease syndrome) • • • • Fungal Diseases • • • • This is angiotensin-converting enzyme 2. Normally it breaks down proteins ( especially angiotensin II) which can increase inflammation and the death of cells in the alveoli (critical for oxygenation of blood). These harmful effects of ANG II are reduced by ACE2 When COVID-19 is bound to ACE2 then it cannot prevent the damaging effects of ANG II Age: immunosenescence – Most cases were at first in elderly patients – Many died due to multi-organ failure Immunocompromise Co-morbid conditions – E.g. pre-existing lung or heart conditions Critically ill patients found to have: – lymphopenia, especially in the peripheral blood T cells – Increased plasma concentration of inflammatory cytokines (IL-6, IL-10), chemokines like IL-8, TNF alpha – Elevated D-dimer and fibrinogen = increased clotting (hypercoagulable) Histoplasmosis Coccidioidomycosis Aspergillosis Pneumocystis jiroveci (especially in AIDS and other immune-suppressed individuals like transplant patients) Lecture 17: Upper Alimentary Tract ❑ Describe the major bacterial species in the mouth that contribute to dental caries and periodontal disease Normal flora of the mouth ● Age and dentition dependent ● More organisms/mL saliva than in feces ● Streptococcus species (mostly alpha) *dominant Infections in the oral cavity ● Mouth has a different set of microorganism than the throat due to presence of teeth ● Most organisms make specific attachments to the teeth or the mucosal surfaces Common cause of bad breathe ● Most of the compounds that cause bad breath (hydrogen sulfide, cadaverine, etc) are waste products of bacterial metabolism ● The front / anterior of the tongue often get the flora ribbed off unlike the posterior part o This is why the back smells worse than the front of the tongue Dental caries ● An accumulation of microorganisms and their by products form plaque ● ● Carbohydrates are converted locally under the plaque into lactic acid which attacks the tooth enamel Most important cariogenic bacterium 🡪 Streptococcus mutans ● ● ● o Local immune defense against caries ▪ Saliva that has lysozyme and lactoperoxidase (antibacterial enzymes) ▪ Crevicular fluid in gingival crevice that contains complement, antibodies and neutrophils Prevention of caries 🡪 tooth brushing, flossing, plaque removal, mouthwashes, fluoride treatment If caries goes on for too long the bacteria can penetrate to the inside of the teeth 🡪 contact can be made with nerves and blood vessels which can form an abscess Periodontal disease ● Inflammation and degeneration of supporting teeth structures ● May occur in absence of caries ❑ Define biofilms with respect to dental plaque Dental plaque 🡪 a biofilm ● Plaque usually starts out when encapsulated streptococci congregate and form a community of bacteria and polysaccharide matrix ● As plaque matures anaerobes start to enter o A layer of plaque as thin as 0.1-0.2mm can become depleted of oxygen this is a really good environment or anaerobic bacteria ● As more plaque builds the worse your breath gets ❑ Explain how Candida causes opportunistic oral thrush Candida Albicans ● Opportunistic fungus, yeast-like in culture outside of body, pseudo hyphae in tissues (e.g. tongue) ● Common cause of mouth and throat infection in neonates and in immunosuppressed individuals o Common types of immunosuppression ▪ Inhalation steroids ▪ Chemotherapy ▪ Broad spectrum antibiotic ▪ Immune defects and cancer (including those that are very young) ● Thrush 🡪 growth of mycelium of pseudo hyphae on tongue, may spread to the esophagus (painful and hard to swallow) ❑ Describe Actinomyces as a cause of infection in the oral cavity ● ● ● ● Actinomyces israelii: Gram positive filamentous anaerobic rod Abscess formation, healing and scarring leads to deformation of tissue, hence “lumpy jaw” Tendency to chronic infection Dental procedures (= wounds) can trigger infection ❑ Identify Vincents Angina as a severe oral disease Vincent’s Disease “Trench mouth” ● Also called acute necrotizing ulcerative gingivitis (ANUG) or Vincent’s Angina ● Caused by anaerobic Gram negative rods together with spirochaetes ● Severe ulcerative disease with pain, breath extremely foul ● Treated with antibiotics active against anaerobes, and surgical removal of necrotic tissue ❑ Describe disease caused by H. pylori, including mechanisms of pathogenicity, detection and treatment Helicobacter pylori ● Wavy Gram negative microaerophilic bacillus ● Cause of peptic ulcer disease (gastric and duodenal ulcers) ● Known for > 100 yrs by pathologists but first cultured in 1982 ● 30-50% of worlds population has antibodies ● ● ● ● ● ● Associated with contaminated drinking water and wells Specialized bacterium: survives in acid conditions of the stomach Stomach lined with a layer of mucus protecting the stomach lining from the acidity H. pylori produces large amounts of urease, urea is broken down to ammonia and the pH locally around the bacterium increases Bacteria have special flagella that allow them to move in the thick mucus layer unaffected by stomach acid Increased secretion of gastrin (induces more HCl) Diagnosis ● Stool antigen detection ● Urea breath test (C14 labelled urea) ● Serology, culture of biopsy specimens (invasive methods) Treatment ● ❑ Describe the clinical syndrome caused by the mumps virus and list some basic characteristics about the virus Mumps ● ● ● ● ● Acid antagonist + at least 2 different antibiotics o E.g. erythromycin and metronidazole RNA, enveloped Parotid gland = salivary gland o Droplet infection o Most infectious 48 hours before symptoms begin o Viruses multiply in lymph glands in throat, then to the parotid glands via the blood Inflammation and swelling of the parotid glands, fever, pain on swallowing Complications: encephalitis, pancreatitis, orchitis (inflammation of testis), oophoritis (inflammation of ovaries) Sterility can be an end result when teenage and adults get mumps! Lecture 18: lower alimentary tract infections • Identify the dominating genus of bacteria that constitute the normal flora in the gastrointestinal tract ● ● Predominant flora of the intestine: Gram negatives, both anaerobes and aerobes Bacteroides species* (dominate) • Differentiate between intoxications and infections with emphasis on individual organisms Main pathogenic mechanisms of lower alimentary tract and pathogens ● Attachment ● ± Cell invasion ● Loss of microvilli ● Exotoxin production: 2 basic actions of exotoxin on the gut: ● 1. increase secretion of water and electrolytes o e.g. Vibrio cholerae enterotoxin ● 2. inhibit protein synthesis and cause cell death o e.g. Clostridium difficile cytotoxin • Differentiate between dysentery and gastroenteritis Dysentery ● Severe diarrhea with blood often pus and or mucus ● E.g. Entamoeba histolytica and Shigella dysenteriae Gastroenteritis ● Inflammation of the stomach and the intestinal mucosa, no pus ● E.g. Vibrio cholerae and Cryptosporidium Common symptoms: diarrhea, vomiting abdominal cramps and nausea • Describe the major causes of intoxications and the major causes of gastroenteritis by identifying the endotoxin and exotoxins • Identify common sources of GI infections Staphylococcal food poisoning ● S.aureus produces