Microbial Mechanisms of Pathogenicity

Lecture Overview

  • Microbial Mechanisms of Pathogenicity

  • Key Topics Covered:

    • How Pathogens Cause Disease

    • Virulence Factors of Bacterial and Viral Pathogens

    • Virulence Factors of Eukaryotic Pathogens

  • Source material from: Openstax Microbiology textbook, Chapter 15, Microbial Mechanisms of Pathogenicity

Epidemiological Triangle

  • Components:

    • Host Factors: Individual characteristics affecting vulnerability and response to infection.

    • Immune System: Body's defense mechanisms against pathogens.

    • Environmental Factors: External conditions influencing the likelihood of transmission and survival of pathogens.

    • Source: Original host from which the pathogen originates.

    • Reservoir: Natural habitat where the pathogen survives; can be living or inanimate.

    • Transmission: Method by which a pathogen is spread from source to host.

    • Etiological Agent Factors: Characteristics of the pathogen that contribute to disease causation.

Key Definitions

  • Pathogenicity:

    • Definition: The ability of an organism to cause disease.

  • Virulence:

    • Definition: The degree or severity of pathogenicity exhibited by a pathogen.

  • Attenuation:

    • Definition: Loss of virulence factors; the pathogen remains infectious but is weakened.

  • Virulence Factors (VF):

    • Definition: Molecules or structures that promote infection and disease, including:

    • Toxins

    • Enzymes

    • Capsules

    • Functions of Virulence Factors:

    • Adhesion to host tissues.

    • Invasion of host tissues.

    • Direct cell damage.

    • Evasion of the immune system.

    • Nutrient acquisition.

Establishing Infection

  • Infectious Dose (ID):

    • Definition: The quantity of the microbe necessary to establish an infection in 50% of subjects.

  • Invasion Process:

    • Requires specific virulence factors to establish an infection:

    • Infectious dose of microbe.

    • Breaking through host defense barriers.

    • Entry through a portal of entry.

    • Targeting specific tissues.

    • Portal of exit for spreading.

How Pathogens Enter the Host

  • Most pathogens have preferred portals of entry:

    • Portals of Entry and Exit:

    • Mucous membranes

    • Skin

    • Parenteral route: Deposited directly into tissues through injections, bites, wounds, cuts, surgeries.

Infectious Dose

  • Infectious Dose (ID50):

    • The number of cells or virions needed to establish an infection in 50% of subjects.

  • Lethal Dose (LD50):

    • The dose that kills 50% of a sample population.

  • Highly contagious pathogens typically have a low ID50, indicating ease of transmission.

Adherence to Host Cells

  • First step in pathogenesis following entry.

  • Pathogens utilize adhesins (ligands) to attach to specific host receptors found on:

    • Pilus

    • Fimbriae

    • Flagella

    • Glycocalyx

    • Viral spikes

  • Biofilms:

    • A significant factor in adherence; accounts for 60-80% of human infections.

    • Offers resistance to antibiotics and disinfectants while evading phagocytes by being shielded by an extracellular polymeric substance (EPS).

Establishing Infection: Colonization vs. Invasion

  • Extracellular Pathogens:

    • Colonization: Multiplication at the site of infection while remaining outside host cells.

  • Intracellular Pathogens:

    • Invasion: Involves penetrating host tissues through the secretion of enzymes or induced endocytosis, multiplying inside host cells. Requires specific invasins as virulence factors.

Examples of Invasion Mechanisms

  • H. pylori: Uses flagella and urease as invasins to penetrate the stomach lining through mucin layers covering epithelial cells.

Enzymatic Virulence Factors for Infection

  • Pathogens secrete enzymes to facilitate tissue invasion:

    • Coagulase: Forms protective fibrin clots around bacteria (e.g., Staphylococcus aureus).

    • Kinases: Dissolve fibrin clots to spread the infection (e.g., streptokinase, staphylokinase).

    • Hyaluronidase: Breaks down hyaluronic acid in connective tissue to assist in spreading.

    • Collagenase: Degrades collagen, leading to tissue breakdown (e.g., in Clostridium perfringens gas gangrene).

    • IgA protease: Destroys mucosal antibodies, aiding attachment to mucous membranes.

Evasion of Host Defenses

  • To establish infection, pathogens must overcome:

    • Physical and Chemical Barriers: (e.g., skin, mucous membranes, lysozymes)

    • Innate Immune Responses: (e.g., phagocytes, complement system)

    • Adaptive Immune Responses: (e.g., antibodies, T cells)

  • Pathogen strategies include:

    • Avoiding phagocytosis.

    • Surviving inside phagocytes.

    • Suppressing or evading immune signaling.

    • Altering surface antigens (antigenic variation).

    • Mimicking host molecules.

Strategies to Avoid Phagocytosis

  • Capsules: Prevent phagocytosis (e.g., Streptococcus pneumoniae, Bacillus anthracis).

  • Cell wall Components:

    • M proteins (e.g., from Streptococcus pyogenes) resist phagocytosis.

    • Mycolic acid (from Mycobacterium tuberculosis) resists digestion within macrophages.

  • Biofilm Formation: Protects pathogens from antibodies and antibiotics.

Antigenic Variation and Immune Suppression

  • Antigenic Variation: Surface protein alterations prevent recognition by previously formed antibodies (e.g., Neisseria gonorrhoeae).

