Microbial Mechanisms of Pathogenicity

Burkholderia Species & Microbial Mechanisms of Pathogenicity

Pathogenicity and Virulence

• Pathogenicity: The ability of a microorganism to cause disease.

• Virulence: The degree of pathogenicity, or how severe the disease is.

How Microorganisms Enter a Host

• Portals of entry: Sites through which microorganisms enter the host.

  • Mucous membranes: Respiratory system, digestive canal, urinary system, genital system, and conjunctiva.

  • Skin: When penetrated or compromised.

  • Parenteral route: Direct deposition into tissues when barriers are penetrated (e.g., injections, bites, wounds, cuts, surgery).

• Most pathogens have a preferred portal of entry.

Numbers of Invading Microbes

• $ID_{50}$ (Infectious Dose 50):

  • The number of microbes required to cause infection in 50% of a sample population.

  • Measures the virulence of a microbe. A lower $ID_{50}$ indicates higher virulence.

• Example: Bacillus anthracis $ID_{50}$

• As the number of virus particles increases, so does the percentage of infected population, until it reaches $ID_{50}$.

Lethal Dose

• $LD_{50}$ (Lethal Dose 50):

  • The amount of toxin required to kill 50% of a sample population.

  • Measures the potency of a toxin. The lower the $LD_{50}$, the higher the potency.

Adherence

• Adherence (Adhesion): The process by which almost all pathogens attach to host tissues.

• Adhesins (Ligands): Surface molecules on the pathogen that bind to receptors on the host cells.

  • Examples: Glycocalyx, fimbriae, viral spikes.

How Pathogens Penetrate Host Defenses

• Capsules:

  • Glycocalyx around the cell wall.

  • Impair phagocytosis, making it harder for immune cells to engulf and destroy the pathogen.

• Biofilms:

  • Help evade phagocytosis.

  • Provide antimicrobial resistance through the extracellular polymeric substance (EPS).

• Cell Wall Components:

  • M protein: Resists phagocytosis (e.g., Streptococcus pyogenes).

  • Opa protein: Allows attachment to host cells (e.g., Neisseria gonorrhoeae).

  • Waxy lipid (Mycolic acid): Resists digestion by phagocytes (e.g., Mycobacterium tuberculosis).

• Enzymes:

  • Coagulases: Coagulate fibrinogen, forming fibrin clots.

  • Kinases: Digest fibrin clots.

  • Hyaluronidase: Digests hyaluronic acid, a host polysaccharide that holds cells together.

  • Collagenase: Breaks down collagen.

  • IgA proteases: Destroy IgA antibodies.

• Antigenic Variation:

  • Pathogens alter their surface antigens, rendering host antibodies ineffective.

  • Examples: Influenza virus, Neisseria gonorrhoeae, Trypanosoma brucei gambiense.

• Invasins:

  • Rearrange actin filaments of the cytoskeleton, causing membrane ruffling.

  • Actin polymerization (e.g., Shigella and Listeria).

  • Allow pathogens to enter cells and move between them.

• Survival Inside Phagocytes

  • Salmonella
    *Plasma memb, changes use actin to move from one host cell to another (straight to it)

Using the Host’s Nutrients: Siderophores

• Iron is required for most pathogenic bacteria.

• Siderophores: Proteins secreted by pathogens that bind iron more tightly than host cells and host iron-binding proteins.

Direct Damage

• Disrupts host cell function.

• Uses host cell nutrients.

• Produces waste products.

• Multiplies in host cells and causes ruptures.

Production of Toxins

• Toxins: Poisonous substances produced by microorganisms.

  • Cause fever, cardiovascular problems, diarrhea, and shock.

• Toxigenicity: The ability of a microorganism to produce a toxin.

• Toxemia: Presence of toxin in the host’s blood.

• Intoxications: Presence of toxin without microbial growth.

Exotoxins

• Proteins produced and secreted by bacteria (both gram-positive and gram-negative).

• Antitoxins: Antibodies against specific exotoxins that provide immunity.

• Toxoids: Inactivated exotoxins used in vaccines.

• Types:

  • A-B toxins

  • Membrane-disrupting toxins

  • Superantigens

  • Genotoxins (damage DNA, causing mutations, disrupting cell division, and potentially leading to cancer).

• A-B toxins: Contain an enzyme component (A part) and a binding component (B part) (e.g., Diphtheria toxin).

