Microbial Mechanisms of Pathogenicity Notes

Pathogenicity and Virulence

• Pathogenicity: The ability to cause disease.
• Virulence: The extent of pathogenicity; how much disease can be caused.
• Many factors determining a microbe's pathogenicity are unclear.
• Disease occurs when microbes overpower the host's defenses.
• Microbes need to:
  • Gain entry.
  • Adhere.
  • Penetrate.
  • Cause damage.

Disease Mechanisms

• Pathogens can damage hosts through:
  • Direct damage in the immediate area.
  • Growth and multiplication, clogging cells and passageways.
  • Release of toxins that spread through blood and lymph to areas far from the original site of invasion.
  • Hypersensitivity reactions, where the host's immune response causes damage.

Entry into the Host - Portals of Entry

• Pathogens must enter the host to cause disease through specific areas called portals of entry.

Entry of a Microbe

• Microbes need to adhere, penetrate, and cause damage.
• Gain access via a preferred portal of entry.
  • Example: Streptococcus pneumoniae should be inhaled, not through ingestion
  • Example: Smallpox should be introduced via the respiratory tract, not the vein
• Portals of Entry:
  • Mucous membranes
    • Respiratory tract
    • Gastrointestinal tract
    • Urogenital tract
    • Conjunctiva
  • Skin (though rare due to its toughness)
    • Example: Necator americanus (hookworm)
  • Parenteral route
    • Puncture or injection

Portals of Entry - Details

• Mucous Membranes
  • Respiratory tract: Easiest and most frequent portal of entry.
    • Inhaled droplets or dust particles containing microorganisms.
    • Examples: common cold, tuberculosis, pneumonia, influenza, measles.
  • Gastrointestinal tract: Microorganisms in food, water, or contaminated fingers.
    • Most are destroyed by acid and enzymes in the stomach, but survivors can cause disease.
    • Examples: polio, hepatitis A, typhoid fever, amoebic dysentery, cholera.
  • Genitourinary tract: Sexually transmitted diseases.
    • Examples: HIV, genital warts, herpes, syphilis, gonorrhea.
• Skin
  • Some microorganisms enter through openings (hair follicles, sweat glands).
  • Hookworm larvae (Necator americanus) bore through intact skin.
  • Some fungi grow on the keratin of skin or infect the skin itself.
• Parenteral Route
  • Deposition of microorganisms directly into tissues beneath the skin or mucous membranes.
  • Examples: punctures, injections, bites, cuts, wounds, surgery, splitting due to swelling or drying.

Portals/Numbers of Microbes

• Preferred Portal:
  • Not all microbes cause disease when they have entered the body.
  • Salmonella typhi causes disease when ingested, but not when placed on skin.
  • Inhaled Streptococcus can cause pneumonia, but if swallowed, it doesn't.
  • Some microorganisms have more than one portal of entry (Yersinia pestis).
• Number of Invading Microbes:
  • Virulence or potency of toxins is expressed as $LD_{50}$ (lethal dose for 50% of hosts).
  • Dose required to produce demonstrable infection is the $ID_{50}$ (infectious dose for 50% of hosts).

Adherence

• After entry, almost all pathogens attach themselves to host tissue.
• Adherence is often a necessary step in pathogenicity.
• Attachment occurs through binding of surface molecules on the pathogen (adhesins or ligands) to complementary surface molecules (receptors) on host cells.
• Adhesins/ligands are mostly glycoproteins or lipoproteins.
• Receptors are surface molecules on the host cell.

Adherence Mechanisms

• Adhesins/ligands bind to receptors on host cells to prevent being flushed off.
• Mechanisms to adhere and avoid host defenses:
  • Glycocalyx: Streptococcus mutans produces dextran (plaque).
  • Waxes: Mycobacteria
  • Fimbriae: Escherichia coli
  • M protein: Streptococcus pyogenes
• Cell wall components
  • M protein on Streptococcus pyogenes surface mediates attachment and helps resist phagocytosis.
  • Mycolic acids in Mycobacterium tuberculosis resists digestion by phagocytes

Key Traits of a Pathogen

• The ability to:
  1. Adhere to host surfaces and avoid being washed off.
  2. Avoid phagocytosis to prevent host defenses from destroying it.
  3. Penetrate the host and spread.
  4. Produce enzymes to spread, prevent host defenses, and cause damage at or near the site of infection.
  5. Produce toxins to cause damage at a distant site.

Penetration of Host Defenses

• Capsules:
  • Prevent phagocytosis and help with attachment (adherence).
  • Bacterial capsules help resist host defenses by impairing phagocytosis.
  • Phagocytic cells cannot adhere to the bacterium.
  • Antibodies to the capsule can be made, facilitating destruction by phagocytosis.
  • Examples: Streptococcus pneumoniae, Klebsiella pneumoniae, Hemophilus influenzae, Bacillus anthracis, Yersinia pestis.

