Microbial Mechanisms of Pathogenicity

Definitions

Understanding the 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 caused by the microorganism 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 is critical for their ability to cause disease.

• Mucous membranes: Includes the 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 complementary receptors on host cells. Examples include:

• Glycocalyx: Streptococcus mutans uses dextran to adhere to teeth.

• Fimbriae: Actinomyces adheres to the glycocalyx of S. mutans.

• Viral spikes: Spikes of SARS-CoV-2 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 (Streptococcus pyogenes) resists phagocytosis; Opa protein (Neisseria gonorrhoeae) allows attachment; mycolic acid (Mycobacterium tuberculosis) resists digestion by phagocytes.

Enzymes

Pathogenic bacteria produce enzymes that facilitate invasion and evasion:

• Coagulases: Coagulate fibrinogen, forming 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 the 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 bacteria survive inside phagocytes by escaping the phagosome, preventing lysosomal fusion, or requiring a low pH in the phagolysosome.

• Examples: Shigella and Listeria

Biofilms

Biofilms are communities of microorganisms encased in an extracellular polymeric substance (EPS). They resist antibiotics and disinfectants, evade phagocytes, and are involved in 65% of all infections.

Using the Host’s Nutrients: Siderophores

Pathogenic bacteria require iron, which is limited in the host. Siderophores are proteins secreted by pathogens that bind iron more tightly than host iron-binding proteins, facilitating iron acquisition.

Direct Damage

Microorganisms can directly damage host cells by disrupting cell function, using nutrients, producing waste products, and causing cell rupture during multiplication.

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 the blood, and intoxications occur when toxins are present without microbial growth.

Exotoxins

Exotoxins are proteins secreted by bacteria, usually gram-positive, that destroy host cells and inhibit metabolic functions. They are highly specific and can be lethal. Antitoxins are antibodies against exotoxins, and toxoids are inactivated exotoxins used in vaccines.

Mechanisms of Exotoxins

A-B toxins consist 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 responses by releasing cytokines, 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 death, stimulating macrophages to release cytokines and causing fever, chills, weakness, and shock.

Pyrogenic Response to Endotoxins

Endotoxins induce fever by stimulating macrophages to release cytokines, which act on the hypothalamus to increase body temperature.

Limulus Amebocyte Lysate (LAL) Assay

The LAL assay detects endotoxins using blood from horseshoe crabs. Amebocytes in the blood lyse in the presence of endotoxin, producing a clot.

Comparison of Exotoxins and Endotoxins

Exotoxins and endotoxins differ in their origin, chemical nature, effects, and mechanisms:

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. Methylation of viral RNA may mimic host RNA.

Cytopathic Effects (CPE) of Viruses

CPE are visible effects of viral infection on host cells. They include cell death (cytocidal effects), cell damage without death (noncytocidal effects), disruption of cell junctions, cytokine storms, inclusion bodies, and syncytium formation.

Transformation and Interferons

Viruses can transform host cells, causing loss of contact inhibition and unregulated growth (cancer). Infected cells may produce alpha and beta interferons, which protect neighboring cells by inhibiting viral protein synthesis and inducing 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: Inhibit protein synthesis.

• Proteases: Modify host cell membranes (Candida albicans).

• Capsules: Prevent phagocytosis (Cryptococcus neoformans).

• Ergot alkaloids: Cause hallucinations.

• Aflatoxin: Carcinogenic toxin produced by Aspergillus.

• Mycotoxins: Produced by mushrooms, neurotoxic and potentially deadly (phalloidin, amanitin).

Pathogenic Properties of Protozoa

Protozoa cause symptoms through their presence and waste products. They evade host defenses by digesting cells and tissue fluids (Giardia intestinalis), growing in phagocytes (Toxoplasma gondii), and antigenic variation (Trypanosoma).

Pathogenic Properties of Helminths

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

Pathogenic Properties of Algae

Some algae produce neurotoxins, such as saxitoxin, which cause paralytic shellfish poisoning. This is associated with red tides (blooms of Alexandrium), and the toxin is concentrated in mollusks consumed by humans.

Portals of Exit

Microorganisms exit the host via specific portals, facilitating transmission:

• Respiratory tract: Coughing and sneezing

• Gastrointestinal tract: Feces and saliva

• Genitourinary tract: Urine; secretions from the penis and vagina

• Skin

• Blood: Arthropods that bite; needles or syringes