Microbial Mechanisms of Pathogenicity (Chapter 15) - Study Notes

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Microbial Mechanisms of Pathogenicity

Introduction

This chapter explores how microorganisms cause disease (pathogenicity), the degree of their ability to do so (virulence), and the various mechanisms by which they invade hosts, evade defenses, and inflict damage. Understanding these processes is essential for studying infectious diseases and developing effective treatments.

How Microorganisms Enter a Host

Definitions

Pathogenicity: The ability of a microorganism to cause disease.
Virulence: The degree of pathogenicity, or how severe the disease caused by the microorganism is.

Portals of Entry

Microorganisms must enter the host through specific portals to initiate infection. Most pathogens have a preferred portal of entry.

Mucous membranes: Includes respiratory tract, digestive canal, genital system, urinary system, and conjunctiva.
Skin: Generally impenetrable unless compromised; entry possible via hair follicles and sweat gland ducts.
Parenteral route: Direct deposition into tissues beneath the skin or mucous membranes (e.g., punctures, injections, bites, cuts, wounds, surgery).

Mucous Membranes

Respiratory tract: Most common portal (inhalation).
Digestive canal: Entry via contaminated food, water, or fingers.
Genital system: Portal for sexually transmitted infections (STIs).

Skin

Unbroken skin is a strong barrier; most organisms cannot penetrate.
Entry possible through hair follicles and sweat gland ducts.

Parenteral Route

Microorganisms bypass skin/mucous membrane barriers via punctures, injections, bites, cuts, wounds, or surgery.

Numbers of Invading Microbes

Infectious and Lethal Dose

ID50: Infectious dose for 50% of a sample population; measures virulence.
LD50: Lethal dose for 50% of a sample population; measures toxin potency.

Portal of Entry	ID50 (Bacillus anthracis)
Skin	10–50 endospores
Inhalation	10,000–20,000 endospores
Ingestion	250,000–1,000,000 endospores

Toxin	LD50
Botulinum	0.03 ng/kg
Shiga toxin	250 ng/kg
Staphylococcal enterotoxin	1350 ng/kg

Adherence

Mechanisms of Adherence

Pathogens must attach to host tissues to establish infection. This process is called adherence (adhesion).

Adhesins (ligands): Molecules on pathogens that bind to specific receptors on host cells.
Glycocalyx: Example—Streptococcus mutans uses dextran to adhere to teeth.
Fimbriae: Example—Actinomyces adheres to the glycocalyx of S. mutans.
Viral spikes: Example—SARS-CoV-2 spikes bind to ACE2 receptors on host cells.

How Pathogens Penetrate Host Defenses

Capsules

Glycocalyx around the cell wall impairs phagocytosis.
Examples: Streptococcus pneumoniae (pneumonia), Haemophilus influenzae (pneumonia, meningitis), Bacillus anthracis (anthrax), Yersinia pestis (plague).

Cell Wall Components

M protein: Resists phagocytosis (Streptococcus pyogenes).
Opa protein: Allows attachment to host cells (Neisseria gonorrhoeae).
Waxy lipid (mycolic acid): Resists digestion by phagocytes (Mycobacterium tuberculosis).

Enzymes

Coagulases: Coagulate fibrinogen, forming fibrin.
Kinases: Digest fibrin clots.
Hyaluronidase: Digests hyaluronic acid, which holds host 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.

Penetration into the Host

Invasins: Surface proteins that rearrange actin filaments, causing membrane ruffling and engulfment (e.g., Shigella, Listeria).
Use actin to move from cell to cell.
Survival inside phagocytes: Require low pH in phagolysosome, escape from phagosome before lysosomal fusion, or prevent fusion of lysosome with phagosome.

Biofilms

Resist antibiotics and disinfectants.
Involved in 65% of all infections.
Biofilm bacteria are more resistant to phagocytosis, shielded by extracellular polymeric substance (EPS).

How Bacterial Pathogens Damage Host Cells

Using the Host’s Nutrients: Siderophores

Iron is essential for most pathogenic bacteria.
Siderophores: Proteins secreted by pathogens that bind iron more tightly than host iron-binding proteins.

Direct Damage

Disrupts host cell function.
Uses host cell nutrients.
Produces waste products.
Multiplies in host cells, causing ruptures.

Production of Toxins

Toxins: Poisonous substances produced by microorganisms; cause fever, cardiovascular problems, diarrhea, and shock.
Toxigenicity: Ability to produce a toxin.
Toxemia: Presence of toxin in the host's blood.
Intoxications: Presence of toxin without microbial growth.

Exotoxins

Properties

Proteins produced and secreted by bacteria.
Soluble in bodily fluids; destroy host cells and inhibit metabolic functions.
Highly specific and sometimes highly lethal.
Antitoxins: Antibodies against specific exotoxins.
Toxoids: Inactivated exotoxins used in vaccines.

