Innate Immunity to Extracellular Bacteria

The principal mechanisms of innate immunity to extracellular bacteria are complement activation, phagocytosis, and the inflammatory response.

• Complement activation. The major constituent of the cell walls of gram-positive bacteria, peptidoglycan, activates the alternative pathway of complement in the absence of antibody (see Chapter 12). LPS in the cell walls of gram-negative bacteria also activates complement by the alternative pathway. Bacteria that express mannose on their surface may bind mannose-binding lectin, which activates complement by the lectin pathway. One result of complement activation is opsonization and enhanced phagocytosis of the bacteria. In addition, the membrane attack complex lyses bacteria, especially Neisseria species that are particularly susceptible to lysis because of their thin cell walls, and complement byproducts stimulate inflammatory responses by recruiting and activating leukocytes.

• Activation of phagocytes and inflammation. Phagocytes use various surface receptors, including mannose receptors and scavenger receptors, to recognize extracellular bacteria, and they use Fc receptors and complement receptors to recognize bacteria opsonized with antibodies and complement proteins, respectively. Toll-like receptors (TLRs) and various cytoplas-mic sensors of microbial products participate in the activation of phagocytes as a result of encounter with microbes. Some of these receptors function mainly to promote the phagocytosis of the microbes (e.g., mannose receptors, scavenger receptors); others stimulate the microbicidal activities of the phagocytes (mainly TLRs); and yet others promote both phagocytosis and activation of the phagocytes (Fc and complement receptors) (see Chapter 4). In addition, dendritic cells and phagocytes that are activated by the microbes secrete cytokines, which induce leukocyte infiltration

TABLE 15-1 Examples of Pathogenic Microbes

Microbe

Examples of Human Diseases

Mechanisms of Pathogenicity

Extracellular bacteria

Staphylococcus aureus

Skin and soft tissue infections, lung abscess Systemic: toxic shock syndrome, food poisoning

Skin infections: acute inflammation induced by toxins; cell death caused by pore-forming toxins Systemic: enterotoxin ("superantigen"Hnduced cytokine production by T cells causing skin necrosis, shock, diarrhea

Streptococcus pyogenes (group A)

Pharyngitis

Skin infections: impetigo, erysipelas; cellulitis Systemic: scarlet fever

Acute inflammation induced by various toxins, e.g., streptolysin 0 damages cell membranes

Streptococcus pyogenes (pneumococcus)

Pneumonia, meningitis

Acute inflammation induced by cell wall constituents; pneumolysin is similar to streptolysin 0

Escherichia coli

Urinary tract infections, gastroenteritis, septic shock

Toxins act on intestinal epithelium chloride and water secretion; endotoxin (LPS) stimulates cytokine secretion by macrophages

Vibrio cholerae

Diarrhea (cholera)

Cholera toxin ADP ribosylates G protein subunit, which leads to increased cyclic AMP in intestinal epithelial cells and results in chloride secretion and water loss

Clostridium tetani

Tetanus

Tetanus toxin binds to the motor end plate at neuromuscular junctions and causes irreversible muscle contraction

Neisseria meningitidis (meningococcus)

Meningitis

Acute inflammation and systemic disease caused by potent endotoxin

Corynebacterium diphtheriae

Diphtheria

Diphtheria toxin ADP ribosylates elongation factor 2 and inhibits protein synthesis

Intracellular Bacteria

Mycobacteria

Tuberculosis, leprosy

Macrophage activation resulting in granulomatous inflammation and tissue destruction

Listeria monocytogenes

Listeriosis

Listeriolysin damages cell membranes

Legionella pneumophila

Legionnaires' disease

Cytotoxin lyses cells and causes lung injury and inflammation

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