Host Evasion and Bacterial Numbers

Host Evasion Overview

• Pathogens must evade the immune system to cause disease.
• They also have to overcome limits to entry into the host.
• Main routes of entry are mucous membranes and skin.
• Deep penetration occurs through wounds and trauma.
• Mucous membranes include respiratory, GI, and genitourinary tracts.
• Skin acts as a barrier to absorption, unlike mucous membranes.
• Mucous membranes are more sensitive due to thinner layers and absorptive functions.
• Most bacteria species have a preferred route of entry often linked to receptors and immune evasion.
• Streptococcus pneumoniae prefers entry via the lungs, not ingestion.
• Mycobacterium tuberculosis also prefers entry via the lungs.

Importance of Bacterial Numbers

• The number of bacteria matters for causing disease.
• More bacteria increase the likelihood of survival through acidic environments like the stomach.
• Bacteria coordinate their activity to cause disease at higher numbers through quorum sensing.
• At a critical population density, bacteria release signals which prompt gene expression.
• This coordination leads to secretion of virulence factors.
• In low populations, bacteria do not secrete these factors.

Infectious Dose (ID50) and Lethal Dose (LD50)

• ID50: infectious dose required to cause disease symptoms in 50% of the population.
• LD50: lethal dose required to kill 50% of the population.
• Bacillus anthracis (anthrax) has different ID50 levels based on entry route.
  • Cutaneous: 10-50 spores.
  • Inhalation: 10,000-20,000 spores.
  • GI tract: 250,000-2,000,000 spores.
• Botulinum toxin has a low LD50 in mice, around 0.03 nanograms per kilogram.
  • Equivalent to roughly 1.5-2 nanograms for an adult human.
  • This equates to 0.00002 milligrams for an adult human.

Bacterial Adherence

• Bacteria must bind to host tissues or cells to interact with them.
• Pathogens use adhesions or ligands (surface proteins, glycoproteins, or glycolipids).
• These bind to specific receptors on host cells, similar to how viruses bind.
• Receptors on host cells serve normal functions, and bacteria exploit them for interaction, unless they are white blood cells.

Evading Host Defenses

• Capsules protect bacteria from the immune system unless antibodies are present.
• Removing capsule-related genes makes bacteria vulnerable to the immune system.
• Mycobacterium tuberculosis has waxy surface lipids that resist macrophage phagocytosis.
• Some pathogens invade immune cells and live inside them.
• Hiding inside white blood cells helps evade detection as the immune system look for external threats.

Bacterial Enzymes

• Bacteria secrete exoenzymes to cause damage.
• Coagulases clot fibrinogen to create fibrin, forming a protective clot around bacteria.
  • Staphylococcus aureus uses this mechanism.
  • Coagulase-positive Staph can do this, but coagulase-negative cannot.
• Kinases, like streptokinase produced by Streptococcus pyogenes, break down fibrin to prevent isolation.
• Hyaluronidase hydrolyzes hyaluronic acid, which holds cells together, allowing bacteria to infiltrate tissues.
  • Staphylococcus aureus does this, and the reaction contributes to tissue blackening.

Antigenic Variation

• Bacteria change surface proteins to evade immune responses.
• Neisseria gonorrhoeae uses pili for attachment.
• Through random genetic shifts, they can change or stop producing pili.
• This makes existing antibodies ineffective.

Invasions

• Invasions are proteins that trigger ruffling of the cell surface to allow bacteria to enter.
• Salmonella typhimurium produces invasion, inducing membrane ruffles to trap bacteria.
• Pathogenic E. coli also uses this mechanism.
• Once inside, bacteria use the host cell's cytoskeleton to move around.

Biofilms

• Biofilms are structured communities of bacteria encased in a matrix.
• Bacteria attach to surfaces and secrete exo-polysaccharides.
• Exo-polysaccharides is a sticky carbohydrate matrix that traps water and nutrients.
• Quorum sensing activates the production of exo-polysaccharides.
• Bacteria form towers within the biofilm, where they can differentiate, with some detaching and swimming off to form new colonies.
• Towers facilitate nutrient exchange due to increased surface area.
• Small molecules diffuse more quickly than the large ones that make up many antibiotics and antibodies, which renders treatments less effective.
• Biofilms protect bacteria from the host's immune system and antibiotics.
• They can form in various locations, such as catheters or lungs.
• A heart valve transplant is an example of a serious issue if infected, because biofilms are hard to remove.

Biofilms and Cystic Fibrosis

• Cystic fibrosis patients have impaired lung clearance, leading to bacterial colonization and biofilm formation.
• Bacteria become trapped, grow, divide, and form biofilms in the patient's lungs.
• A late stage infection leads to an inability to do gas exchange properly.
• Treatments have improved for CF patients, but antibiotics will struggle to penetrate, and breathing exercises can help break up the material.
• This leads to early death.

Causing Damage

• Bacteria compete for nutrients with the host cells.
• Siderophores trap metal ions like calcium, iron, and magnesium, depriving the host of essential minerals.
• Direct damage occurs through bacterial growth.
• Intracellular and extracellular growth damages tissue.
• Cell death, waste production, and physical multiplication lead to tissue damage.
• Staphylococcus skin infections cause damage through both specific factors and general growth.

Exotoxins vs. Endotoxins

• Specific toxins cause disease
• Exotoxins are secreted by living cells.
  • Clostridium botulinum is an example
  • These are proteins that are soluble and effective at low concentrations.
  • Based on the effect, they are divided into different groups such as neurotoxins, hepatotoxins, cytotoxins etc
  • Antitoxins (antibodies) can neutralize exotoxins.
• Endotoxins
  • Antitoxins also act against individual toxins.
  • Anti-toxins are used instead of antibiotics because they act against the toxins secreted by exosins.
  • LPS in the body can not make humans as sick as bacteria does

Types of Exotoxins

• AB toxins
  • AB toxins have an active (A) domain and a binding (B) domain.
  • The Clostridium toxin is an AV bacteria
  • Binding domain allows entry into cells.
  • Active domain has a specific function.
  • Genotoxins are a type of AV toxin that effects and damages the DNA.
  • Causes double-strand breaks in DNA.
  • Inability to perform gene expression will occur
  • The bacteria needs to produce these proteins for survival but can not produce the desired result of protein production.
  • Helicobacter pylori, grown in the stomach is an example
• Toxins that Disrupt Membranes
  • Disrupting membranes causes cell lysis.
  • Bacteria create channel proteins
  • Leads to everything leaking out of the cell
  • Causes loss in proteins, and nutrients with protein channels that affect white blood cells etc.
• Super Antigens
  • They create very strong immune responses:
  • Stimulate T cell proliferation.
  • Increased cytokine production.
  • This can cause problems, side effects and lead to death, if overstimulated
  • The immune system causes severe reactions
  • Food poisoning is an example of this.

Endotoxins

• Endotoxins are part of the bacterial cell and released upon cell death
• Lipopolysaccharide (LPS)
  • Component of the outer membrane of gram-negative bacteria.
  • Toxic in humans when released.
  • Can stimulate white blood cells to release cytokines, leading to a cytokine storm (this will be talked about in immunology).
• LPS do not make people sick unless the bacteria die, which causes a breakdown of the LPS component for athletes which then causes disease