exotoxins called enterotoxins which are head stable (to 30 min boiling) and resistant to enzymatic destruction in the GI tract ● Grows quickly and easily in food ● Salt tolerant, osmotically stable due to cell wall ● Fairly high resistance to heat (60 degrees Celsius) 30min ● Temperatures in food kept warm 🡪 conducive to growth o Custards, gravy, cream pie, ham ● Adequate refrigeration prevention o Staphylococcal enterotoxin ▪ Triggers vomiting reflex ▪ Causes abdominal cramps ▪ Usually occurs in 2-4 hours after ingestion ▪ No lasting side effects Bacillus cereus ● Food associated disease can have 2 forms o Diarrhea from production of enterotoxin in gut (8-16hr) o Vomiting due to ingestion of enterotoxin in food (1-6hr) ● Gram positive bacilli, aerobic, spore forming ● Heating food may not kill spores ● Commonly acquired from rice dishes ● Self limiting disease Salmonella Gastroenteritis ● Gram negative non-spore forming bacilli, motile ● There 2 types of salmonella o Gastroenteritis 🡪 S. enterica o Typhoid fever 🡪 S. typhi ● Salmonella Gastroenteritis o Over 2000 serotypes for human disease o Salmonella enterica is the group name then each serotype has its own name o o o o o o Incubation period 🡪 12-36 hours Bacteria killed by gastric acid (need a lot of bacteria for infection) Meat products, eggs, poultry, reptile skin S.enteriditidis can infect chickens 🡪 eggs then have the bacteria inside of them Usually not treated with antibiotics (may prolong shedding) No vaccine Typhoid Fever ● Caused by S,typhi ● Very different pathogenesis from zoonotic forms ● Spread only from humans to humans ● Higher fever > 40 degrees Celsius, headache ● Diarrhea starts in the 2nd or 3rd week but is not the main characteristic ● Causes sepsis 🡪 enteric fever ● Bacteria multiply in phagocytic cells, this means they can spread to the blood quickly ● After recovery, carrier state in gall bladder ● Treatment 🡪 antibiotics e.g. ceftriaxone Shigellosis ● infection, not intoxication, Gram negative bacilli, non-motile o 4 species: o S. dysenteriae (A)*** o S. boydii (B) o S. flexneri (C) o S. sonnei (D) ● Severity depends on the infecting strain (more virulent strains contain a plasmid essential for attachment and entry of bacteria into cells ● Transmitted from person to person, no animal reservoir ● Growing bacteria produce a shiga like toxin (cytotoxin) 🡪 main virulence factor Campylobacter Gastroenteritis ● Facultatively anaerobic gram negative, spiral formed bacilli ● Leading cause of foodborne bacterial illness in the US and Canada ● commensals of poultry and cattle ● self limiting disease ● Prevention: hygienic measures associated with handling of poultry etc and monitoring of water ● Can get complications of IBS and Guillan Barré Syndrome ● No vaccine Escherichia coli Gastroenteritis ● Most strains of E. coli are harmless and are normal residents of the GI tract ● Pathogenic strains have special fimbriae for attachment to intestinal cells and produce toxins o Enterohemorrhagic E.coli (EHEC) ▪ Increasing importance in US, Canada and rest of the developed world 🡪 Hamburger Disease ▪ Best known as serotype 🡪 O157:H7 ▪ Produce shiga-like toxins 🡪 hemorrhagic colitis (inflammation of intestine with bleeding) HUS (hemolytic uremic syndrome) ● HUS complication 🡪 kidney failure, 5-10% of small children with EHEC get HUS, mortality rate (5%) o Found in poorly handled meat, poultry, raw alfalfa sprouts o Also transmitted by contaminated water o Disease usually self limiting in adults but children and elderly 🡪 complications o No vaccine Clostridium (perfringens, welchii) Gastroenteritis ● Gram positive bacilli, spore forming, anaerobic ● grows in intestinal tract and produces an exotoxin that causes abdominal pain and diarrhea ❑ most cases mild, occur 8-12 hours after ingestion ● can be serious in folks who lack trypsin or eat a diet rich in trypsin inhibitors (like soybeans)– result is Pigbel (gangrene of intestines) ● meat dishes (stews) ● often not treated ● no vaccine Vibrio cholerae ● Facultatively anaerobic gram negative “vibrio” 🡪 comma shaped bacterium ● Can have >20 l fluid loss/day “rice water stool” ● Vibrio cholerae survives high pH and high salt ● Killed by gastric acid, need large numbers ● Virulence factors: exotoxin, (cholera enterotoxin), heat labile o TCP (toxin co-regulated pili) ● Fecally contaminated water: major source of infection ● Global pandemic ● 2010 Haiti 650,000 infected and >8,000 died ● Vaccine exists, 40-60% effective (oral vaccine Dukoral) ● Treatment: rehydration glucose + electrolytes • Describe some clinical features of viral intestinal infections with norovirus, rotavirus, Hepatitis A,B,C,D and E Viral gastroenteritis ● infection seen in all parts of the world ● in developing countries viral gastroenteritis is a major cause of death, especially in children ● not distinguishable clinically from other causes of gastroenteritis ● viruses are specific to humans ● fecal-oral transmission 90% of cases caused by rotavirus or norovirus Rotavirus (Gastroenteritis) ● RNA, wheel shaped virus, non-enveloped ● most common cause of viral gastroenteritis in children ● same incidence in developed and underdeveloped nations* ● disease of children, most severe cases < 2 years ● incubation 2-3 days ● often nosocomial Symptoms 🡪 low grade fever, diarrhea, vomiting (1 week duration) ● Vaccines 🡪 Rotorix and Rotateq Norovirus Gastroenteritis ● RNA, small round, non-enveloped ● causes major epidemics of viral gastroenteritis (2/3 of cases of all cause food poisoning) ● 2 day incubation period, pathogenesis similar to Rotavirus ● Symptoms: -nausea, abdominal cramps, diarrhea, vomiting for 1-3 days, sudden onset -self-limiting ● -NO PRODROME ● Also known as cruise ship virus Hepatitis ● Inflammation of the liver ● o Hepatitis A, B, C, D, E (5 different viruses) ● o CMV and EBV can also cause infectious hepatitis Lecture 19: Urinary tract infections ● Know the medical terminology used to describe the urinary system ● ● ● Define UTI: asymptomatic vs symptomatic, common causes and definitions, differentiate between uncomplicated and complicated UTI Urethritis o o Infection of the urethra ❑ Cystitis o ❑ Infection of the urinary bladder ❑ Ureteritis o ❑ Infection of the ureters ❑ Pyelonephritis o ❑ Infection of the kidney Asymptomatic UTI ● Presence of significant numbers of bacteria (bacteriuria) in absence of symptoms ● Can cause complications (scarring) in young children and in pregnant women UTI ● ● ● More common in females Majority of infections are acute and uncomplicated e.g cystitis, urethritis Most common type of nosomial infection Urine 🡪 complicated (also involves other GI systems) ● Kidney 🡪 removes wastes from blood (filtration) ● Valves control against backwards flow of urine from bladder (storage) 🡪 ureters ● Urine is normally low pH, has some antimicrobial properties and is normally sterile ❑ Identify the major cause of UTI as E. coli Lower UTI ● Painful urination (dysuria) ● Urgency and frequency of micturition (peeing) increased ● Catheter related infections are usually symptomactic ● Cloudy urine due to WBC (pyuria) and bacteria (bacteriuria) Upper UTI (Kidney) ● Fever and some of the same symptoms as lower UTI ● May have lower back pain E.coli, motile can have a capsule or cannot ● ● ● Has O (somatic), H (flagellar), K (capsular), F (fimbrial) antigens Adhesion: p-fimbriae attach to uroepithelial cells Usually susceptible to many antibiotics o Other Gram negative bacilli that live in the colon can also cause UTI, but less commonly unless it is an elderly or catheterized patient Staphylococcus saphrophyticus ● Gram positive cocci in clusters, coagulase negative ● infections in healthy young women Streptococcus agalactiae (Group B) ● Gram positive cocci in chains ● Beta-hemolytic on blood agar ● Important if the patient is pregnant ● Neonatal meningitis, sepsis and respiratory failure for the infected neonate. ● B is bad for Babies (but A is Also bad for babies and moms) Enterococcus faecalis or faecium ● Correct genus name is Streptococcus ● Gram positive elongated cocci, often short chains or pairs ● May produce alpha, beta or no (gamma) hemolysis on BAP ● Common in UTI ● Bile and salt resistant ● VRE 🡪 problem! ❑ Summarize problems associated with catheter use and biofilms ● ● Significant Bacteriuria o 100x10^6 cfu/ml midstream urine, normally only one of species ▪ Exceptions ● Catheterized patients, infants, immunosuppressed urine held in bladder for < 4 hours, infection with S.saphrophyticus ▪ Contaminated urine 🡪 has often several species growing Women usually have UTI more than men Explain why babies are very susceptible to infection Perinatal or Neonatal infections ● Infections in the first 4 weeks of life ● Usually acquired through pathogens during birth ● Host factors 🡪 immature immunity o Breached skin barrier common during the trauma of birth ● Severity depends on the infectious agent and when it is acquired List common causes of congenital infections and identify main characteristics of the organisms Congenital infections ● ● ● ● ● ● Fetus is most infected in utero Often result of a primary infection of the mother during pregnancy not seen with latent infection Fetus may die, spontaneously abort or survive, often with abnormalities Stage of pregancy when infection occurs is important for development of abnormalities in the fetus Fetus cannot protect itself immunologically from infection Striking feature of these infections is the lack of symptoms in the mother! Congenital CMV (cytomegalovirus) ● ● ● Mother infected with a first infection during pregnancy 40% babies infected at birth but effects may not become apparent until later in life (around 15yrs old) If manifest at birth o severe developmental disabilities o spasticity o eye abnormalities o hearing defects o hepatosplenomegaly o thrombocytopenic purpura o anaemia Congenital Hepatitis B and C ● ● ● ● Earlier in life the infection, the greater the chance to become chronic Chronic infection = increased risk of liver cancer 70-90% of neonates with HBV become chronic 10% chronic if infected between birth and 6 years of age ● ● Normal to both vaccinate newborns with Hep B vaccine and give them hepatitis immunoglobulin Vaccination of newborns is a goal of WHO Congenital Rubella ● ● Fetus is especially susceptible when mother in first trimester during infection (heart, brain, eyes, ears formed) Fetal death 🡪 common when infection is around the 1st month o 26% abnormalities if infected in 2nd month o 18% abnormalities if infected in 3rd month o 7% abnormalities if infected in 4th month Congenital Toxoplasmosis ● Only 10-15% of infections are symptomatic in the fetus when infected during the first trimester but these give severe defects Clinical features of severe disease: ● Congenital HIV ● ● ● Reduction in vertical transmission in western world due to treatment of mothers before birth (<1%) Elective Caesarians, no breast feeding unless necessary o *WHO has recommended mothers in underdeveloped countries with poor hygienic conditions, lack of antivirals etc to breast feed for 6 mo Failure to thrive HIV and pregnancy ● Perinatal transmission o 5-33% in US, 60% in Africa o Decreasing in groups receiving anti-viral therapy during pregnancy (<1% transmission in Canada) o HIV can be transmitted to fetus during gestation, at delivery or by breast feeding o Maternal plasma viral load most important factor in determining chance of transmission to fetus o Vitamin A deficiency in pregnancy 🡪 higher risk of infection Impact of HIV on pregnancy outcome ● maternal HIV is not associated with abnormalities, premature delivery, low birth weight or miscarriage ● infection of embryo seems to occur more often in last 2 months ● mothers CD4+ count and viral load should be closely monitored and appropriate anti-retroviral therapy given before, during and after delivery Congenital Syphilis ● ● ● identify the effects of common infectious diseases in the neonate Neonatal Herpes Streptococcus agalactiae (group B) Risk to infant 🡪 disseminated Herpes infection, encephalitis Can be due to either HSV 1 or HSV 2 ● ● ● ● ● ● ● Neonatal gonorrhea and chlamydia Syphilis is transmitted to the fetus via the placenta Severe damage to fetus o Mental development o Nerve system o Abnormalities due to tissue damage (e.g. perforation of hard palate), face deformities o Death (sometimes) Hutchinson’s teeth 🡪 characteristic abnormality ● ● Leading cause of neonatal meningitis and sepis Very rapid progression of disease Infection can be early onsent (2-7 days) or late onset (between 7 and 12 days) Early onsent 🡪 common o Risk factors 🡪 prematurity and prolonged rupture of membranes Portal entry 🡪 respiratory tract Late onsent infection 🡪 not acquired at birth but in the hospital by mother/ nurses/baby Mortality of infection due to meningitis 🡪 50% Chlamydia 🡪 usually begin as eye infection, progress to pneumonia/meningitis/sepsis but takes a month long GC infection (ophthalmia neonatorum) in newborns, infection can become obvious within a week and spread (development of sepsis) ● Describe preventative measures for congenital infections ● ● ● Screening during pregnancy Reduction of infection rates in population Vaccination where possible Ch 20 : STI’s List some general characteristics of agents causing STI and describe the severity of disease from urethritis to PID STI typical characteristics ● Sexually transmitted infection ● No vaccines commonly available (except HPV) ● Characteristic common to organisms causing STI ● Tend to produce negligible symptoms initially (easily ignored) ● May persist and symptoms may occur ● Lack of immunity: agents are poorly antigenic or have immune evasion capability ● Fastidious, adapted to be spread from mucous membrane to mucous membrane (sensitive to drying) PID (pelvic inflammatory disease) ● Extensive infection 🡪 cervix, uterus, fallopian tubes, ovaries ● Can spread to peritoneal cavity and cause hepatitis ● Over 50% of women with PID are asymptomatic but can have sequalae (complications following) ● Symptoms 🡪 lower abdominal pain radiating to back, discharge from vagina ● Chlamydia trachomatis 🡪 most common cause followed by Neisseria gonorrhoeae Describe how STIs are transmitted and prevented Identify the major STI organisms and their characteristics including virulence factors and complications of infection Chlamydia trachmomatis ● Most common bacterial STD ● Gram negative type (LPS in cell wall) but cannot