Mechanisms of Pathogenicity Study Guide

Terminology and Fundamentals of Pathogenicity

  • Pathogenicity: Defined as the ability of a microbe to cause disease in a host.

  • Virulence: The degree or extent of pathogenicity. It measures how effectively a pathogen can cause disease.

    • Virulence is directly related to the number of virulence factors present in the microbe.

    • It is also determined by the level of toxicity these factors present to humans.

Overview of Pathogenesis

Pathogenesis follows a structured progression of events (as seen in Figure 15.9):

  1. Portal of Entry: The specific route or mechanism by which a microbe enters the host body.

  2. Adherence: The process by which the microbe attaches itself to host tissues.

  3. Penetration or Evasion of Host Defenses: This stage allows the microbe to replicate and colonize the host by overcoming the immune system.

  4. Damage to Host: The stage where the microbe causes clinical disease symptoms.

  5. Portal of Exit: How the microbe leaves the body to find a new host.

    • Microbes typically use the same portal for exit as they did for entry.

    • Microbes often have a "preferred portal" (refer to Table 1).

Portals of Entry and Exit

Microbes enter and leave the body through specific channels:

  • Mucous Membranes: These are thin tissues lining all body cavities that have external openings. Examples include:

    • Conjunctiva: The mucous membrane of the eye.

    • Respiratory mucosa: Lining the respiratory tract.

    • Gastrointestinal (GI) mucosa: Lining the digestive tract.

    • Urogenital mucosa: Lining the urinary and reproductive tracts.

  • Skin Surface: Recognized as the largest organ of the body.

    • The skin covers the entire body and is usually impenetrable to most microbes when intact.

    • Structure: Composed of two layers, the epidermis and the dermis.

    • Natural Openings: Even on intact skin, microbes can enter through:

      • Hair follicles

      • Sweat ducts

  • Parenteral Route: This involves a break in the skin barrier that allows microbes direct access to the bloodstream.

    • The primary (#1) way this occurs is through bug bites.

    • Other methods include cuts, injections, or the drying and swelling of skin which renders it no longer intact.

Quantifying Virulence and Invading Microbes

  • General Rule: The higher the number of microbes a host is exposed to, the greater the chance the microbe has of overcoming the host's defenses.

  • Virulence Comparisons: An organism is considered more virulent if it requires fewer cells or fewer toxins to cause disease or death.

  • Relative Virulence Measurements:

    • ID50: The infectious dose required to cause infection in 50%50\% of the population.

    • LD50: The lethal dose required to kill 50%50\% of the population.

Virulence Measurement Examples

  • Bacterial Cell Comparison (LD50):

    • Streptococcus: 5050 cells.

    • Salmonella: 50005000 cells.

  • Toxin Comparison (LD50):

    • Botulinum: 0.03 ng0.03\,\text{ng}.

    • Shigella: 350 ng350\,\text{ng}.

    • Staphylococcus: 1350 ng1350\,\text{ng}.

Virulence Factors in Bacteria

Virulence factors are bacterial structures or proteins that facilitate adherence, penetration, or host damage. Key factors include:

  • Adherence and Motility Factors:

    • Type 1 fimbriae: Used for adherence to host cells.

    • Flagellum: Provides motility; contains the H antigen which assists in adherence and inhibits killing by phagocytes.

    • Pili: Specialized surface factors for adherence.

  • Immune Evasion Factors:

    • Vi capsule antigen: Inhibits the binding of complement proteins.

    • O antigen: Part of the LPS layer; inhibits killing by phagocytes.

    • Anti-phagocytic proteins: Proteins induced by oxyR that prevent the microbe from being destroyed by phagocytes.

    • Capsule: Hides cell wall surfaces to block phagocytosis.

  • Toxins and Enzymes:

    • Endotoxin: Located in the LPS layer; triggers fever.

    • Enterotoxin: Causes symptoms like diarrhea.

    • Cytotoxin: Inhibits host cell protein synthesis, induces calcium influx into the host, and aids adherence.

    • Siderophores: Proteins that bind and "steal" iron from the host.

  • Specialized Structures:

    • Injectosome: A complex formed by inv and prg products used to deliver effector proteins.

    • Virulence plasmid: Extrachromosomal DNA containing genes for various virulence factors.

Mechanisms of Bacterial Adherence

  1. Specific Methods:

    • Adhesins: A general term for surface factors (like Pili and Fimbriae) that bind to specific complementary receptors on human cells.

  2. Non-specific Methods:

    • Glycocalyx: Bacteria use sticky sugars to attach to surfaces.

    • Biofilm production: Aggregations of bacteria held together by sticky sugars.

