Mechanism of Mechanism of PathogenicityPathogenicityMechanism of Mechanism of PathogenicityPathogenicity
Host vs Parasite: Host vs Parasite: Advantage ParasiteAdvantage Parasite
Pathogenicity and Virulence
Pathogenicity - ability of MO to cause disease
Virulence - degree of pathogenicity; disease-evoking power of MO
Measurement - MO’s virulence tested experimentally in animals or in lab LD50 (Lethal Dose) - number MO (or amount
toxin) needed kill 50% inoculated hosts (test population)
ID50 (Infectious Dose) - number MO needed to cause disease in 50% test population
Infection, Virulence, Disease
Lower the LD50 or ID50, the more virulent the MO
Likelihood disease results from infection: Increasing numbers of MO Decreasing resistance of host
Host Disease Factors Susceptible (overall health) Gender (female, male) Nutritional status (balanced, diet) Weather and climate (seasons, hot, cold,
moisture) Fatigue (lack of rest, sleep) Age (very young, old) Habits (active/inactive, over/under weight) Life style (physical, mental, social, spiritual) Pre-existing illness (inherited, chronic, infection) Emotional disturbance (stress, anger) Chemotherapy (legal, illegal drugs)
Disease By MO
Must gain entrance to host Portal of entry - avenue by which
MO enters host Include:
Mucous membrane Skin Parenteral route
Entry Mucous Membrane: RT, GI Tract
Respiratory Tract – easiest, most frequent; via aerosols, direct mucous membrane contact (i.e., influenza, pneumonia, TB, measles, smallpox)
Gastrointestinal Tract – ingested via food, water, dirty hands; entry fecal-oral route: Survive HCl (stomach), bile and digestive
enzymes (small intestine) Exit in feces (i.e. polio, infectious hepatitis,
typhoid fever, bacillary dysentery, amoebic dysentery, cholera)
Entry Mucous Membrane: GU Tract,
Eye Genitourinary Tract – Via close contact: Treponema pallidum (syphilis) Neisseria gonorrhoeae (gonorrhea) Trichomonas vaginalis (trichomoniasis) Herpes simplex virus type II (genital herpes)
Conjunctiva of the eye – Via direct contact: Haemophilus aegyptius - contagious
conjunctivitis, “pinkeye” Chlamydia trachomatis – trachoma, may lead to
blindness
Entry: Skin and Parenteral
Skin – few MO gain entry through hair follicles and sweat ducts Necator americanus (hookworm) Schistosoma sp. (schistosomiasis) actually
bore through skin Parenteral route – MO directly deposited
into tissues when skin or mucous membrane barriers penetrated or injured Tetanus Subcutaneous mycoses (fungal infections)
Multiple Portal of Entry
Many MOs have preferred portal of entry and only cause disease through that route: Salmonella typhi only cause disease when it
comes in through the GI tract Some MOs initiate disease from variety of
portals of entry (flea/tick bite, ingestion, aerosol, contact infected animal): Yersinia pestis – bubonic plague Francisella tularensis – tularemia, rabbit
fever
MO Attachment MO must attach or
adhere to host tissues Attachment via
surface projections called adhesin, colonization factor, ligand (often glyco or lipoprotein) on MO which bind specifically to receptor (carbohydrate,lipid, protein) on host cell
Pili (Fimriae) Bacterial adhesin may be fimbrial
or afimbrial in nature E. coli has ligand on pili which
attach it to intestinal epithelial cell
Ligand Neisseria gonorrhoeae has ligand on pili
that attach to epithelial cells in GU tract Streptococcus mutans adheres to
surfaces of tooth enamel via extracellular polysaccharide that it secretes
Streptococcus pyogenes binds to fibronectin on surface of epithelial cells via M protein and lipoteichoic acid in its cell wall
Virus Ligand
Sendai virus glycoprotein project from surface of virus envelope to attach to cell receptor
Rhinovirus proteins (VP1, VP2, VP3) form a “canyon” buried in surface of the virus for attachment to cell receptor (ICAM-1)
MO Resistance of Host Defense
MO produce substances that allow it to disseminate
Capsule - interfere cells function in phagocytosis of MO
M protein -Streptococcus pyogenes resist phagocytosis
IgA protease - produced by some MO, cleave IgA (important in host preventing MO attachment)
MO Resistance Antigenic variation - to escape host immune
defense recognition Resistant to complement-mediated
bacteriolysis – sterically hinder attachment of complement components
Survive inside phagocytic cells - prevent phagosome-lysosome fusion or resistant to lysosomal enzymes
Escape the phagosome - before phagosome-lysosome fusion
Downregulate MHC class I expression - avoid immune recognition
Downregulate CD4 expression of T lymphocytes – interfere with immune response
Bacteria Blocking Phagosome - Lysosome
Fusion
Bacteria Escape Before Phagosome – Lysosome
Fusion
MO Resistance Immunologically privileged site (macrophage) -
protected from immune defense Shed antigen or decrease expression antigen -
prevent immune recognition Immunosuppress the host – hinder immune
defense Siderophore - acquire iron (nutrition factor)
needed by host Hypothermic factor - decrease host
temperature Leukocidan - kill WBCs, hinder immune defense
MO Resistance Coagulase - fibrin clot
to wall off MO, protect from host defense