use gram stain (infectious particles too small) ● Unique developmental cycle with an infectious from (EB) and metabolically active form (RB) ● Obligate intracellular parasites ● Must get ATP (energy) from the host cell Pathogenicity ● Elementary bodies (EBs) bind host cell receptors, internalized in a host cell membrane bound vacuole ● Chlamydia vacuole (inclusion) does not fuse with the host lysosome ● Chlamydia then replicates in the host cell and can lyse the host cell, causing inflammation ● No exotoxins produced, inflammation causes the damage ● Serotype D-K infect only columnar and transitional epithelial cells including neonates eyes (inclusion conjunctivitis as opposed to trachoma) ● LGV (lymphogranuloma venereum) 🡪 invasive, causing systemic disease Genital infection with C. trachomatis D-K ● endemic ● highest frequency in 15-25 year olds ● 50% asymptomatic in women ● PID (pelvic inflammatory disease) (50% asymptomatic) o scarring of fallopian tubes o ectopic pregnancy ● cause of NGU (non-gonococcal urethritis in men) (old term) LGV (Lymphogranuloma venereum) ● C. trachomatis (L-1,L-2, L-3) ● Characterized by suppurative inguinal adenitis ● More common in tropics ❑ Lesion forms on genitals, infects nearby lymph glands ● Untreated can result in tissue damage, fibrosis, elephantiasis Laboratory Diagnosis: -DNA probes, PCR (urine and secretions) ● Treatment ● -tetracycline or macrolides (e.g. azithromycin) ● -partner tracing ● NO VACCINE Gonorrhea (GC ) / the clap ● Caused by Neisseria gonorrhoeae ● Gram negative aerobic diplococci ● - Twitching motility ● - No capsule ● - Humans are the only reservoir Transmission ● Direct contact → transmitted through sexual contact Pregnant women can transmit infection to their child, this can result in ophthalmia neonatorum Clinical features Men ● Much more likely to show symptoms compared to females ● • Symptoms o • Purulent urethral discharge o • Painful urination ● • Uncommon, but can lead to epididymitis and reactive arthritis Women ● ● Majority are asymptomatic (50-80%_ Symptoms o Vaginal discharge o Painful urination o Vaginal bleeding o Lower abdominal pain o 10-20% acquire pelvic inflammatory disease (PID) Rectal gonorrhea o Majority asymptomatic o Discharge, rectal bleeding Pharyngeal gonorrhea o Majority asymptomatic o Sore throat and cervical adenitis Disseminated Gonococcal Infection (DGI) o Primary symptom is fever o Bacteremia may lead to endocarditis and meningitis, but majority result in monoarticular arthritis Gonorrhea virulence factors ● Pili 🡪 adhesin and invasin, bind to non-clliated epithelial cells ● Opa 🡪 outer membrane proteins, adhesins and invasins, adhere to a vaeirty of eukaryotic cells, one strain can express 0-11 Opa (avg 🡪 3) ● LOS (lipooligosaccharide) 🡪 high branched sugar structure bound to Lipid A, contains sialic acid residues, gives capsule like properties, inflammation induced by lipid A ● IgA Protease 🡪 cleaves IgAs on musical surface, allows adherence of bacteria to the basement membrane Immune evasion ● Sialic acid 🡪 attached to LOS (self identification) ● Phase variation (can turn on or off OPA and LOS) ● Antigenic variation (gene conversion) ● MEAN NO LIFE LONG IMMUNITY Lab diagnosis ● If you find gram – diplococci in WBC’s from pus or urethral discharge (men only) ● Culture, DNA probes, PCR ● Antibiotic susceptibility tests as there is increasing resistance to antibiotics Treatment ● Always treat clients with antibiotics as if they have all three of the bacterial STI’s: Chlamydia trachomatis, Neisseria gonorrhoeae and Treponema pallidum! ● penicillin was drug of choice, but many GC strains now produce beta-lactamase ● partner tracing and treatment important ● notifiable disease to MHO ● No vaccine available, no immunity formed Prevention ● Case finding and partner notification are key to controlling infection ● Abstinence ● Safe sex Syphilis ● ● ● ● ● ● Treponema pallidum 🡪 spirochaete, cell walls contain lipids (no LPS and not visible gram stain) Cannot be cultured in vitro Known for hundred’s of years prevalence low but increasing, often found with other STI high risk population = sex workers and meth users but incidence is rising in other populations as well closely related to other Treponema species causing tropical diseases o e.g. T. pertenue - yaws o T. carateum – pinta Pathogenesis ● Portal of entry 🡪 breaks in skin or mucous membranes ● Poorly antigenic due to lipid content in cell walls, only dead treponema can activate immune system and induce antibody formation ● Have endoflagella (axial filament): helps to move through tissues ● Spread of the spirochaete systemically before immune defenses can activate ● Inflammatory responses cause “gumma” formation in 3rd stage syphilis o Gummas can look like thickened scar tissue due to chronic inflammation or appear as tissue deformities Gumma ● ● ● Diagnosis o Serology (antibodies to T.pallidum) o Wet mount direct microscopy (only used if there is new fresh chancre) Complications o Aortic aneurysm o CNS damage (paresis), blindness, seizures, dementia o Congenita syphilis Treatment o Penicllin o No resistance o Haemophilus ducreyi HPV (Genital Warts) ● ● ● ● ● Small aerobic gram negative rods Causes chancroid Soft chancre, painful Treated with ceftriaxone No permanent immunity -papillomavirus, DNA nonenveloped viruses (> 60 types) -certain serotypes are associated with cervical cancer and cancer of the penis e.g. types 16, 18 -warts of the genital tract may be either flat or raised (“condylomata accuminata”) -cervical (usually flat) warts removed by laser or podophyllin, visualized by acetic acid Vaccine ● ● HSV 1 and 2 No immunity and no vaccine ● ● ● ● ● ● There are 9 genotypes of HPV 16,18 (70% of cervical cancer), 31,33,45,52,58(also causes cancer) and 6,11 (genital warts) Cervarix (16,18) DNA virus, enveloped Incubation 🡪 1 week Primary lesions are vesicles which break down to form shallow ulcers causing pain and discomfort in the genital area and urination Chronic infection and latent infection Most infectious when vesicles are apparent but can infect when asymptomatic Complications 🡪 encephalitis or disseminated herpes in fetus Lecture 21: Wound and Device related infections • Describe common causes of prosthetic device related infection Prosthetic devices → things that we put into the body that have a function Device related infections ● Risk of infection increases with insertion of protheses (e.g. artificial joints), pacemakers, intravenous lines ● One of the most common causes of this type of infection is the patients normal skin flora o E.g. staphylococcus epidermidis or transient skin flora e.g staphylococcus aureus ● Permanent pacemakers and defibrillators → treatment is removal of device and antibiotics ● Infections of vascular grafts e.g. CABG (coronary artery bypass graft) o Result from: ▪ Intraoperative contamination (contamination during the operation) ▪ Extension from adjacent infected tissue ▪ Hematogenous seeding → contamination in the bloodstream ● S.aureus most common pathogen ● Intravenous catheter → 4 sources of infection o Peripheral and central venous catheter o Total parenteral nutrition catheters o Arterial lines List methods used for dialysis and identify infectious