Mechanism of Pathogenicity Host vs Parasite: Advantage 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  LD 50 (Lethal Dose) - number MO (or amount toxin) needed kill 50% inoculated hosts (test population)  ID 50 (Infectious Dose) - number MO needed to cause disease in 50% test population

Infection, Virulence, Disease  Lower the LD 50 or ID 50, 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 d isease 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