Lecture 12: Mechanisms of Pathogenicity

(Mechanisms of Pathogenicity) Lecture 12 Pathogen: a microorganism that can cause a disease Primary pathogen: always causes disease, even in healthy immunocompetent individuals eg. Bacillus anthracis Opportunistic pathogen: a microorganism that may cause disease if given the right circumstances eg. candida albicans → immunosuppression pseudomonas aeruginosa → burns, CF, HIV, and neutropenic cancer patients Pathogenicity: ability to cause disease by evading or overcoming the host defenses Virulence: the extent to which the microorganism is pathogenic Virulence factors: molecules/structures produced by pathogens that contribute to their "pathogenicity" or ability to cause disease eg. the capsule around Streptococcus pneumoniae (cant cause disease without it) Portals of Entry · how the pathogen gains entry to the host ↳ mucous membranes ↳ skin ↳ parenteral route (via mouth) · surgical sites and implants can provide a "route" to bypass these (open wound, therefore it’s important to have sterile equipment) · some microorganisms have a "preferred" portal of entry ↳ only capable of causing disease via a specific route because they have the receptors they need to cause disease 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: eg. corynbacterium diphtheriae, vibrio cholerae, clostridium tetani, botulinum, perfringens, bordetella pertussis Adherence: first step in infection · structures on the pathogens called adhesins or ligands that 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 (eg. Mannose) · Adhesins possessed by bacteria: ↳ N. gonorrhreae: 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 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 Antigenic 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 - eg. Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacillus anthracis, Yersinia pestis and Cryptococcus neoformans (a yeast) ② Cell Wall Components a. Fc receptors on microorganisms prevent opsonization - · bind the FC portion of antibodies produced to the bacterium. Phagocytes also have FC receptors and are looking to bind the FC portion on organisms that are opsonized eg. S. aureus has Protein A in the cell wall (protein A is a Fc receptor which prevents opsonization) phagocyte cannot bind to FAB portion b. M protein - c. Mycolic Acids - eg. Streptococcus pyogenes eg. Mycobacterium tuberculosis the cell wall that allows attachment of the bacterium resistant to digestion inside the ↳ heat and acid resistant protein filament in ↳ waxy substances in cell walls make the bacteria to epithelial cells and inhibits phagocyte phagocytosis Super long chain ③ Biofilms · Community of bacteria (single or mixed species), often surrounded by shared glycocalyx · reduces antibiotic effectiveness and WBC penetration (hard to get through the matrix) eg. Porphyromonas gingivalis in oral cavity (plaque on teeth) Pseudomonas aeruginosa in lungs, on medical implants ④ Exoenzymes · released from bacterial cells · Leucocidin: destroys WBC ↳ eg. S. aureus, Actinobacillus species · Kinase: breaks down fibrin and dissolves clots formed by the body to isolate infection ↳ eg. Streptococcus pyogenes · Hemolysin: breaks down RBC ↳ eg. Staph, Strep, Listeria, Clostridium (Streptolysin S and O in S. pyogenes) · Coagulase: forms clots: converts fibrinogen to fibrin (protein strands), clot can wall off the bacteria from the host defenses ↳ ONLY Staphylococcus aureus (not epidermidis) · Collagenase: breaks down collagen (connective tissues) ↳ eg. Clostridium perfringens · Lecithinase: destroys plasma membranes ↳ eg. Clostridium perfringens · Proteases: inactivates antibodies and other body proteins, like IgA protease ↳ eg. Neisseria gonorrhoeae Coagulase Test · positive = clot formed → coagulase present · negative = no clot → no coagulase present For sure on exam! ⑤ Invasins · surface proteins on some bacteria which activate actin, the cytoskeleton of eukaryotic cells · rearranges and facilitates bacterial engulfment into the host cell eg. pedestal formation: Salmonella and pathogenic E. coli, Listeria uses actin as propellent · some bacteria use their invasins from one host cell to another (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 an abnormally large immune response ↳ normally 1% of Th cells are activated, but with superantigens up to 20% of Th lymphocytes are used · unspecific binding to MHC II and TCR · results in excessive release of cytokines (inflammation response) ↳ this results in nausea, fever, diarrhea, shock, death eg. 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 shock · can destroy cells - some inhibit protein synthesis, leading to cell death · Two major types: a. Endotoxin like LPS, Lipid A portion (only G-) -molecule that contributes to the structure of the bacteria b. Exotoxins including superantigens -an "extra” protein that is made by bacterium to affect cells other than itself a. Endotoxins · outer cell wall of G- bacteria (LPS) · LPS is made of polysaccharide and a Lipid A portion · Lipid A is the endotoxin (heat stable) · causes chills, fever, weakness, aches, shock, death · activates the blood clotting system, DIC (disseminated intravascular coagulations) · shock: life threatening loss of blood pressure ↳ septic shock: caused by bacteria ↳ endotoxic shock: caused by Gram- bacteria b. Exotoxins · produced by some bacteria and released into tissues (can be G+ or G-) · genes for exotoxins are carried by bacteriophages or plasmids eg. diphtheria toxin, tetanus toxin · 3 types based on function: ↳ cytotoxins, neurotoxins, enterotoxins · very potent, but most are sensitive to heat (heat labile) · body produces antibodies called 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 · Diptheria · Whooping cough · Listeriosis · Necrotizing fasciitis · Cholera... etc. Effects of Exotoxins: · flaccid paralysis due to botulism toxin from Clostridium botulinum · spastic paralysis (lockjaw) due to tetanus toxin from Clostridium tetani ⑧ Secretion Systems · some bacteria have genes encoded on their chromosome that code for pathogenic characteristics (Often G-) Needle punctures host cell eg. Type III secretion apparatus - enables the bacterial cell to inject proteins into a host cell, killing or altering it · Pathogenicity Island: the chromosomal region where genes are clustered 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 eg. Neisseria gonorrhoeae, Trypanosoma species ⑩ Intracellular Growth · Obligate intracellular bacteria: can only grow inside of host cells, often in a protected vacuole eg. Chylamidia, Rickettsia · Facultative intracellular bacteria: bacteria that can multiply inside or outside of host cells, but use intracellular growth to evade host defences eg. Bordetella, Mycobacterium, Salmonella Horizontal Gene Transmission · conjugation: transferral of plasmids containing genes for virulence attributes or antibiotic resistance · transduction: acquisition of genes for toxin production (eg. C. diptherial bacteria via transferral by a bacteriophage) · transformation: acquiring gene for toxin, capsule production, etc. by absorbing naked DNA from the environment around bacterium Plasmids · plasmid: small circular DNA molecules separated from the main bacterial chromosome · plasmids may encode antimicrobial resistance or virulence factors eg. toxins, like tetanus toxin, staphlylococcal enterotoxin, heat labile toxins of E. coli Bacteriophages · Viruses which infect specific bacteria and transfer genes by transduction eg. Corynebacterium diphtheriae ↳ not pathogenic unless it is "lysogenized" by a "phage" and then produces toxin Viral Pathogenic Effects · different from bacteria due to the nature of the virus, which invades the host cells and resides intracellularly, somewhat protected from the immune cells · viruses with a segmented genome can undergo recombination with other viruses (if they are infecting the host cell) · most effects caused by inflammation & activation of immune system, producing disease (+ symptoms) 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 ↳ giant cell dies when viruses use up all building material and cause necrosis of tissue ↳ permits viral multiplication without exposing virus to antibodies eg. RSV, measles How Viruses can Cause Disease: