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