  • Immune Suppression: Pathogens interfere with components of the immune response, such as complement or cytokines.

  • Intracellular Survival: Pathogens like Listeria monocytogenes and Mycobacterium tuberculosis escape or tolerate phagolysosomal destruction.

Direct Host Damage by Pathogens

  • Toxins: Molecules that cause adverse effects in the host:

    • Disrupt normal cell functions and can cause tissue damage.

  • Types of Toxins:

    • Endotoxins: Found in the Gram-negative bacterial cell wall – released upon cell death.

    • Exotoxins: Proteins secreted by bacteria, highly specific, and vary in lethality.

  • Key Definitions:

    • Toxigenic: Microbes that produce toxins.

    • Toxemia: Toxins in the bloodstream.

    • Intoxication: Presence of toxins without active microbial growth.

Exotoxins: Characteristics and Specifics

  • Exotoxins:

    • Definition: Proteins produced and secreted by bacteria, soluble in bodily fluids, destroy host cells and inhibit metabolic functions.

    • Features: Highly specific for targets, some are lethal.

    • Term Definitions:

    • Antitoxins: Antibodies against specific exotoxins providing immunity.

    • Toxoids: Inactivated exotoxins that can be used in vaccines.

    • Examples:

    • Tetanus toxin: from Clostridium tetani

    • Cholera toxin: from Vibrio cholerae

    • Neurotoxins: Specifically target neurons.

    • Enterotoxins: Specifically target the gastrointestinal tract.

    • Hepatotoxins: Specifically target the liver.

    • Nephrotoxins: Specifically target the kidneys.

Endotoxins: Properties

  • Endotoxins:

    • Definition: Lipopolysaccharides (LPS) found only in the outer membrane of Gram-negative bacteria, released upon cell death.

    • Lipid A: Triggers intense inflammatory response leading to:

    • Endotoxic shock or septic shock, characterized by decreased blood pressure, multi-organ failure, and death.

Comparing Endotoxins and Exotoxins

Properties

Endotoxins

Exotoxins

Composition

Lipid

Protein

Source

Gram-negative bacteria

Gram-negative and Gram-positive bacteria

Release

From Gram-negative cell wall on division or death

Released actively by growing bacteria

Mechanism of Action

Causes systemic inflammation

Causes cell toxicity, specific to targets

Vaccine Target

No

Yes (some)

Fever-inducing

Yes

Sometimes

Neutralizable by Antibody

No

Yes (most)

Toxicity Level

Lower (relatively high LD50)

Higher (many have a low LD50)

Summary of Bacterial Virulence Factors

  • Bacterial species exhibit various virulence factors including:

    • Adhesins for attachment.

    • Invasins for tissue penetration.

    • Evasion strategies against the immune system.

    • Capsules and surface proteins for protection.

    • Biofilm formation as a defensive strategy against treatments.

    • Antigenic variation to maintain infection.

    • Direct cell damage through toxins and secreted enzymes.

    • Nutrient acquisition strategies like siderophores that sequester iron.

Pathogenic Properties of Viruses

  • Viral Mechanisms for Evading Host Defenses:

    • Intracellular location allows viruses to evade detection.

    • Direct attacks on immune components.

    • Methylation of viral RNA mimicking host RNA.

    • Antigenic Variation: Changes in surface proteins that prevent recognition.

    • Cytopathic Effects (CPE): Visible effects of viral infections which vary by virus and can assist in diagnosis.

    • Latency: Viruses that remain dormant in the host (e.g., HSV, HIV).

Antigenic Variation in Influenza Virus

  • Antigenic Drift: Results in small antigenic changes over time due to mutations in genes coding for surface proteins (neuraminidase and hemagglutinin).

  • Antigenic Shift: Occurs when two different influenza viruses infect a cell simultaneously leading to genetic recombination, resulting in new mixed proteins which can cause pandemics.

Pathogenic Properties of Fungi

  • Capsules: Help resist phagocytosis (e.g., Cryptococcus neoformans).

  • Toxins (Mycotoxins): Example: aflatoxin from Aspergillus can lead to liver cancer.

  • Cell-Wall Components: Trigger inflammation (e.g., Candida albicans).

  • Proteases: Modify host cell membranes, allowing fungal invasion.

Pathogenic Properties of Protozoa and Helminths

  • Protozoa:

    • Exhibit antigenic variation (e.g., Plasmodium, Trypanosoma).

    • Can reside intracellularly to evade detection (e.g., Toxoplasma gondii).

    • Direct tissue destruction occurs through feeding and enzyme secretion.

  • Helminths:

    • Utilize host tissues for growth and can cause damage through large parasitic masses.

    • Produce waste products leading to various symptoms.

Learning Objectives

  • Upon completion of lecture and readings, students should:

    • Identify the principal portals of entry for pathogens.

    • Define essential terms such as pathogen, true pathogen, opportunistic pathogen, pathogenicity, and virulence.

    • Compare the functions of coagulases, kinases, hyaluronidase, and collagenase.

    • Discuss antigenic variation and provide examples.

    • Describe invasins and their role in bacterial entry via the host cell cytoskeleton.

    • Compare and contrast exotoxins and endotoxins.

    • Define and provide examples of toxin-related terms (antitoxin, toxoid, toxemia, intoxication).

    • Discuss pathogenic properties of fungi, protozoa, and helminths.