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Overview of Pathogenesis (Slide 1)
Pathogenesis: Process of how infections develop
Exposure to Pathogens: Coughing, sneezing, vectors (insects), formites (pathogens on inanimate surfaces), injury
Adherence of pathogen to tissues: Slime layer, pili, adhesion molecules
Colonization: Factors that allow pathogen to evade immune system, grow within host
Escape: Exit Strategies
Virulence (Slide 2)
Virulence: Relative ability of pathogen to cause disease
Depends on presence of cell structures and/or production of toxins or other EC proteins called virulence factors
Virulence factor genes found in plasmids, lysogenic phage, and separately on chromosomes (can be transferred horizontally)
Virulence factors related to cell structures include flagella, pili, cell membrane (LPS), capsule, OMVs (Outer Membrane Vesicles)
Biofilms are formedby a combo of slime and other adhesive molecules. Able to adhere very well to tissues and capable of clogging catheters.
Pili (Slide 3)
A) Some strains of E.Coli have specialized fimbiae/pili called Colonization Factor Antigens (CFAs) that allow them to adhere to intestinal cells, colonize and produce disease. A single mutation can convert E.coli from pathogenic to non-pathogenic
N. Gonorrhoaeae, N. Menigitides use pili to adhere to genital cells and upper respiratory epithelial cells. Have ability to change genes to evade immune system
B) Vibrio Cholerae--Fimbriae key to colonization/infection
C) Candida Albicans--Produces fimbriae for adhesion to epithelial cells
Capsules/Slimes (Slide 4)
Capsules: usually composed of high mol. weight polysaccharides or AAs (B. Anthracis) and help microbes evade immune cells
Some slime layers allow adhesion to tissue
Capsules of S. pneumoniae can help to determine patient prognosis. Won't cause disease if no capsules are being formed
Other Ways of Evading Immune System (Slide 5)
Complement: N. Gonorrhoeae has special Lipoologosaccharides (LOS) that prvents MAC formation. Many species have complement specific proteases.
Ig-Antigenic Variation: Has many genes for flagella that are expressed. Constantly changing surface proteins, leading to relapses in lyme disease
Ig-Proteases: N. Gono secretes an IgA protease. S. Aureus makes protein A that binds to IgG to inhibit opsonization. Chew up Ig's.
Evading Phagocytosis (Slide 6)
Coagulase/Streptokinase allow microbes to produce, hide in, and grown in clots and then released.
Leukocidins made microbes that kill phagocytic cells
Actin-Based motility: Pathogens able to make molecules that llow it to commandeer actin system that benefits itself. Allows pathogen to escape from phagosome and make rocket like structures that propel pathogens forward out of the cell and into neighboring ghost cells.
Proteins that prevent fusion of phago- and lysosome
Many pathogens make factors that inactive or compensate for lysosomal action (i.e. producing hi levels of SOD)
Outer Membrane Vesicles: Emerging Concepts (Slide 7)
Some pathogenic bacteria form vesicles from OM filled with toxins
Only known to be a part of Gram (-) Negative bacteria
Vesicles fuse with target cells, delivering cytotoxis molecules directly into cytoplasm of host cell and adhesins into host cell CM
Vesciels can also serve as decoys, binding to LPS receptors on phagocytic cells.
Exotoxins (Slide 8)
Proteins made and released by pathogens (Gram + or -). Made from lysogenic phage or plasmid genes (horizontal transmission
Neurotoxins: Exotoxins that act on nerves to cause/block muscle contraction
- Enterotoxins act on GI tract to cause diarrhea
- -Infectious diarrhea caused by growth of microbe in intestine
- -Food poisoning caused by growth of microbe in food, making toxins that are consumed
Pyrogenic Exotoxins: cause release of cytokines-rash, fever
Tissue Invasive Toxins destroy DNA, NAD, and lyse RBCs and WBCs
Superantigens cause pan-activation of immune system
Botulism and Tetanus (Slide 9)
Botulism toxin (anaerobe) is ingested in food (canned food) binds to motor neurons and blocks release of acetylcholine, result in flaccid paralysis (muscles cannot contract. Basis for botox
Tetanus toxin works at spinal chord neurons, inhibits release of neurotransmitters that normally block the contraction of opposing. Opposing muscles contract at the same time
Both are AB toxins: the enzymatic subunits are proteases that block the fusion of neurotransmitter filled vesicles w/the CM of the neurons
AB Toxins (Slide 10)
Common type of 2-component exotoxins produced by many pathogens
B subunit delivers A toxin
ADP ribosyl transferases are a common "A" subunit in AB toxins using NAD as a source of ADP ribose
"A" targets vary, including EFs and other proteins synthesis targets, factors that increase cAMP.
All target proteins are inactivated when ADP ribose is covalently attached
Membrane-Disrupting Exotoxins (Slide 11)
2 main types, both result in lysis of host cells
Pore-Forming: leukocidins produced by penumo-, strepto-, and staphlococci. Hemolysins target erythrocytes, releasing Fe
Phospholipases: Several varieties destabilize membranes of attacking immume system cells
Superantigens (slide 12)
Exotoxins that bind to an MHC molecule and TCR outside of and independent of antigne-binding, causing pan-activation of T-cells and toxic shock
Toxic Shock by S.aureus and scarlet fever by s. pyogenes are examples of bacterial superantigen-caused diseases
Viruses (rabies virus, some influenza?) can also produce superantigens
Pathogenicity islands: Type III secretion systems (Slide 13)
Refers to islands of DNA that has been transmitted horizontally from one microbe into another (remnants of insertion sequences still present at end of clusters and GC content diff. from that of surrounding DNA)
Refers to clustered virulence factor genes.
Type III secretion systems often found in clusters. Gene products allow direct transfer of toxins into cytoplasm of host cell, delays antitoxin response by host
Endotoxins (LPS) Vs. Exotoxins
Exotoxins: Proteins. Usually do not directly produced fever. Transferred horizontally (plasmids). Heat sensitive, usually excreted outside of living cell, produced by Gram (+ and -) bacteria. Highly toxic and fatal. Nontoxic toxoids used to immunize.
Endotoxins: LPS, found on outer membrane. Lipid A is most toxic. Only found in Gram (-) bacteria. Elicit high fever. Heat stable. Weakly immunogenic. Less potent alone but ellicit strong immune system response. No toxoids therefore no vaccines can be made.
Dissemination (Slide 15)
Typically microbes invade circulatory system
From host-to-host: Vectors (arthropod/insects).
Exotoxins often lead to release and spread of pathogens (coughing, diarrhea) from host to host
Anthrax produces endospores once host dies