Lecture Note 12: Mechanisms of Pathogenicity

Lecture 12: Mechanisms of pathogenicity Definitions: ●​ Pathogenicity: Ability to cause disease ●​ Pathogen: a microorganism that can cause disease ○​ Primary pathogen: always causes disease, even in healthy immunocompetent individuals ex. Bacillus anthracis ○​ Opportunistic pathogen : a microorganism that may cause disease if given the right circumstances ■​ Ex. candida albicans → immunosuppression ■​ Mucor species → diabetics ■​ Pseudomonas aeruginosa → burns, CF, HIV, and neutropenic cancer patients ●​ Virulence: the extent to which the microorganism is pathogenic (how much) ○​ Virulence factors: molecules/structures produced by pathogens that contribute to their pathogenicity (ability to cause disease , yes/no) ■​ Ex. Streptococcus pneumoniae is a pathogen, but only when it produces a capsule (the virulence factor) ●​ Otherwise, out body can use phagocytosis if it has no cell wall, to protect ourselves Portals of Entry ●​ How does the pathogen gain entry to the host? ○​ Mucous membranes ○​ Skin ○​ Parenteral route via mouth ●​ Some organism have a preferred portal of entry ○​ Only capable of causing disease via a specific route b/c they would have the receptors they need to cause disease here ●​ Surgical sites and implants can provide a route to bypass these portals of entry ○​ Surgical sites are open wounds so it’s important that they are sterile ●​ Tropism refers to the ability of immune cells, pathogens, or molecules to preferentially migrate or target specific tissues, organs, or cell types. ○​ This is determined by interactions between surface receptors on the immune cells (or pathogens) and chemical signals(such as cytokines or adhesion molecules) in the body ○​ Determinants of Tropism ■​ Distribution of cell receptors for microbes ■​ Accessibility of correct host cell types ■​ Other competing microbes ■​ Appropriate nutrients for growth ■​ Physical and innate defenses at the site of infection ●​ Age, etc. factor in as well ■​ Permissive environmental condition (ex. pH) ●​ Some pathogens remain at site of infection and cause disease without spreading through the entire system ○​ They may produce toxins that get into cells and cause the disease process ○​ Examples of exotoxin producing bacteria ■​ Ex. corynebacterium diphtheria ■​ Vibrio cholerae ■​ Clostridium tetani, botulinum, perfergens ■​ Bordetella pertussis Adherence: First step in infection ●​ Structure on the pathogens called adhesins or ligands recognize and bind to “receptors” on host cells (specific responses) ○​ Most adhesins on pathogens are glycoproteins or lipoproteins ○​ Most receptors on host cells are sugars (Ex. mannose) ●​ Examples of adhesins that different bacteria have ○​ N. gonorrhoeae: pili or fimbriae display adhesins ○​ S. mutans: glycocalyx for adhesion (Cell capsule) ○​ Enteropathogenic E. coli: specialized fimbriae that only bind to certain intestinal cells Factors that help the bacteria evade or penetrate host defenses 1.​ Capsules 2.​ Cell wall components 3.​ Biofilms 4.​ Enzymes 5.​ Invasins 6.​ Superantigens 7.​ Toxins 8.​ Secretion systems 9.​ Antigen variation 10.​intra/extracellular growth 1.​ Capsules ●​ Glycocalyx= capsule slime layer. Sugar coat ●​ Initially prevents the phagocyte from recognizing and ingesting the bacteria ○​ Inhibiting complement activation ●​ Many bacteria can produce capsules in the right environmental conditions ○​ Ex. Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacillus anthracis ○​ Example of yeast: cryptococcus neoformans 2.​ Cell wall components a)​ Fc receptors on microorganisms prevent opsonization i)​ Cell wall of bacterium has antibodies on surface whose Fc receptors stick on surface, keeping phagocytes that also have Fc receptors from binding to Fc of bacteria ii)​ Ex. S. aureus has Protein A in the cell wall - a Fc receptor which prevents opsonization . b)​ M protein i)​ Ex. Streptococcus pyogenes 1)​ Heat and acid resistant protein filament in the cell wall that allows attachment of the bacteria to epithelial cells and inhibits phagocytosis c)​ Mycolic acids i)​ Ex. Mycobacterium tuberculosis 1)​ Waxy substances (mycolic acid carbon chains) in cell walls make the bacterium resistant to digestion inside the phagocyte 3. Biofilms “United we stand” for bacteria -​ Community of bacteria (single or mixed species) that is often surrounded by shared glycocalyx (cell wall) -​ This reduces antibody effectiveness (therefore reducing WBC penetration as it is hard to get through the matrix) -​ Ex. porphyromonas gingivalis in oral cavity, pseudomonas aeruginosa in lungs and medical implants 4. Exoenzymes Released from bacterial cells ●​ Leucocidin: destroys WBC ○​ Produced by S. aureus, Actinobacillus species ●​ Kinase: breaks down fibrin and dissolves clots formed by the body to isolate the infection (important for spread) ○​ Produced by streptococcus pyogenes ●​ Hemolysin: breaks down RBC red blood cells ○​ Produced by 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 ○​ Produced by only Staphylococcus aureus (not epidermis) ○​ Coagulase test ■​ Blood Positive for bacteria = clot formed → coagulase present. ●​ Bacteria can evade immune clearance ■​ Blood Negative for bacteria= no clot formed → coagulase absent ●​ Blood remains fluid so our immune system can fight more easily ●​ ●​ Collagenase: break down collagen (connective tissue) ○​ Produced by clostridium perfringens ●​ Lecithinase: destroy plasma membranes ○​ Produced by clostridium perfringens ●​ Proteases: inactivate antibodies and other proteins, like IgA protease ○​ Produced by Neisseria gonorrhoeae 5. Invasins ●​ Are Surface proteins on some bacteria that activate actin (The cytoskeleton of eukaryotic cells) ●​ Rearrances and facilitates bacterial engulfment into the host cell ○​ Ex. pedestal formation with Salmonella and pathogenic E.Coli, Listeria uses actin as propellent ●​ Some bacteria use their invasins to move from one host cell to another ex. Shigella and Listeria ○​ These bacteria infect intestinal epithelial cells laterally as well from the outside in 6. Superantigens ●​ Also called Type 1 exotoxins ●​ Protein antigens that stimulate a very large immune response. cause an extreme immune response by bypassing normal antigen presentation. ○​ Normally <1% Of the T helper cells are activated by an infection, but with a superantigen as activator, the response can go up to 20% of all T helper lymphocytes ●​ Normally, an antigen must be processed and presented by antigen-presenting cells (APCs) to T-cells via the MHC-II complex, activating only a specific subset of T-cells. ●​ Superantigens skip this step by directly binding to both the MHC-II molecule on APCs and the T-cell receptor (TCR) on many T-cells, regardless of antigen specificity. ●​ This results in the massive activation of 20-30% of T-cells (compared to <1% in a normal response), leading to an uncontrolled release of cytokines (cytokine storm). ●​ ●​ Unspecific binding to MHC II and TCR ●​ Results in excessive release of cytokines ○​ This results in nausea, fever, diarrhea, shock, death ○​ Ex. Staphylococcus aureus TSST-1 toxin which causes toxic shock syndrome 7. Toxins ●​ Often a primary virulence factor ●​ Usually proteins that can produce symptoms of fever, heart failure, diarrhea, edema, or chock ●​ Can destroy cells. Some inhibit protein synthesis leading to cell death ●​ 2 types ○​ 1. Endotoxin like LPS, Lipid A portion (only G-): Molecule that contributes to the structure of the bacteria ■​ 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) ■​ Activates the blood clotting system (DIC, disseminated intravascular coagulation) ■​ Causes chills, fever, weakness, aches, shock, death ●​ Shock: life threatening loss of blood pressure. ○​ If caused by bacteria → septic shock ○​ If caused by gram negative bacteria → endotoxic shock ○​ 2. Exotoxins including superantigens: An extra protein that is made by bacteria to affect cells other than itself ■​ Produced by certain bacteria and released into tissues (can be G+ or G-) ■​ Genes for exotoxins are carried by bacteriophages or plasmids ●​ Ex. diphtheria toxin, tetanus toxin ■​ There are 3 types based on function ●​ a) cytotoxins ●​ b) neurotoxins ●​ c) enterotoxins ■​ They are very patent protein, but most are sensitive to heat (heat labile) ■​ Body produces antibodies and antitoxins for neutralization ■​ Common structure is A-B toxins where A is the toxic part and B binds to cells ■​ Diseases caused by exotoxins ●​ Botulism ●​ Tetanus ●​ Diphtheria ●​ Whooping cough ●​ Listeriosis ●​ Necrotizing fasciitis ●​ Cholera ■​ Effect of exotoxins ●​ Flaccid paralysis: due to botulism toxin from clostridium botulinum ●​ Spastic paralysis (lockjaw): due to tetanus toxin from clostridium tetani 8. Secretion Systems ●​ Done by some bacteria, especially the G- genes encoded on their chromosome that code for pathogenic characteristics ex. Coding for a Type III secretion apparatus ●​ Chromosomal region where the genes are clustered is called a pathogenicity Island ●​ Ex. Type III secretion apparatus enables a bacterial cell in inject proteins into a host cell, killing or altering it ●​ 9. Antigenic Variation ●​ Pathogens have antigens on their surfaces to which B cells produce antibodies ●​ Some pathogens change the makeup of their antigens as they replicate (mutate) and the immune system no longer recognizes them ○​ Ex. Neisseria gonorrhoeae, Trypanosoma species 10. Intracellular growth ●​ Obligate intracellular bacteria : can only grow inside of host cells, often in a protected vacuole ○​ Ex. chlamydia, Rickettsia ●​ Facultative intracellular bacteria: bacteria that can multiply outside of host cells, but often use intracellular growth as means of evading the host defenses ○​ Ex. Bordetella, mycobacterium, salmonella Bacteria can share or acquire new DNA ●​ 3 Methods of horizontal gene transmission/foreign DNA uptake ○​ Conjugation :transferral of plasmids containing genes for virulence attributes or antibiotic resistance. This is how 2 live bacterial cells directly pass DNA between each other ○​ Transduction : acquisition of genes for toxin production ex. C diphtheria 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 ex. Toxins (like tetanus toxin), staphylococcal enterotoxin, heat labile toxins of E-coli Bacteriophage ●​ Viruses which infect specific bacteria and transfer of genes is by transduction ○​ Ex. Corynebacterium diphtheria ■​ Not pathogenic unless it is “lysogenized” by a “phage” and then produces toxin Viral - Pathogenic effects ●​ Viruses Are different from bacteria due to nature of virus, which invade the host cells and resides intracellularly, somewhat protected from the immune cells ●​ Viruses with a segmented genome can undergo recombination with other viruses (providing they are infecting the host cells) ●​ Most effects caused by inflammation & activation of the immune system, producing disease ○​ Viral Pathogenesis: Cytopathic effects ■​ Killing or damaging of the host cell ■​ Different strain of virus cause different CPE ■​ Syncytium formation: infected cells fuse to form a giant cell with many nuclei ●​ Giant cell dies when viruses use up all building material and cause necrosis of tissue ●​ Permits viral multiplication without exposing virus to antibodies ○​ Ex. RSV, measles ●​ Viral pathogenicity: what can viruses do to cause disease