Microbial Mechanisms of Pathogenicity: Study Notes

Microbial Mechanisms of Pathogenicity

Introduction

This chapter explores how microorganisms cause disease, focusing on the mechanisms by which pathogens enter, survive, and damage the host. Understanding these processes is essential for microbiology students to grasp the basis of infectious diseases and host-pathogen interactions.

How Microorganisms Enter a Host

Portals of Entry

Pathogens must enter the host through specific portals to initiate infection. The main portals of entry include:

• Mucous membranes: Respiratory tract (most common), digestive canal, genitourinary system, and conjunctiva.

• Skin: Usually impenetrable unless through hair follicles or sweat gland ducts.

• Parenteral route: Direct deposition into tissues beneath the skin or mucous membranes via punctures, injections, bites, wounds, or surgery.

Most pathogens have a preferred portal of entry, which is critical for their ability to cause disease.

Numbers of Invading Microbes

• 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.

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

Example: Bacillus anthracis has different ID50 values depending on the portal of entry (e.g., 10–50 endospores via skin, 10,000–20,000 via inhalation).

Adherence

Pathogens must attach to host tissues to establish infection. This process, called adherence, involves:

• Adhesins (ligands): Surface molecules on pathogens that bind to specific receptors on host cells.

• Examples:

  • Glycocalyx of Streptococcus mutans enables adherence to teeth.

  • Fimbriae of Actinomyces adhere to the glycocalyx of S. mutans.

  • Viral spikes (e.g., SARS-CoV-2) bind to ACE2 receptors on host cells.

Penetration or Evasion of Host Defenses

Capsules

Some bacteria produce a glycocalyx capsule around their cell wall, which impairs phagocytosis by host immune cells.

• Examples: Streptococcus pneumoniae, Haemophilus influenzae, Bacillus anthracis, Yersinia pestis

Cell Wall Components

• M protein: Resists phagocytosis (Streptococcus pyogenes).

• Opa protein: Facilitates attachment to host cells (Neisseria gonorrhoeae).

• Waxy lipid (mycolic acid): Resists digestion by phagocytes (Mycobacterium tuberculosis).

Enzymes

• Coagulases: Coagulate fibrinogen to form clots.

• Kinases: Digest fibrin clots.

• Hyaluronidase: Digests hyaluronic acid, aiding tissue penetration.

• Collagenase: Breaks down collagen.

• IgA proteases: Destroy IgA antibodies.

Antigenic Variation

Pathogens can alter their surface antigens, rendering host antibodies ineffective. This allows them to evade the immune response.

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

Penetration into the Host Cell

• Invasins: Surface proteins that rearrange actin filaments, causing membrane ruffling and bacterial engulfment (e.g., Shigella, Listeria).

• Survival inside phagocytes: Some bacteria survive by escaping the phagosome, preventing lysosomal fusion, or requiring low pH in the phagolysosome.

Biofilms

Biofilms protect bacteria from antibiotics, disinfectants, and phagocytosis. The extracellular polymeric substance (EPS) shields bacteria, making infections harder to treat.

How Bacterial Pathogens Damage Host Cells

Using the Host’s Nutrients: Siderophores

Pathogens secrete siderophores to bind iron more tightly than host proteins, depriving host cells of this essential nutrient.

Direct Damage

• Disruption of host cell function

• Consumption of host nutrients

• Production of waste products

• Multiplication inside host cells, causing cell rupture

Production of Toxins

Toxins are poisonous substances produced by microorganisms that can cause fever, cardiovascular problems, diarrhea, and shock.

• Toxigenicity: Ability to produce toxins

• Toxemia: Presence of toxins in the blood

• Intoxications: Disease caused by toxins without microbial growth

Exotoxins

Exotoxins are proteins secreted by bacteria, usually highly specific and potent. They can be neutralized by antitoxins and inactivated for use in vaccines (toxoids).

Types of Exotoxins

• A-B toxins: Consist of an active (A) and binding (B) component. The B part binds to the host cell, and the A part exerts the toxic effect (e.g., diphtheria toxin).

• Genotoxins: Damage DNA, potentially leading to mutations and cancer.

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

• Superantigens: Cause intense immune responses by stimulating excessive cytokine release, leading to fever, shock, and sometimes death.

Diseases Caused by Exotoxins

Disease	Bacterium	Type of Exotoxin	Mechanism
Botulism	Clostridium botulinum	A-B	Neurotoxin; prevents nerve impulse transmission; flaccid paralysis.
Tetanus	C. tetani	A-B	Neurotoxin; blocks muscle relaxation; uncontrollable contractions.
Diphtheria	Corynebacterium diphtheriae	A-B	Cytotoxin; inhibits protein synthesis.
Cholera	Vibrio cholerae	A-B	Enterotoxin; causes diarrhea.
Anthrax	Bacillus anthracis	A-B	Shock and immune suppression.
Food poisoning	Staphylococcus aureus	Superantigen	Enterotoxin; diarrhea.
Toxic shock syndrome	S. aureus	Superantigen	Shock, low blood pressure.

