If wounding has occurred, the injury to blood vessels immediately triggers two protective enzyme cascades. One is the kinin system of plasma proteases that is triggered by tissue damage to generate several polypeptides that regulate blood pressure, coagulation, and pain. Although we will not fully describe its components here, one inflammatory mediator produced is the vasoactive peptide bradykinin, which increases vascular permeability to promote the influx of plasma proteins to the site of tissue injury. It also causes pain. Although unpleasant to the victim, pain draws attention to the problem and leads to immobilization of the affected part of the body, which helps to limit the spread of the infection.
The coagulation system is another protease cascade that is triggered in the blood after damage to blood vessels, although its full description is also outside our present scope. Its activation leads to the formation of a fibrin clot, whose normal role is to prevent blood loss. With regard to innate immunity, however, the clot physically encases the infectious microorganisms and prevents their entry into the bloodstream. The kinin and the coagulation cascades are also triggered by activated endothelial cells, and so they can have important roles in the inflammatory response to pathogens even if wounding or gross tissue injury has not occurred. Thus, within minutes of the penetration of tissues by a pathogen, the inflammatory response causes an influx of proteins and cells that may control the infection. Coagulation also forms a physical barrier in the form of blood clots to limit the spread of infection. Damage to tissues can occur in the absence of infection by microbes, such as physical trauma, ischemia, and metabolic or autoimmune disorders. In such sterile injury, many of the changes associated with infection, such as neutrophil recruitment, can also occur, in addition to activation of the kinin system and clot formation.
3-4 Toll-like receptors represent an ancient pathogen-recognition system.
Section 1-5 introduced pattern recognition receptors (PRRs), which function as sensors for pathogen-associated molecular patterns (PAMPs). Cytokine and chemokine production by macrophages is the result of signaling by these PRRs that is induced by a wide variety of pathogen components. The existence of these receptors was predicted by Charles Janeway, Jr., before mechanisms of innate recognition were known, based on the requirement for adjuvants in driving immune responses to purified antigens. Jules Hoffmann discovered the first example of such a receptor, for which he was awarded part of the 2011 Nobel Prize in Physiology or Medicine. The receptor protein Toll was identified earlier as a gene controlling the correct dorso-ventral patterning embryo of the fruitfly Drosophila melanogaster. But in 1996, Hoffmann discovered that in the adult fly, Toll signaling induces the expression of several host-defense mechanisms, including antimicrobial peptides such as drosomycin, and is critical for defense against Gram-positive bacteria and fungal pathogens.
Mutations in Drosophila Toll or in signaling proteins activated by Toll decreased the production of antimicrobial peptides and led to susceptibility of the adult fly
Fig. 3.9 Toll is required for antifungal responses in Drosophila melanogaster.
Flies that are deficient in the Toll receptor are dramatically more susceptible than wild-type flies to fungal infection. This is illustrated here by the uncontrolled hyphal growth (arrow) of the normally weak pathogen Aspergillus fumigatus in a Toll-deficient fly. Photo courtesy of J.A. Hoffmann.
MOVIE 3.5 to fungal infections (Fig. 3.9). Subsequently, homologs of Toll, called Toll-like receptors (TLRs), were found in other animals, including mammals, in which they are associated with resistance to viral, bacterial, and fungal infection. In plants, proteins with domains resembling the ligand-binding regions of TLR proteins are involved in the production of antimicrobial peptides, indicating the ancient association of these domains with this means of host defense.