risks • ● ● ● ● ● Dialysis → a method of removing the toxic wastes from the body in patients with renal failure There are 2 major methods o Intravenous / hemodialysis o Peritoneal dialysis Hemodialysis → machine and series of filters blood removed and passed back in again through another line Peritoneal dialysis o Have a permanent connection in abdomen o Drain all fluid out first o Then perfuse with new fluid o Wait 5 hours then drain Early symptoms of peritonitis o Moderately severe abdominal pain → dominant symptom o Pain aggravated by motion, even breathing o Anorexia, nausea, vomiting, fever, abdominal distension o Complication → development of an intraperitoneal abscess Peritonitis Identify the most common cause of skin abscesses and abdominal abscesses • Describe how osteomyelitis occurs ● ● ● ● Infectious risks of both types of dialysis Hemodialysis → contamination of equipment with Hepatitis B, C, HIV (blood borne pathogens) Peritoneal dialysis → risk for contamination of abdominal cavity with bacteria from skin Peritonitis → major complication of peritoneal dialysis ● ● ● ● Most commonly caused by staph aureus Localized lesion with accumulation of pus anywhere in the body Result of external or internal infection Internal abscesses (intra abdominal) are often polymicrobial ● Infection or abscess of the bone o By nearby site of infection, after trauma (like a fracture or from circulating microbes) o Most common cause of nearby site is polymicrobial (mix of G- and G+) o Difficult to treat bone as it is difficult to get antibiotic into o Long treatment periods o Any bacterium that can get into bone can cause this Surgical infections ● Contamination of the surgical site during operation or infection of the site after surgery o Associated with hygenic conditions in the operating room, immune status of the patient and often the competence of the surgeon o Common to have normal skin flora infecting a surgical site ● Pre and per -operative antibiotic therapy used for “dirty” surgery (intestinal surgery which has lots of bacteria) • Describe different causes of infections in different types of bites Consequences of wounds 1. Delayed healing 2. Formation of abscesses 3. Dissemination or spread of the infection into nearby tissues or the blood lymph Snake bites ● Venom causes tissue necrosis where infection can develop ● Pseudomonas aeruginosa, salmonella sepcies are common (any dirty bacteria) Human bites and “Clenched fist” injuries ● More often infected than animal bites ● Eikonella corrodens common ● Both aerobic and anaerobic bacteria implicated (oral flora) Differentiate between superficial infection, cellulitis, gangrene and necrotizing fasciitis • Cellulitis ● ● ● Acute spreading infection of the subcutaneous tissues Can profess to necrotizing fascitis, gangrene Originates from superficial skin lesions or trauma o E.g. boils or ulcers ● Majority of cases caused by S.aureus and S.pyogenes ● Must be treated immediately with IV antibiotics Intravenous drug users ● Many are immunocompromised → many infections ● Often get cellulitis or lymphangitis with staphylococcus aureus due to sharing of needles Anaerobic cellulitis ● Areas of traumatized tissue or poor blood circulation ● Diabetics very prone to cellulitis of the feet ● Causative organism depend on the type of trauma o Infection in lower half → fecal flora o Infection in upper half → oral flora ● Foul smelling exudate → pus, marked swelling ans gas ● Treatment usually IV antibiotics and surgical debridement of the wound Gas grene ● Classical gas gangrene usually caused by clostridium perfringens (G+ anaerobic spore forming bacilli) o C.perfringens spores in soil and feces ● Usually result of traumatize tissue with poor blood supply with anaerobic conditions in the wound ● Organisms multiply in subcutaneous tissues and invade deeper tissues, thrive on dead tissue ● Produce gas as a byproduct of metabolism (crackling sound on palpitation) ● Cause an anaerobic cellulitis followed by necrosis ● Alpha toxin destroys tissue cells and WBC, collagenase, hyaluronidase further break down tissue Describe the pathogenesis of tetanus Explain the increased susceptibility to infection with Pseudomonas aeruginosa as a result of burns • ● ● ● ● ● ● Also called lockjaw Caused by clostridium tetani, anaerobic spore forming gram positive bacillus, often found in soil Symptoms caused by neurotoxin tetanospasmin (bacteria do not invade, release toxin which diffuses to CNS) Toxin enters the CNS via peripheral nerves or blood and acts on anterior horn cells Tetanospasmin blocks release of inhibitory neurotransmitters (glycine and GABA) across the synapse → causes spasms Death usually from spasms of respiratory muscles, pneumonia or regurgitating stomach contents into lungs ● ● >50% of cases due to puncture wounds Neonatal tetanus still happens! • 58,000 cases worldwide in 2008 to nonvaccinated mothers o traditional practices during childbirth – packing the umbilical stump with earth o use of nonsterile instruments • o Toxoid vaccine exists, also antitoxin (TIG) ● ● Burns o o o o o ● ● ● ● Infections result from disruption in normal homeostasis Mortality rate with burns >40% of body surface area high Important to maintain blood flow to affected area Necrotic (dead) tissue → good medium for growth of bacteria Decreased immune defenses in large burns (cell “burns out” close burn wound asap and use topical antibiotics prophylactically as well as surgical excision of necrotic tissue hemorrhage, eschar formation or greenish discolouration indicate infection often both gram negatives and gram positives mixed infections Pseudomonas aeruginosa commonly infects burn wounds Pseudomonas aeruginosa ● ● ● ● ● Widespread in nature, water, soil Very common in wounds and hard to treat due to antibiotic resistance Motile Gram negative bacteria, grow in almost anything (even some disinfectants), grow aerobically or anaerobically Causes tissue damage and prevents healing, -increased risk for septic shock Endotoxin in cell wall ● ● Produce pyocyanin (greenish blue pigment toxic for WBC) Exotoxins are produced: exoenzyme S, Toxin A, proteases, hemolysins, phospholipase C Lecture 22 : CNS infections Describe the major route by which CNS infections occur ● ● ● ● ● ● Brain and spinal cord → CNS and are both enclosed by bone All nerves in body connected to spinal cord Motor nerves → brain to periphery Sensory nerves → periphery to the brain Axons → long extensions of nerve cells that transmit impulses (bundles of axons make up nerves) Gangia → small bodies containing sensory nerve cells located near the spinal column (but outside of it) o Motor nerves → located in the spinal column o Lower back → dorsal root ganglia o Head → trigeminal ganglia List the most common causes of acute bacterial meningitis and chronic bacterial meningitis ● Meninges → 3 membranes that cover the brain and spinal cord ● Meningitis → inflammation or infection of meninges ● Encephalitis → generalized infection of the brain o CSF ▪ Fills the four ventricles in the brain ▪ Flows in the subarachnoid space ▪ Cushions the spinal cord ▪ Normally low level of antibodies and complement ▪ Sterile (100-160ml) normally few WBC/ml (0-5) ▪ Very nutrient rich (ultra