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Tag words: innate immunity, natural immunity, antimicrobial defense, individual resistance, cellular defense, lysozyme, complement, normal flora, inflammation, inflammatory exudate, phagocytosis, opsonization, neutrophils, macrophages, oxidative burst, mast cells.









Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interest include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Immune Defense against Bacterial Pathogens: Innate Immunity (page 6)

(This chapter has 6 pages)

© Kenneth Todar, PhD

Toll-Like Receptors

Macrophages, dendritic cells, and epithelial cells have a set of transmembrane receptors that recognize different types of molecular determinants associated with both pathogenic and non pathogenic bacteria. Foremost among these are Toll-like receptors (TLRs).

In macrophages and dendritic cells, a pathogen is exposed to a TLR when it is engulfed within the phagosome membrane. Depending on which TLR it binds to will determine what the response will be. In this way, the TLRs identify the nature of the pathogen and turn on a response appropriate for dealing with it, generally by expression of various cytokines. Humans have 12 different TLRs, each of which specializes in a slightly different response to a pathogen (be it a bacterium, virus or protozoa).

For example TLR-2 binds to the peptidoglycan of Gram-positive bacteria such as streptococci and staphylococci; TLR-3 binds to double-stranded RNA; TLR-4 is activated by the lipopolysaccharide (endotoxin) in the outer membrane of Gram-negative such as Salmonella and E. coli; TLR-5 binds to the flagellin of motile bacteria like Listeria; TLR-6 forms a heterodimer with TLR-2 and responds to peptidoglycan and certain bacterial lipoproteins. TLR-7 binds to the single-stranded RNA genomes of viruses such as as influenza, mumps and measles.

In all these cases, binding of the pathogen to the TLR initiates a signaling pathway that leads to the activation of a transcription factor that turns on cytokine genes such as those for tumor necrosis factor-alpha (TNF-α), Interleukin-1 (IL-1), and chemotactic attractants that attract white blood cells to the site. These effector molecules lead to inflammation at the site. Even before these late events occur, the binding of Gram-positive bacteria to TLR-2 and Gram-negative bacteria to TLR-4 enhances phagocytosis and the fusion of the phagosomes with lysosomes.



Formation of the phagolysosome

The phagosome migrates into the cytoplasm and collides with lysosomal granules which explosively discharge their contents into the membrane-enclosed vesicle (phagosome). Membranes of the phagosome and lysosome actually fuse resulting in a digestive vacuole called the phagolysosome. Other  lysosomes will fuse with the phagolysosome. It is within the phagolysosome that killing and digestion of the engulfed microbe take place. Some of the microbicidal constituents of the lysosomes of neutrophils and macrophages include lysozyme, cationic proteins, various proteases and  hydrolyases and peroxidases. The killing processes are confined to the phagolysosome, such that none of the toxic substances and lethal activities of the phagocytes are turned against themselves.

Intracellular killing of organisms

After phagolysosome formation the first detectable effect on bacterial physiology, occurring within a few minutes after engulfment, is loss of viability (ability to reproduce). The exact mechanism is unknown. Inhibition of macromolecular synthesis occurs later. By 10 to 30 minutes after ingestion many pathogenic and nonpathogenic bacteria are killed followed by lysis and digestion of the bacteria by lysosomal enzymes. The microbicidal activities of phagocytes are complex and multifarious. Metabolic products, as well as lysosomal constituents, are responsible. These activities differ to some extent in neutrophils, monocytes and macrophages.

The microbicidal activities of phagocytes are usually divided into oxygen-dependent and oxygen-independent events.

Oxygen-independent activity

Lysosomal granules contain a variety of extremely basic proteins that strongly inhibit bacteria, yeasts and even some viruses. A few molecules of any one of these cationic proteins appear able to inactivate a bacterial cell by damage to their permeability barriers, but their exact modes of action are not known. The lysosomal granules of neutrophils contain lactoferrin, an extremely powerful iron-chelating protein, which withholds potential iron needed for bacterial growth. The pH of the phagolysosome may be as low as 4.0 due to accumulation of lactic acid, which is sufficiently acidic to prevent the growth of most pathogens. This acidic environment apparently optimizes the activity of many degradative lysosomal enzymes including lysozyme, glycosylases, phospholipases, and nucleases.

Oxygen-dependent activity

Liganding of Fc receptors (on neutrophils, monocytes or macrophages) and mannose receptors (on macrophages) increases their O2 uptake, called the respiratory burst. These receptors activate a membrane-bound NADPH oxidase that reduces O2 to O2- (superoxide). Superoxide can be reduced to OH. (hydroxyl radical) or dismutated to H2O2 (hydrogen peroxide) by superoxide dismutase. O2-, OH., and H2O2 are activated oxygen species that are potent oxidizing agents in biological systems which adversely affect a number of cellular structures including membranes and nucleic acids. Furthermore, at least in the case of neutrophils, these reactive oxygen intermediates can act in concert with a lysosomal enzyme called myeloperoxidase to function as the myeloperoxidase system, or MPO.

Myeloperoxidase is one of the lysosomal enzymes of neutrophils which is released into the phagocytic vacuole during fusion to form the phagolysosome. Myeloperoxidase uses H2O2 generated during the respiratory burst to catalyze halogenation (mainly chlorination) of phagocytosed microbes. Such halogenations are a potent mechanism for killing cells.

When the NADPH oxidase and myeloperoxidase systems are operating in concert, a series of reactions leading to lethal oxygenation and halogenation of engulfed microbes occurs.

Intracellular digestion

Dead microbes are rapidly degraded in phagolysosomes to low molecular-weight components. Various hydrolytic enzymes are involved including lysozyme, proteases, lipases, nucleases, and glycosylases. Neutrophils die and lyse after extended phagocytosis, killing, and digestion of bacterial cells. This makes up the characteristic properties of pus.

Macrophages egest digested debris and allow insertion of microbial antigenic components into the plasma membrane for presentation to lymphocytes in the immunological response.



Figure 7. Phagocytosis of Streptococcus pyogenes by a macrophage. CELLS alive!

Bacterial Defense Against Phagocytosis

Pathogenic bacteria have a variety of defenses against phagocytes. In fact, most successful pathogens have some mechanism(s) to contend with the phagocytic defenses of the host. These mechanisms will be discussed in detail later as part of the determinants of virulence of pathogens. However, in general, pathogens may resist phagocytosis by:

Evading phagocytes by growing in regions of the body which are not accessible to them

Avoiding engulfment by phagocytes after contact

Being able to kill phagocytes either before or after engulfment

Being able to survive inside of phagocytes (or other types of cells) and to persist as intracellular parasites




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