Microbial Mechanisms of Pathogenicity: Study Notes

Microbial Mechanisms of Pathogenicity

Definitions

Understanding the basic terminology is essential for studying microbial pathogenicity. Pathogenicity refers to the ability of a microorganism to cause disease, while virulence is the degree of pathogenicity, indicating how severe the disease can be.

How Microorganisms Enter a Host

Microorganisms must enter the host through specific portals to initiate infection. The main portals of entry include mucous membranes, skin, and the parenteral route. Most pathogens have a preferred portal of entry, which influences their ability to cause disease.

• Mucous membranes: Includes respiratory tract, digestive canal, genital system, urinary system, and conjunctiva. The respiratory tract is the most common portal (inhalation).

• Skin: Unbroken skin is generally impenetrable, but entry can occur via hair follicles or sweat gland ducts.

• Parenteral route: Microorganisms are deposited directly into tissues beneath the skin or mucous membranes via punctures, injections, bites, cuts, wounds, or surgery.

Numbers of Invading Microbes

The number of microbes required to cause infection or death is measured by ID50 (infectious dose for 50% of a sample population) and LD50 (lethal dose for 50% of a sample population). These values help quantify the virulence and potency of pathogens and their toxins.

Adherence

Adherence is a critical step in pathogenesis, where pathogens attach to host tissues using specific molecules called adhesins or ligands. These bind to receptors on host cells, facilitating colonization and infection.

• 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 adhere to ACE2 receptors on host cells.

Capsules and Cell Wall Components

Some bacteria evade host defenses by producing capsules or modifying their cell wall components.

• Capsules: Glycocalyx around the cell wall impairs phagocytosis. Examples: Streptococcus pneumoniae, Haemophilus influenzae, Bacillus anthracis, Yersinia pestis.

• Cell wall components: M protein (resists phagocytosis, Streptococcus pyogenes), Opa protein (attachment, Neisseria gonorrhoeae), mycolic acid (resists digestion, Mycobacterium tuberculosis).

Enzymes

Pathogenic bacteria produce enzymes that facilitate invasion and evasion of host defenses.

• Coagulases: Coagulate fibrinogen to form fibrin.

• Kinases: Digest fibrin clots.

• Hyaluronidase: Digests hyaluronic acid, which holds cells together.

• Collagenase: Breaks down collagen.

• IgA proteases: Destroy IgA antibodies.

Antigenic Variation

Pathogens can alter their surface antigens, rendering host antibodies ineffective. This mechanism is seen in viruses and bacteria such as influenza virus, Neisseria gonorrhoeae, and Trypanosoma brucei gambiense.

Penetration into the Host

Bacteria use invasins to rearrange actin filaments in host cells, causing membrane ruffling and engulfment. Some pathogens survive inside phagocytes by escaping from the phagosome or preventing lysosomal fusion.

• Invasins: Surface proteins that facilitate entry and movement within host cells. Examples: Shigella, Listeria.

• Survival inside phagocytes: Adaptations include requirement for low pH, escape from phagosome, and prevention of lysosomal fusion.

Biofilms

Biofilms are communities of microorganisms encased in a protective matrix. They resist antibiotics and disinfectants, play a role in evading phagocytes, and are involved in 65% of all infections.

Using the Host’s Nutrients: Siderophores

Pathogenic bacteria require iron for growth. Siderophores are proteins secreted by pathogens that bind iron more tightly than host cells, facilitating iron acquisition.

Direct Damage

Microorganisms can cause direct damage by disrupting host cell function, using host nutrients, producing waste products, and multiplying within host cells, leading to cell rupture.

Production of Toxins

Toxins are poisonous substances produced by microorganisms. They cause fever, cardiovascular problems, diarrhea, and shock. Toxigenicity is the ability to produce toxins, toxemia is the presence of toxins in blood, and intoxications refer to toxin presence without microbial growth.

Exotoxins

Exotoxins are proteins secreted by bacteria, highly specific and often highly lethal. They are soluble in bodily fluids and destroy host cells or inhibit metabolic functions. Antitoxins are antibodies against exotoxins, and toxoids are inactivated exotoxins used in vaccines.