filtrate of blood) o Blood brain barrier ▪ Thin cell layer → restricts passage of cells and molecules from blood to CSF and vice versa ▪ Prevents some antibiotics from entering the CSF, only a few can cross the intact blood brain barrier ● E.g. ceftriaxone (note penicillin does not cross the BBB if it is intact and not inflamed) ● Routes microorganisms take to the CNS: Blood, nerves and bone o Bloodstream and Lymphatics: -chief source of CNS infections, but organisms must pass through the blood-brain barrier (some viruses can pass through unhindered e.g. polio) o Nerves: -some viruses can travel up the axon cytoplasm and travel along nerve bundles e.g. rabies, HSV o Bone: -skull fractures, or osteomyelitis, mastoiditis ● Bacterial meningitis o 3 bacterial species ▪ S.pneumoniae ▪ H. influenzae type b ▪ N. meningitidis o All may have capsules and evade phagocytes in the bloodstream (capsules = most important virulence factor for meningitis) ● Pyogenic meningitis (acute) o Neutrophils o Elevated protein o Decreased glucose o Positive gram stain and or culture o Caused by S.pneumoniae, N.meningitidis, H. influenzae, S.agalactiae ● ● Granulomatous and Lymphocytic meningitis (chronic) o Predominant cell → lymphocyte/monocyte o CSF protein moderately increased o CSF glucose moderately decreased o Negative gram stain ▪ M.tuberculosis and L.monocytogenes hard to find in smear ● Viral agent will not be visible General symptoms of meningitis o sore throat o fever, headache* o irritability o neck stiffness o photophobia o reduced alertness o loss of consciousness, confusion ● ● Describe botulism and the mechanisms of pathogenicity ● ● ● ● ● ● ● ● ● ● Neonatal meningitis o Caused by many different bacteria o Most common in S.agalactiae (strep b group) second most common is E.coli o Symptoms and signs are diffuse (hard to diagnose infection) ▪ Fever, poor feeding, vomiting, respiratory distress, diarrhea o Complications are devastating ▪ ⅓ of cases have cerebral or spinal nerve palsy, epilepsy, mental deficits or hydrocephalus Viral meningitis o Viruses are the major cause of acute aseptic meningitis syndrome o Abrupt onset, varies in severity o characterized by a lymphocytic pleocytosis o Difficult to diagnose viral agent, most caused by enteroviruses or herpes viruses o Usually self limiting Clostridium botulinum, an anaerobic spore-forming, Gram positive bacillus normally found in soil and water sediments cause of a food poisoning, often home canned vegetables due to production of an exotoxin o can also result from a wound o different strains of C. botulinum produce different toxins which all have the same end result o most potent bacterial toxin produced, but… inactivated by boiling 5 min Clinical symptoms o Progressive flaccid paralysis 1-10 days o Nausea, double vision o Difficulty swallowing o General weakness Infant botulism many cases associated with ingestion of honey infants do not have a good stomach acidity or protective gut flora < 1 yr ….. (spores germinate) Symptoms: lethargy, constipation Treatable with no ill consequences for the child, providing the diagnosis is made in time. Treat with anti-toxin (BabyBIG®) Botox ● ● ● ● ● Describe clinical disease caused by polio, mechanism of pathogenicity and prevention of disease by vaccine ● ● ● ● Botulinum toxin is very toxic, and would make a good bioweapon. 400 grams is enough to kill the worlds population Minute amounts of toxin administered under the skin can remove frown lines and wrinkles – and it can be used therapeutically for many conditions involving muscle spasicity Paralysis primarily of peripheral nerves Toxin binds to the neuron and prevents the release of acetylcholine across the synaptic cleft (needed for nerve innervation) Poliomyelitis o Enterovirus: RNA, nonenveloped small virus o disease initiated by ingestion of the polio virus o most cases are asymptomatic, < 1 % result in paralysis o multiplies in throat and small intestine, then invades through the Peyer’s patches in the intestine to get to the lymph & blood, then CNS o death of motor neurons in anterior horn Paralytic polio o Affects the CNS, first symptoms are usually severe myalgia in one limb, motor or sensory disturbances, weakness (may be transient or permanent) ▪ Bulbar → involves one or more cranial nerve centers including respiratory center in medulla oblongata ▪ Spinal → 30% affect lower limbs o Virus usually transmitted by the oral-fecal route, similar to other enteroviruses ▪ Tropism → GI tract Polio vaccines o Identify the rabies agent and how to reduce transmission ● ● Describe the agent responsible for West Nile Fever and identify the vector ● ● ● ● Family: flaviviridae Small 40-60 nm, enveloped RNA virus 1937 → first isolated in west nile province, Uganda Outbreaks in egypt, israel, south africa, asia, europe, eventually North America in humans and horses ● Clinical WNV disease o Most cases asymptomatic or mild (15-20%) of individuals bitten by an infected musquito develop symptoms of some kind o Mortality usually only in elderly and immunocompromised o Symptoms → fever, headache, body aches, can have rashes or not, swollen lymph glands o Development of encephalitis/meningitis in <1% of infected individuals o Long term neurological effects in 50% of WNV neurological syndrome Complicated WNV o found mostly in elderly, people with pre-existing chronic conditions and immunocompromised o rapid onset severe headache, high fever, stiff neck, vomiting, drowsiness, confusion, muscle weakness, coma o meningitis (inflammation of lining of brain and spinal cord) o encephalitis (inflammation of brain) o never seen before complication is a polio-like paralysis syndrome ▪ Transmission ● Mosquito borne virus, birds are the reservoir ● Several species of mosquitoes but culex is common ● Affects many mammals ● >75 species of birds can be infected o Most common birds (corvids) ▪ Crow ▪ Raven ▪ Jay ▪ Magpie ▪ Prevention ● Avoid mosquito bites, use DEET containing repellents ● For humans: supportive treatment, no vaccine or antiviral available yet ● Recognize how prions can cause irreversible brain damage Rabies (hydrophobia) o Zoonotic viral disease (RNA, rhabdovirus, enveloped) can infect all species of mammals o Virus usually contracted by bite or lick of rabid animal → virus can penetrate an intact mucous membrane as well o Death if symptoms develop Clinical rabies o Virus initially multiplies in muscle cells, then travel slowly up the peripheral nerves to the CNS, causes encephalitis o Average incubation is 30-50 days but can be up to a year o First symptoms → sore throat, headache, fever, discomfort at site, muscle spasms and convulsions (swallowing muscles often spasm and sight of water can trigger spasms) ▪ If the disease develops then mortality is 100% o If bitten → immediately wash the wound with ordinary hand soap and water (reduces infections by 50%) o Get medical help! RIG (rabies immunoglobulin) and inactivated vaccine ● ● ● ● ● Defined as late as 1982 by Stanley Prusiner Protein misfolding disease Self protein (PrC) becomes changed and nonfunctional (PrP) Prions are misfolded proteins that act as infectious agents in susceptible exposed animals Examples of prion disease o : Mad Cow Disease (BSE, bovine