Protein A (S. aureus), Protein G (S. pyogenes) - bind the Fc portion of IgG, hinder PMN opsonization
Apoptosis (program cell death) substance - target host macrophage
Flagella - allow MO to move away from phagocytes
MO Resistance: Preventing uptake of
bacteria Secrete molecules
that block uptake of MO by phagocyte (by depolymerizing actin)
Substance delivered directly to phagocyte via bacteria Type III secretion system
MO Dissemination Kinase - break down fibrin clots (in host
inflammatory reaction) that prevent MO from spreading
Hemolysin - destroy RBCs, tissue cells; many act as porin to alter membrane permeability
Hyaluronidase - dissolves hyaluronic acid which hold cells together
DNAse - salvage nucleotides; also help MO to spread by breakdown of viscous nucleic acid which hinder movement
MO Dissemination Collagenase - break down collagen which
forms framework of muscle Lipase - break down cell lipids Necrotizing factor - kill host cells Apoptosis (program death) substance –
destroy tissue, cell Actin - recruited for intracellular movement
MO Disease: Direct Damage Attachment, penetration and
multiplication may cause direct damage Penetration may involve:
Outer membrane proteins Type III secretion systems deliver substances
induce uptake of bacteria in nonphagocytic cells
Note: previously Type III secretion system also deliver substances that block uptake of MO by phagocytic cells
Bacteria Secretion System Type II and Type III -
export proteins through inner and outer membranes of MOs
Type II - general secretory pathway, secretes substances outside the bacteria; similar pathway found in Gram(+)
Type III - act as molecular syringe to inject substances, including toxins, directly into target cells; found in Gram (-) bacteria (Salmonella, Shigella, EPEC)
MO Direct Damage: Toxins
Toxins can also cause direct damage Poisonous substances produced by MO May be entirely responsible for its
pathogenicity Toxigenicity: capacity to produce a toxin Toxemia: refers to symptoms caused by
toxins in the blood Two types: Exotoxin and Endotoxin
MO Exotoxins
Most, but not all, produced by Gram(+) Secreted via Type II secretion system Soluble in body fluids and transported
rapidly throughout body Protein whose gene may be bacterial,
carried on plasmid, or encoded in lysogenic bacteriophage
Botulinum Exotoxin Among the most lethal toxins known to
humans One mg botulinum toxin kill 1 million
guinea pigs Cause of the disease and disease specific Host produce antitoxins (antibodies) which
provide immunity against effects of toxin Inactivated by heat, formaldehyde, iodine
or other substances to produce toxoids when injected no longer cause disease, but stimulate body to produce protective antitoxin antibodies (vaccine)
Exotoxin Structure
Many have an A (toxic effect) / B (binding)
structure
Botulinum Neurotoxin: Flaccid Paralysis
Clostridium botulinum Toxin not released until death of MO Acts at neuromuscular junction to
prevent transmission of nerve impulse leading to flaccid paralysis and death from respiratory failure
Tetanus Neurotoxin: Spastic Paralysis
Clostridium tetani Causes excitation of CNS leading to
spasmodic contractions and death from respiratory failure
Also called “lockjaw”
Diphtheria Cytotoxin Corynebacterium diphtheriae Inhibits protein synthesis in
eukaryotic cells and can cause death in patient
Enterotoxin Staphylococcal enterotoxin -
Staphylococcus aureus; induces vomiting and diarrhea by preventing absorption of water in intestine
Others – Escherichia, Salmonella, Vibrio, Shigella causes enteritis, cholera, dysentery
Vibrio Enterotoxin
Vibrio cholerae Alters water and electrolyte
balance in intestine leading to very severe, life threatening, watery diarrhea
MO Endotoxins On outer membrane of most Gram(-) Lipid A toxic part of LPS
(lipopolysaccharide) Exert effects when bacteria die and LPS
released All produce same signs and symptoms,
i.e. not disease specific Symptoms include fever (pyrogenic
response), weakness, generalized aches and pains, and sometimes shock
Antibodies against endotoxin do not protect host from their effects
Only large doses are lethal; leads to “septic shock”
Endotoxins: Pyrogenic Response
Exotoxin versus Endotoxin
Exotoxins versus Endotoxins
MO Indirect Damage: Hypersensitivity
Occur due to immunopathologic mechanisms
Immediate hypersensitivity reactions (due to IgE antibodies)
MO Immunopathogenesis Cross-reacting or auto antibody form:
Bind to host tissue, activate complement resulting in damage to tissue
Immune complexes are antigen-antibody complexes that form in bloodstream: Can trigger severe inflammatory reactions resulting in
damage to host tissues May get trapped in capillaries and trigger complement
cascade with resulting tissue damage
Portal of Exit
MO needs to have portal of exit Usually related to part of body infected Most common are: respiratory tract and
gastrointestinal tract May also exit: genital tract, urine, skin,
biting insect, or contaminated needle
Summary: Mechanism of Pathogenicity
Class Assignment Textbook Reading: Chapter 2 B.
Pathogenesis of Infection Key Terms Learning Assessment Questions