OVERVIEW

• Bacteria produce toxins to break down host tissues and promote their own growth.
• Toxins facilitate invasion, release nutrients from host cells, and resist destruction by the immune system.
• Furthermore, as bacteria colonize the host, they trigger immune and inflammatory responses; in fact, the symptoms of many infections are the result of host immune response.

ENDOTOXINS

• Endotoxins are part of the cell wall of Gram-negative bacteria
  – The lipopolysaccharide endotoxin extends from the outer membrane
  – Three important regions of the endotoxin, starting at the cell membrane: Lipid A, Core polysaccharides, and the O-antigen
• They have relatively low toxicity
• Upon infection and endotoxin release, the Lipid A portion of the lipopolysaccharide interacts with Toll-Like Receptor 4 on macrophage surfaces and triggers cytokine release, potentially inciting cytokine storms.
• Indicate four important consequences:
  – Complement activation, which results in neutrophil chemotaxis and inflammation.
  – Cytokines IL-1 and IL-6 induce fever.
  – Tissue factor activation leads to coagulation.
  – Tumor necrosis factor, nitric oxide, and bradykinin induce hypotension (low blood pressure) via vasodilation.

• Recognize that, in acute, local conditions, these reactions can protect the host from infection; however, in large quantities, endotoxin can be fatal.
• Endotoxin is a major cause of septic shock.

EXOTOXINS

• Polypeptides secreted by both gram-positive and gram-negative bacteria.
• Many are dimeric in structure, with A and B subunits.
  – The A subunit is the toxic active Portion; the B subunit is the Binding portion that attaches to the host cell.
• Highly toxic, even in small quantities.
• Directly kill or alter host cell functions.

Mechanisms:

• ADP-ribosylation adds ADP-ribose to proteins in the host cell.
  – Diptheria toxin inhibits protein synthesis, leading to cell death; other toxins that act via ADP-ribosylation can hyperactivate protein synthesis.

• Increase Cyclic AMP
  – In the case of heat-labile enterotoxin, this results in fluid and electrolyte loss into the lumen of the gastrointestinal tract, which causes watery diarrhea.

• Proteases
  – Botulinum toxin is a neurotoxin that blocks acetylcholine release, producing paralysis.

• Super antigens
  – For example, Toxic Shock Syndrome toxin overstimulates T cells, triggering cytokine storms.

INFLAMMATION

Two main types of inflammation associated with bacterial pathogens:

• Purulent inflammation is characterized by neutrophilinfiltration and pus formation from liquefied tissues.
• Granulomatous inflammation, which occurs in chronic inflammation, is characterized by aggregates of macrophages and epithelioid cells, called granulomas, aka, tubercles (as in tuberculosis).

Recall that inflammation is characteristic of early immune responses:

• When controlled and acute, it has protective effects for the host: eradication of microbes and tissue healing.
• However, when uncontrolled or chronic, inflammatory and immune responses cause significant damage to the host.
  – For example, let’s consider two disease states that can occur after Group A streptococcus (Streptococcus pyogenes) infection.

1. Post-streptococcal glomerulonephritis:
   Neutrophil infiltration and deposition of antigen-antibody complexes in the basement membrane, which damage the renal filtration system. Be aware that the initial infection occurred elsewhere in the body, such as the skin or throat, leading to circulating immune complexes that became fixed to the glomeruli.
2. Rheumatic fever and heart disease, which develop in the weeks following untreated pharyngeal infection by Group A streptococcus. The host’s innate and adaptive responses lead to valve thickening, which can cause severe valvular stenosis. In the histological sample, we can see areas of calcification and fibrosis have damaged the valve tissue.