Endotoxins

Endotoxins are lipid A components of the lipopolysaccharide (LPS) layer of gram-negative bacteria. They are released when bacteria die and the cell wall breaks apart.

• Stimulate macrophages to release cytokines, causing fever, chills, weakness, and shock.

• Can cause disseminated intravascular coagulation and endotoxic shock.

• May weaken the blood-brain barrier.

Pyrogenic Response

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

Detection of Endotoxins

The Limulus amebocyte lysate (LAL) assay is used to detect endotoxins. Amebocytes from horseshoe crab blood lyse in the presence of endotoxin, forming a clot.

Comparison of Exotoxins and Endotoxins

Property	Exotoxins	Endotoxins
Bacterial Source	Gram-positive and gram-negative	Gram-negative
Chemistry	Proteins (A-B structure)	Lipid A of LPS
Heat Stability	Unstable (destroyed at 60–80°C)	Stable (withstands autoclaving)
Toxicity	High	Low
Fever-Producing	No	Yes
Immunology	Can be neutralized by antitoxin; toxoids for vaccines	Not easily neutralized; no effective toxoids
Lethal Dose	Small	Large
Representative Diseases	Tetanus, botulism, diphtheria	Typhoid fever, meningococcal meningitis

Plasmids, Lysogeny, and Pathogenicity

Plasmids may carry genes for toxins, antibiotic resistance, and virulence factors. Lysogenic conversion can change microbial characteristics, such as toxin production, due to prophage incorporation.

• R plasmids: Encode antibiotic resistance.

• Virulence plasmids: Encode toxins and enzymes (e.g., tetanus neurotoxin, staphylococcal enterotoxin).

• Lysogenic conversion: Can result in new toxin production (e.g., diphtheria toxin).

Pathogenic Properties of Viruses

Mechanisms for Evading Host Defenses

• Intracellular location shields viruses from immune detection.

• Attachment to host cell surface molecules.

• Direct attack on immune system components.

• Methylation of viral RNA to mimic host RNA.

• Antigenic variation.

Cytopathic Effects (CPE)

Cytopathic effects are visible changes in host cells due to viral infection. They can be cytocidal (cell death) or noncytocidal (cell damage without death).

• Disruption of cell junctions

• Cytokine storm induction

• Inhibition of macromolecular synthesis

• Lysosomal enzyme release

• Inclusion body formation (e.g., Negri bodies in rabies)

• Syncytium formation (fusion of cells)

• Antigenic changes on cell surface

• Chromosomal damage

• Loss of contact inhibition (unregulated growth, cancer)

• Interferon production

Interferons

Alpha and beta interferons are produced by virally infected cells to protect neighboring cells by inhibiting viral protein synthesis and inducing apoptosis. Some viruses can evade interferon effects.

Examples of Cytopathic Effects

Virus (Genus)	Cytopathic Effect
Poliovirus (Enterovirus C)	Cytocidal (cell death)
Genital warts virus (Alphapapillomavirus)	Inclusion bodies, transformation
Adenovirus (Mastadenovirus)	Basophilic inclusion bodies in nucleus
Rabies (Lyssavirus)	Inclusion bodies in cytoplasm
CMV (Cytomegalovirus)	Inclusion bodies in nucleus and cytoplasm
Measles virus (Morbillivirus)	Cell fusion
HIV (Lentivirus)	Destruction of T cells
SARS-CoV-2 (Betacoronavirus)	Syncytia, cilia shrinkage, altered junctions

Pathogenic Properties of Fungi, Protozoa, Helminths, and Algae

Fungi

• Toxic metabolic products and allergens

• Trichothecene toxins inhibit protein synthesis

• Proteases modify host cell membranes (Candida albicans)

• Capsules prevent phagocytosis (Cryptococcus neoformans)

• Ergot alkaloids cause hallucinations

• Aflatoxin (carcinogenic, produced by Aspergillus)

• Mycotoxins (e.g., phalloidin, amanitin) are neurotoxic

Protozoa

• Cause symptoms by their presence and waste products

• Evade defenses by digesting cells, growing in phagocytes, or antigenic variation

• Examples: Giardia intestinalis, Toxoplasma gondii, Trypanosoma

Helminths

• Use host tissue for growth, causing cellular damage

• Produce large parasitic masses and waste products that cause symptoms

Algae

• Some produce neurotoxins (e.g., saxitoxin) causing paralytic shellfish poisoning

• Associated with red tides (dinoflagellate Alexandrium)

Portals of Exit

Pathogens leave the host through specific portals, often the same as the portals of entry:

• Respiratory tract: Coughing, sneezing

• Gastrointestinal tract: Feces, saliva

• Genitourinary tract: Urine, genital secretions

• Skin

• Blood: Biting arthropods, needles, syringes