• Membrane-disrupting toxins: lyse host cells by disrupting plasma membranes.
  * Leukocidins—kill phagocytic leukocytes.
  * Hemolysins—kill erythrocytes by forming protein channels.
  * Streptolysins—produced by streptococci

• Superantigens: Cause an intense immune response due to the release of cytokines from host cells (T cells).

  • Cause symptoms of fever, nausea, vomiting, diarrhea, shock, and death.

Diseases Caused by Exotoxins

Endotoxins

• Lipid A portion of lipopolysaccharides (LPS) of gram-negative bacteria.

Endotoxins and the Pyrogenic Response

1. A macrophage ingests a gram-negative bacterium.

2. The bacterium is degraded in a vacuole, releasing endotoxins, which induce the macrophage to produce cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-$α$).

3. The cytokines are released into the bloodstream by the macrophages.

4. The cytokines induce the hypothalamus to produce prostaglandins, resetting the body's

ID50 and LD50

• ID50 (Infectious Dose 50): The number of microbes required to cause infection in 50% of a sample population. It measures the virulence of a microbe; a lower ID50 indicates higher virulence.

• LD50 (Lethal Dose 50): The amount of toxin required to kill 50% of a sample population. It measures the potency of a toxin; the lower the LD50, the higher the potency.

Factors Contributing to Adherence

• Adhesins (Ligands): Surface molecules on the pathogen that bind to receptors on host cells. Examples include:

  • Glycocalyx

  • Fimbriae

  • Viral spikes

Factors Allowing Invasiveness

• Capsules: Impair phagocytosis.

• Biofilms: Help evade phagocytosis and provide antimicrobial resistance.

• Cell Wall Components:

  • M protein (e.g., Streptococcus pyogenes): Resists phagocytosis.

  • Opa protein (e.g., Neisseria gonorrhoeae): Allows attachment to host cells.

  • Waxy lipid (Mycolic acid) (e.g., Mycobacterium tuberculosis): Resists digestion by phagocytes.

• Enzymes: Coagulases, kinases, hyaluronidase, collagenase, IgA proteases.

• Antigenic Variation: Pathogens alter their surface antigens.

• Invasins: Rearrange actin filaments of the cytoskeleton, allowing pathogens to enter cells.

Role of Biofilms in Invasiveness

• Biofilms help pathogens evade phagocytosis and contribute to antimicrobial resistance through the extracellular polymeric substance (EPS).

Siderophores

• Siderophores are proteins secreted by pathogens that bind iron more tightly than host cells and host iron-binding proteins, which is crucial since iron is required for most pathogenic bacteria.

Exotoxins

• Exotoxins are poisonous substances produced and secreted by microorganisms, causing various symptoms.

• Types of Exotoxins:

  • A-B toxins

  • Membrane-disrupting toxins

  • Superantigens

  • Genotoxins

Endotoxins

• Endotoxins are the lipid A portion of lipopolysaccharides (LPS) of gram-negative bacteria. They are not secreted but released upon the death of the bacterium.

• Differences between Endotoxins and Exotoxins:

  • Chemical Structure: Endotoxins are lipid-based; exotoxins are usually proteins.

  • Production: Endotoxins are part of the bacterial cell wall, while exotoxins are secreted by live bacteria.

Pyrogenic Mechanism Associated with Endotoxins

1. A macrophage ingests a gram-negative bacterium.

2. The bacterium is degraded in a vacuole, releasing endotoxins, which induce the macrophage to produce cytokines (IL-1 and TNF-α).

3. Cytokines are released into the bloodstream.

4. Cytokines induce the hypothalamus to produce prostaglandins, resetting the body's temperature.

Main Differences between Endo and Exotoxins

• Endotoxins:

  • Structure: Lipid A

  • Source: Released upon cell lysis of gram-negative bacteria

• Exotoxins:

  • Structure: Proteins

  • Source: Secreted by living bacteria into the environment

Toxins Produced by Fungi

• Specific fungi produce mycotoxins, which can cause a range of health issues, including respiratory problems, allergies, and toxic effects leading to illness.

Portals of Entry/Exit

• Microorganisms enter the host through:

  • Mucous membranes: Respiratory system, digestive canal, urinary system, genital system, and conjunctiva.

  • Skin: Compromised skin or direct penetration.

  • Parenteral route: Direct deposition into tissues (e.g., injections, bites, wounds).

Order of Events for Microbial Pathogenicity

1. Exposure to pathogens

2. Adherence to host tissues

3. Invasion and colonization

4. Evasion of host defenses

5. Damage to host tissue

6. Transmission of pathogens to a new host