    • Capsule production: Example includes Streptococcus mutans in tooth plaque.

Evasion and Penetration of Host Defenses

Microbes must overcome both physical barriers and immune system defenses to colonize the host.

Cell Wall Components for Evasion

  • Acid Fast Wall: Contains mycolic acid (a wax layer) that blocks digestion inside phagocytes.

  • M protein: Found on the cell surface or fimbriae. It is heat and acid resistant, aids in attachment, and blocks phagocytosis.

  • Opa protein: Facilitates attachment and allows the microbe to enter inside host cells (penetration).

Extracellular Enzymes

  • Coagulase: Produces blood clots to hide the bacteria from phagocytes.

  • Kinase: Digests blood clots, allowing the bacteria to escape an infection site and spread.

  • Hyaluronidase / Collagenase: Breakdown connective proteins (hyaluronic acid and collagen) between cells, allowing bacteria to penetrate deep into tissues and organs.

  • IgA protease: Destroys antibodies found on mucous membranes to evade the immune response.

Structural Movement and Manipulation

  • Invasin proteins: Rearrange the host cell's cytoskeleton (actin filaments) to pull the bacteria inside the host cell.

  • Flagella: Provide the movement necessary to penetrate tissues or swim away from host defenses.

Antigenic Variation

Microbes alter their surface proteins so the immune system no longer recognizes them.

  • Obtaining New Genes: Example: The Flu virus can combine RNA from two different strains to create a completely new strain.

  • Altering Gene Expression: Example: Neisseria gonorrhoeae (Gonorrhea) can change which version of the Opa protein is expressed on its surface.

Damage to Host Cells

  1. Direct Damage: The microbe multiplies and causes the host cell to lyse (burst) and die.

  2. Nutritional Deprivation: Microbes use Siderophores to bind host iron with higher affinity than host proteins. This leaves the host malnourished.

  3. Toxin Production: This accounts for the majority of damage caused by pathogens.

Endotoxins vs. Exotoxins

Endotoxins

  • Composition: Part of the Lipopolysaccharide (LPS) layer of Gram-negative cell walls.

  • Release: The toxin is released only when the bacteria are killed (e.g., by phagocytes) or the cell wall breaks down.

  • Toxicity: Weakly toxic and rarely fatal.

  • Symptoms: Causes general symptoms, most notably fever production.

Exotoxins

  • Composition: Secreted proteins produced inside the bacteria.

  • Source: Can be produced by both Gram-negative and Gram-positive bacteria.

  • Toxicity: Highly toxic; even small amounts may be fatal.

  • Symptoms: Cause highly specific symptoms associated with the particular toxin.

Exotoxin Nomenclature

Exotoxins are often named based on the system or cell they target:

  • Neurotoxin: Targets the nervous system.

  • Enterotoxin: Targets the intestines.

  • Hepatotoxin: Targets the liver.

  • Cardiotoxin: Targets the heart.

  • Cytotoxins: General cell toxins.

    • Hemolysin: Destroys red blood cells.

    • Leukocidin: Destroys white blood cells.

Mechanisms of Exotoxin Action

  1. Membrane Disruption: Creating protein pores in the host cell membrane, leading to lysis. This is common in cytotoxins like hemolysin.

  2. Superantigens: These overstimulate the immune response, causing massive cytokine release and tissue damage. Example: Toxic Shock Syndrome (TSS) caused by Staphylococcus aureus.

  3. AB Toxins: Toxins containing two distinct protein subunits:

    • B subunit: The "Binding" component; it identifies and binds to the specific target cell or tissue.

    • A subunit: The "Active" component; it enters the cell and mediates specific damage.

Common AB Toxins and Diseases

  • Diphtheria Toxin: Produced by Corynebacterium diphtheriae. It blocks protein synthesis, leading to cell death and extensive organ damage.

  • Botulinum Neurotoxin: Produced by Clostridium botulinum.

    • Mechanism: Blocks the release of the neurotransmitter acetylcholine from motor neurons.

    • Result: Results in flaccid paralysis of muscles. Death usually occurs via suffocation because respiratory muscles cannot contract.

  • Tetanus Neurotoxin: Produced by Clostridium tetani.

    • Mechanism: Blocks the release of inhibitory signals (neurotransmitters) that allow muscles to relax.

    • Result: Results in uncontrollable muscle contractions, famously known as lockjaw. Death usually occurs via suffocation.

  • Cholera (Vibrio) Enterotoxin: Produced by Vibrio cholerae.

    • Mechanism: Causes the host cells to secrete electrolytes (salts) into the GI tract.

    • Result: Leads to severe osmotic diarrhea. Patients may die rapidly due to extreme dehydration.