Mechanisms of Exotoxins

A-B toxins are a major class of exotoxins, consisting of an enzyme component (A part) and a binding component (B part). Genotoxins damage DNA, causing mutations and potentially cancer.

• Membrane-disrupting toxins: Lyse host cells by disrupting plasma membranes (leukocidins, hemolysins, streptolysins).

• Superantigens: Cause intense immune response via cytokine release, leading to fever, nausea, vomiting, diarrhea, shock, and death.

Endotoxins

Endotoxins are the lipid A portion of lipopolysaccharides (LPS) in gram-negative bacteria. They are released during bacterial multiplication or cell death, causing fever, chills, weakness, and shock. Endotoxins stimulate macrophages to release cytokines and may cause disseminated intravascular coagulation and endotoxic shock.

Pyrogenic Response to Endotoxins

Endotoxins induce a pyrogenic response by stimulating macrophages to release cytokines, which act on the hypothalamus to produce prostaglandins, resulting in fever.

Limulus Amebocyte Lysate (LAL) Assay

The LAL assay is used to detect endotoxins. Blood from horseshoe crabs contains amebocytes that lyse in the presence of endotoxin, forming a clot.

Comparison of Exotoxins and Endotoxins

Exotoxins and endotoxins differ in their source, chemical nature, mode of action, and effects on the host.

Property	Exotoxins	Endotoxins
Source	Mostly gram-positive bacteria	Gram-negative bacteria
Chemical nature	Protein	Lipid A (LPS)
Mode of release	Secreted	Released upon cell lysis
Effects	Specific, often highly toxic	General symptoms (fever, shock)
Immunity	Antitoxins, toxoids	No effective immunity
Heat stability	Unstable	Stable
Example	Diphtheria toxin	Salmonella endotoxin

Plasmids, Lysogeny, and Pathogenicity

Plasmids may carry genes for toxins, antibiotic resistance, and enzymes. Lysogenic conversion occurs when a prophage incorporates into the bacterial genome, altering its characteristics and potentially increasing pathogenicity.

Pathogenic Properties of Viruses

Viruses evade host defenses by residing intracellularly, using host cell surface molecules for attachment, attacking immune components, and undergoing antigenic variation. Cytopathic effects (CPE) are visible changes in host cells due to viral infection, which can be cytocidal (cell death) or noncytocidal (cell damage).

• Disrupting cell junctions

• Inducing cytokine storms

• Stopping macromolecular synthesis

• Causing lysosomal enzyme release

• Creating inclusion bodies (e.g., Negri bodies in rabies)

• Fusing cells to form syncytia

Transformation and Interferons

Viruses may transform host cells, causing loss of contact inhibition and unregulated growth (cancer). Alpha and beta interferons are produced by infected cells to protect neighboring cells, inhibit viral protein synthesis, and induce apoptosis. Some viruses evade interferons by blocking their synthesis.

Pathogenic Properties of Fungi

Fungi cause disease through toxic metabolic products, allergic responses, and enzymes that modify host cell membranes. Examples include trichothecene toxins, ergot alkaloids, aflatoxin, and mycotoxins (phalloidin, amanitin).

• Candida albicans: Capsules prevent phagocytosis.

• Cryptococcus neoformans: Capsule-mediated evasion.

Pathogenic Properties of Protozoa

Protozoa cause symptoms through their presence and waste products. They evade host defenses by digesting cells and tissue fluids, growing in phagocytes, and antigenic variation.

• Giardia intestinalis: Digests host cells.

• Toxoplasma gondii: Grows in phagocytes.

• Trypanosoma: Antigenic variation.

Pathogenic Properties of Helminths

Helminths use host tissue for growth, produce large parasitic masses, and cause cellular damage through waste products.

Pathogenic Properties of Algae

Some algae produce neurotoxins such as saxitoxin, which cause paralytic shellfish poisoning. These toxins are concentrated in mollusks that consume dinoflagellates, and humans who eat these mollusks may be affected.

Portals of Exit

Microorganisms exit the host via specific portals, facilitating transmission to new hosts.

• Respiratory tract: Coughing and sneezing

• Gastrointestinal tract: Feces and saliva

• Genitourinary tract: Urine, secretions

• Skin

• Blood: Arthropod bites, needles, syringes