Penetration of Defenses (cont.) - Enzymes

• Extracellular enzymes (exoenzymes) produced by bacteria can aid in virulence.
  • Leukocidins:
    • Destroy neutrophils and leukocytes that are active in phagocytosis.
    • Examples: staphylococci and streptococci.
  • Hemolysins:
    • Bacterial enzymes that cause lysis of erythrocytes (red blood cells).
    • Examples: staphylococci, Clostridium perfringens, and streptococci.
    • Streptolysins are hemolysins produced by streptococci.
      • Streptolysin O is inactivated by oxygen.
      • Streptolysin S has an affinity for albumin; both also lyse white blood cells.

Hemolysins

• Alpha Hemolytic Streptococci - secrete hemolysins that cause the incomplete lysis or RBC’s
• Beta Hemolytic Streptococci - secrete hemolysins that cause the complete lysis of RBC’s

Penetration of Defenses (cont.) - Enzymes (continued)

• Coagulases:
  • Bacterial enzyme that coagulates fibrinogen in blood, causing clotting.
  • Clots may protect bacteria from phagocytosis and may be involved in walling off boils produced by staphylococci.
• Kinases:
  • Produced by bacteria to break down fibrin and dissolve clots formed by the body to isolate infections.
  • Fibrinolysin (streptokinase) is produced by Streptococcus pyogenes and injected to dissolve some types of blood clots in heart attack patients.

Penetration of Defenses (cont.) - Enzymes (continued)

• Hyaluronidase:
  • Secreted by some bacteria, including streptococci (and some clostridia involved in gas gangrene).
  • Hydrolyzes hyaluronic acid that holds together certain cells of the body, particularly in connective tissue.
  • May be involved in blackening of tissue in wounds.
  • Helps microorganisms spread from the initial site of infection.
• Collagenase:
  • Breaks down collagen, which forms connective tissue of muscles and other tissues.
  • Produced by species of Clostridium involved in gas gangrene.

Penetration of Defenses (cont.) - Other Bacterial Substances

• Necrotizing factors: Kill body cells.
• Hypothermic factors: Decrease body temperature.
• Lecithinase: Destroys plasma membranes.
• Protease: Break down proteins, particularly in muscle tissue.
• Siderophores: Scavenge iron from the host's body fluids.

Penetration of Defenses (cont.) - Penetration into Host Cells

• In some cases, attachment signals the host cell to allow the bacterium to enter the cell.
• The host cell cytoskeleton is responsible for the cytoplasmic movements, which bring the bacterium into the cell.
• Salmonella typhimurium and enteropathogenic E. coli produce invasins, surface proteins that cause rearrangement of actin filaments in the cell cytoskeleton to bring the bacterium into the cell.
• Once inside cells, some bacteria such as Shigella and Listeria species can use the actin to propel themselves through the cell and from one host cell to another.

Damage to Host Cells

• Direct damage: Can damage cells directly, such as when penetrating cell membranes or exiting one cell to enter another (reverse phagocytosis).
• Toxins: Poisonous substances produced by some microorganisms.
  • Exotoxins: Produced inside the bacterium and then released into the surrounding medium.
    • Three groups:
      • Cytotoxins: Kill host cells or affect their function.
      • Neurotoxins: Interfere with nerve impulses.
      • Enterotoxins: Affect cells in the gastrointestinal tract.
    • Antitoxins are antibodies produced by the body against exotoxins.
    • Toxoids are inactivated exotoxins injected into the body to produce immunity.

Exotoxins

• Mostly seen in Gram-positive bacteria.
• Most genes that code for exotoxins are located on plasmids or phages.

Damage to Host Cells (cont.) - Toxins (cont.)

• Endotoxins are part of the outer portion of the cell wall of Gram-negative bacteria
• Lipid A, the lipid portion of the LPS of the outer membrane, is the endotoxin.
• Endotoxins are lipopolysaccharides.
• Responses of the host to endotoxin can include:
  • Chills, fever, weakness, generalized aches, even shock and death (also can induce miscarriage).
  • Pyrogenic response (fever).
  • Shock - life-threatening loss of blood pressure; when caused by a Gram-negative organism, it's called septic shock (tumor necrosis factor is involved in the process).

Plasmids/Lysogeny

• Virulence factors can be carried on plasmids or lysogenic phages.
  • Plasmid-encoded: tetanospasmin, heat-labile enterotoxin, staphylococcal enterotoxin, and others.
  • Phage-encoded: lysogenic phages are incorporated in the bacterial cell’s chromosome.
• Changes in the characteristics of the cell are called lysogenic conversion.
  • Includes diphtheria toxin, botulinum neurotoxin, choleratoxin. These are not made unless the bacteria are infected with the bacteriophage (virus).