Types of Exotoxins

A-B toxins: Contain an enzyme component (A part) and a binding component (B part). Example: Diphtheria toxin.
Genotoxins: Damage DNA, causing mutations and potentially cancer.
Membrane-disrupting toxins: Lyse host cells by disrupting plasma membranes (e.g., leukocidins, hemolysins, streptolysins).
Superantigens: Cause intense immune response by releasing cytokines from T cells, leading to fever, nausea, vomiting, diarrhea, shock, and death.

Table: Diseases Caused by Exotoxins

Disease	Bacterium	Type of Exotoxin	Mechanism
Botulism	Clostridium botulinum	A-B	Neurotoxin prevents transmission of nerve impulses; flaccid paralysis results.
Tetanus	C. tetani	A-B	Neurotoxin blocks nerve impulses to muscle relaxation pathway; results in uncontrollable muscle contraction.
Diphtheria	Corynebacterium diphtheriae	A-B	Cytotoxin inhibits protein synthesis, especially in nerve, heart, and kidney cells.
Cholera	V. cholerae	A-B	Enterotoxin causes secretion of large amounts of fluids and electrolytes that cause diarrhea.
Anthrax	Bacillus anthracis	A-B	Two A components enter the cell via the same B component. The A proteins cause shock and reduce immune response.
Food poisoning	S. aureus	Superantigen	Enterotoxin causes secretion of fluids and electrolytes that result in diarrhea.

Endotoxins

Properties

Lipid A portion of lipopolysaccharides (LPS) of gram-negative bacteria.
Released during bacterial multiplication and when gram-negative bacteria die.
Stimulate macrophages to release large quantities of cytokines.
Cause fever, chills, weakness, generalized aches, disseminated intravascular coagulation, endotoxic shock, and may weaken the blood-brain barrier.

Detection

Limulus amebocyte lysate (LAL) assay: Used to test for endotoxins. Blood of horseshoe crabs contains amebocytes that lyse in the presence of endotoxin, producing a clot.

Table: Exotoxins vs. Endotoxins

Property	Exotoxins	Endotoxins
Bacterial Source	Gram-positive and gram-negative bacteria	Gram-negative bacteria
Relation to Microorganism	Metabolic product of growing cell	Present in LPS of outer membrane; released with cell destruction or division
Chemistry	Proteins, usually with two parts (A-B)	Lipid portion (Lipid A) of LPS
Pharmacology (Effect on Body)	Specific for a particular cell function	General effects: fever, weakness, aches, shock
Heat Stability	Unstable; destroyed at 60–80°C	Stable; withstands autoclaving (121°C for 1 hour)
Toxicity	High	Low
Fever-Producing	No	Yes
Immunology (Vaccines)	Can be converted to toxoids to immunize	Not easily neutralized by antitoxin
Lethal Dose	Small	Considerable
Representative Diseases	Gas gangrene, tetanus, botulism, diphtheria, scarlet fever	Typhoid fever, urinary tract infections, meningococcal meningitis

Plasmids, Lysogeny, and Pathogenicity

Plasmids

May carry genes for toxins, antibiotic production, and enzymes.
R plasmids: Encode resistance to antibiotics.
Virulence plasmids: Affect pathogenicity (e.g., tetanus neurotoxin, staphylococcal enterotoxin, adhesins, and coagulase of Staphylococcus aureus).

Lysogenic Conversion

Incorporation of a prophage can change microbial characteristics (e.g., genes for diphtheria toxin, erythrogenic toxin).

Pathogenic Properties of Viruses

Evading Host Defenses

Intracellular location shields viruses from immune detection.
Attachment via host cell surface molecules.
Direct attack on immune system components.
Methylation of viral RNA to mimic host RNA.
Antigenic variation.

Cytopathic Effects (CPE)

Visible effects of viral infection on host cells.
Cytocidal effects: Kill host cells.
Noncytocidal effects: Damage but do not kill host cells; infected cells may continue to grow and divide.
CPE can be used to diagnose viral infections; effects vary by virus.

Examples of Cytopathic Effects

Disrupting cell junctions (e.g., SARS-CoV-2, Alphainfluenzavirus).
Inducing cytokine storms.
Halting macromolecular synthesis.
Causing lysosomal enzyme release and cell death.
Creating inclusion bodies (e.g., Negri bodies in rabies).
Fusing cells to form a syncytium.
Antigenic changes, chromosomal damage, loss of contact inhibition (cancer), and interferon production.

Summary Table: Key Mechanisms of Pathogenicity

Mechanism	Example/Effect
Adherence	Glycocalyx, fimbriae, viral spikes
Penetration/Evasion	Capsules, cell wall components, enzymes, antigenic variation, invasins, biofilms
Damage	Siderophores, direct damage, toxins (exotoxins, endotoxins)
Genetic Elements	Plasmids, lysogenic conversion
Viral Pathogenicity	Evading defenses, cytopathic effects

Additional info: These notes are based on textbook slides and cover the major mechanisms by which microbes cause disease, including bacterial and viral strategies. For more detail, refer to the full textbook chapter and associated figures.