spongiform encephalitis) o Scrapie in sheep Kuru in N. Guinea (transmitted by cannibalism) o CJD, vCJD in humans o Fatal familial insomnia ● ● ● ● Pathogenicity * Prions affect the brain and spinal cord → the abnormally folded protein results in the accumulation of amyloid fibers and eventually parge holes in the brain tissue (sponge like brain tissue) Human diseases = TSE or transmissable spongiform encephalopathies o Kuru (cannibalism) o Creutzfeldt-Jacob Syndrome (CJD) and vCJD o Gerstmann-SträusslerScheinker syndrome o Fatal familial insomnia TSE o BSE and CJD o vCJD ▪ ▪ Lecture 23: CV and Lymphatic Infections Describe the role of the cardiovascular and lymphatic systems in spreading disease ● ● ● Cardiovascular infections o Infections of the blood o Infections of the heart valves and heart o Infections of the vessel walls Systemic infections → disseminated infection o Bacteremia o Septicemia /sepsis ▪ Evidence of infection + systemic response (fever = pyrexia) o Shock ▪ Septic shock → caused by both gram negatives and gram positives but is especially serious if caused by gram negative bacteria due to the release of LPS (can be endotoxic shock) o Common organisms found in positive blood cultures ▪ Staphylococcus aureus and epidermidis ▪ Streptococcus pneumoniae ▪ Enterococci (VRE or non-VRE) ▪ Alpha-streptococci ▪ Gram negatives → Escherichia coli and Klebsiella pneumoniae o Consequences of bacteremia ▪ Bacteremia that clears spontaneously ▪ Bacteremia that seeds into other areas of the body and causes focal infections ▪ Sepsis ▪ Septic shock Infections of the heart o Sub acute bacterial endocarditis ▪ Infection of vales with bacteria in the bloodstream ▪ Vegetations ▪ Persons with abnormal valves ▪ ▪ o o o Describe the clinical entity of septic shock and the cascade of events occuring, including lymphangitis * ● ● ● ● ● Describe Yersinia pestis, Borrelia burgdorferi, Pasteurella multocida as causes of disease How do bacteria get into blood/lymph o Breach of body’s natural first lines of defense (skin → trauma, burns) Infection and inflammation of tissues o Perforation/ penetration of intestine ▪ Appendicitis ▪ Invasion e.g. salmonella ▪ Oral surgery → rift in gums ▪ Kidney infection, pneumonia ▪ Catheters Lymphangitis → inflammation of the lymphatic channels can be caused by spread of infectious agent up the channels which eventually drain into the bloodstream o Dangers of lymphangitis? ▪ microorganisms are spread easily through the lymphatic and cardiovascular systems ▪ gram negative sepsis can lead to shock ▪ endocarditis/pericarditis - serious heart damage by bacteria ▪ asplenic: increased risk for infection with encapsulated organisms Spleen o Functions to remove contaminants and cells and is a major site of production of opsonizing antibodies o Reasons for splenectomy ▪ Trauma, damage, thrombocytopenia where spleen is sequestering platelets o patients without a spleen are very susceptible to infection especially with encapsulated organisms o Need to vaccinate before splenectomy if possible o Need for antibiotic prophylaxis o Septicemia with S. pneumoniae is a common finding in asplenic individuals Other interesting causes of bacterial systemic infections o Anthrax caused by Bacillus anthracis (session 13) o Lyme disease caused by Borrelia bergdorferi o Black death caused by Yersinia pestis o Pasteurella multocida ● Lyme disease (Borrelia burgdorferi) o Borrelia burgdorferi is a microaerophilic spirochaete o “Erythema migrans” – typical bulls eyes rash o Transmitted by ticks (Ixodes) which must be attached about 24 hours before the bacterium is transferred o ticks live on mice and jump on to deer o Borrelia can survive for years in untreated patients within joints, nervous system, skin: o arthritis and chronic neurological disorders common complications ● Yersinia pestis (Plaque) o Also called the “Black Death” o Facultatively anaerobic Gram negative small bacillus that can live in phagocytes o Two syndromes: pneumonic and bubonic o Rat fleas vector for bubonic plague o Human to human transmission for pneumonic plague ▪ Mortality : untreated bubonic 50-80%, pneumonic 100% o Can be treated with tetracycline or streptomycin if caught in time Pasteurella multocida o small facultatively anaerobic Gram-negative bacillus o found often in mouths of domestic dogs and cats o most infections caused by cat bites o untreated can rapidly result in sepsis and septic shock o Need acute treatment with antibiotic even before results of culture have been received ● Identify Yellow Fever as the prototype viral hemorrhagic fevers Fever, weakness, heart murmur, develops slowly α-hemolytic streptococci, S. epidermidis or enterococci from GI tract (very low potential for infection) Acute Bacterial Endocarditis: ▪ rapidly progressive damage to heart valves ▪ often occur when open heart surgery has been done and the wound contaminated ▪ usually caused by S. aureus and other pyogenic bacteria (more aggressive bacteria) Pericarditis ▪ Inflammation of the heart sac (pericardium) ▪ Often caused by streptococcus pyogenes ▪ Can also be caused by viruses e.g., coxsackievirus, a RNA virus that causes “Bornholm disease” this is a self-limiting and different than a bacterial case Cardiovascular disease (atherosclerosis) → inflammatory disease but is also an infectious disease as well ▪ Arteries → thick muscular walls, transport oxygenated blood ● Subject to atherosclerosis ▪ recent research -bacteria/virus in atherosclerotic lesions or “plaque” ▪ C. pneumoniae? ▪ CMV? ▪ HSV? ▪ H. pylori? ▪ Probably a multi-pathogen load predisposes to atherosclerosis ● ● ▪ Viral hemorrhagic fevers o Most are zoonotic diseases o First symptoms are fever, chills, headache, nausea and vomiting o Followed by haundice (liver damage) ▪ Yellow fever ▪ Dengue ▪ WNV ▪ Ebola Yellow fever o RNA virus (flaviviridae) transmitted by mosquitoes (Aedes) o Hemorrhagic fever syndrome characterized by hepatic, renal, myocardial injury, hemorrhage and high death rate o Occurs only in tropical S. America and sub-Saharan Africa o Last case of Yellow Fever in the US 1905 o Monkeys are natural reservoir in wild o o o Describe DF and DHF ● ● Diagnosis is usually made by serology There is no antiviral treatment Live attenuated vaccine is available Dengue Fever o RNA virus (flaviviridae), transmitted by Aedes mosquitoes (day biters) o four different subtypes (antigenically) o milder than Yellow Fever, similar symptoms o endemic in Caribbean and tropics o 100 million cases/year (increasing) o fever, muscle pain, joint pain and rash - also called “breakbone fever” o rarely fatal Dengue Hemorrhagic fever o more severe than DF, causes shock within hours, person is re-infected by another type of dengue virus within 2 years of the first infection o found more often in SE Asia because all four serotypes circulate, however the disease is spreading and we can expect to see more of this ▪ Identify Zika and Ebola as causes of major outbreaks ● Zika virus o o o o o o o ● RNA, enveloped, Flaviviridae family First identified in a rhesus monkey, 1947 in the Zika Forest (Uganda) (mosquito borne) First known outbreak 2007 Micronesia Only 20% of infected get any symptoms, typically mild in nonpregnant individuals Link with Guillan-Barre syndrome known New link with microcephaly in infants (~1600 in Brazil) Spring 2016 No vaccine, no antiviral ▪ Ebola virus o Enveloped RNA virus (filovirus), zoonosis (Africa) o Recent epidemic in west africa > 5000 deaths o Only treatment is aggressive supportive treatment (IV fluids etc) o Transmitted by direct contact with body fluids ▪ Transmitted by direct contact with body fluids ▪ Spread due to lack of education, lack of good health facilities, movement od people in West Africa and traditions for caring for the dead ▪ Use BSL 4 for working with it because there is no cure, can cause a fatal disease and it is easily transmitted o Ebola disease symptoms ▪ Lecture 24: HIV Describe HIV as the cause of AIDS and how it becomes integrated into the genome ● HIV (immunodeficiency virus) o RNA retrovirus o Infects CD4+ t cells, macrophages and dendritic cells o Progresses to AIDS → Acquired immune deficiency syndrome o No vaccine o Subtypes of HIV ▪ HIV 1 → has 11 subtypes (clades), major type of HIV ▪ HIV 2→ found in West africa and much slower ● HIV virus o o o o ● ● Attaches to targe host cell (human CD4+ T lymphocytes, macrphes and dendritic cells) HIV must attach to both CD4+ and chemokine receptors for infection to occur (CCR4, CXCR5) ● ● ● In host cell, viral RNA is released and transcribed into DNA by reverse transcriptase The newly formed viral DN is incorporated into the human DNA chromosome by enzyme integrase New DNA can either produce more virus or can remain latent as provirus which is not detected by the immune system ● HIV special features o Can remain latent as a provirus (no immune response) and in 5% of individuals never produces disease (unaware of infection) o Can also undergo rapid changes in antigenic makeup which helps it evade the host defenses (drug resistance ) Criteria for HIV diagnosis o Repeatedly reactive screening tests for HIV antibodies ▪ ELISA, confirmed by western blotting o Virus PCR —> virus load from blood o Virus culture (not routinely done) o Antigen tests Important to monitor for progression of disease o Viral load → number of HIV particles in blood o Numbers of CD4+ cells ▪ -below 200/mm3 is indicative of clinical AIDS (normal is 800-1000/mm3 ▪ ) -this is because normal CD4+ cells live several years, but infected CD4+ cells only live 2 days ▪ -virus inhibits new production of T cells ● ● Identify how the immune system of patients with HIV becomes compromised A glycolipid envelope with spikes called gp 120 Enveloped = relatively easy to inactivate Two identical single RNA Reverse transcriptase ● ● Stage A: infection is asymptomatic or causes chronic swollen lymph nodes Stage B: persistent infections by opportunists like C. albicans, VZV, cryptosporidia, hairy leukoplakia Stage C: clinical AIDS. Defined by “indicator conditions” such as C. albicans infections of the respiratory mucosa, CMV eye infections, TB, Pneumocystis pneumonia, toxoplasmosis of the brain and Kaposi’s sarcoma. ● CD4+ cells usually decreased to levels <200/mm3 ● nitial symptoms of HIV infection o Mild, flu like symptoms, may go unnoticed from initial infection to full blown disease, may take up to 10 years Define “opportunistic” infections and describe some of the common ones affecting AIDS patients o ● ● ● ● ● ▪ Primary HIV rash Clinical manifestations of HIV infection o Oral diseases associated with HIV ▪ Oral candidiasis → usually C.albicans (most common infection is thrush) o Oral leukoplakia → white lesions (EBV) usually symptomatic and no treatment needed o Gingivitis and periodontitis → severe pain, bleeding gums, loosening of teeth o Oral culcers → HSV 1+ 2, CMV Ocular Infections Very common, range from benign HIV retinopathy to sightthreatening viral infections most common viral cause is CMV retinitis –serious! Varicella-zoster retinitis - severe necrotizing retinitis ocular toxoplasmosis Pulmonary disease ● Leading cause of mortality and morbidity in HIv infected patients ● Pneumocystis jiroveci pneumonia (PJP) (opportunistic) ● bacterial pneumonia ● viral pneumonia • fungal pneumonia o Mycobacterial diseases ● Usually occurs as the first infectious complication ● HIV increased risk for reactivation of latent infections ● HIV patients have 5% to 10% annual risk of developing active disease ● HIV increased risk of symptomatic disease after infection (can’t hold bacteria in granuloma) ● increased incidence of disseminated TB, MDR-TB & XDR-TB Kaposi’s Sarcoma • Associated with infection by HHV 8, treated by radiotherapy ● Well-known AIDS-defining illness. ● vascular neoplastic disorder (cancer), usually seen in late stage HIV infection (AIDS) ● appear as cutaneous red-purple nodules or plaques ● sites usually affected: legs, feet, mucous membranes, hard palate, nose, trunk and scalp Transmission of HIV ● Direct contact with infected fluids o Blood is the most important, highest viral load o Semen also important (up to 50 viruses/ml) ● intimate sexual contact, ● blood contamination from needles, organ transplants, blood transfusion ● transmission of virus is more effective if there are sores present as in cases where there is another STI Vertical transmission ● Vertical transmission ● to the fetus: during pregnancy, delivery and breast feeding ● artificial insemination: if the donor semen is contaminated with HIV ● Taking medicine to keep the virus load low will reduce the risk.( untreated, risk >25% ; virus load <1000 copies/ml, risk< 1%) ● Neonates take meds to prevent HIV infection for 6 months. ● HIV survives 1.5 days inside cells, but only 6 hours outside of cells. CAN NOT ELIMINATE HIV from ● Identify elements of HAART ● Treatments o Nucleoside reverse transcriptase inhibitors”NRTIs o Non - nucleoside reverse transcriptase inhibitors: NNRTIs o Protease inhibitor: PIs o Integrase inhibitors: INSTIs o Fusion inhibitors (Fis) o Chemokine receptor antagonists (CCR5 antagonists) PROBLEM: rapid development of resistance HAART (highly active anti-retroviral therapy): combination of several anti-HIV medicines When do we treat ● In Canada patients are treated as soon as they are found to be infected with HIV, irregardless of their CD4+ count ● Usually triple therapy, but all HIV is genome sequenced to check for mutations that may confer resistance to drugs ● ● Risks Identify major health risks to health care workers o o o o ● ● Deep injury Visible blood on the device Needle placement in an artery or vein Source with late-stage HIV infection and high viral load Prevention o Routinely use barrier such as gloves and or goggles when anticipating contact with blood or body fluids o Immediately wash hands and other skin/ eye surfaces after contact with blood or body fluids o Carefully handle and dispose of sharp instruments during and after use PEP (post-exposure prophylaxis) o Risk assessment will dictate what post-exposure prophylaxis is used on the HCW: ▪ e.g. low risk (patient had low viral load): 2 drug combo ▪ high risk (patient had high viral load): 3 drug combo o PEP should be started early, preferably within 1-2 hrs up to 36 hrs, o monitoring of antibody levels for at least one year. o Common side effects of PEP ● 2 drugs: 63% : nausea/vomiting/diarrhea/fatigue/headache ● 3 drugs: 83% : same as above