The Innate Immune Response Early Defense Against Pathogens

When a virus infects an immunologically nai've host, one might expect that initially the odds are in favor of the virus. After all, most viruses have relatively short replication cycles, resulting in the rapid release of hundreds of new virions from a single cell. While the body immediately starts mounting specific antibody and cellular immune responses, it takes time for enough virus-specific B and T cells to accumulate in high enough numbers (even locally) to destroy infected cells, and to prevent the infection from spreading to other host cells and tissues. The innate immune response, one of the most primitive and ancient arms of the immune system, plays a critical role in slowing the spread of virus at very early times after infection. This innate response buys the host the critical time it needs to develop the more specific adaptive immune response to control the infection (Fig. 7.1).

Local Immune Response

Fig. 7.1 Schematic representation showing differences in the intensity and time of appearance of local versus systemic immunity against a typical virus infection in mice. IFN = interferon. (Figure courtesy of DC Bloom.)

4 5 6 7 8 9 Days post infection

4 5 6 7 8 9 Days post infection

10 11

Fig. 7.1 Schematic representation showing differences in the intensity and time of appearance of local versus systemic immunity against a typical virus infection in mice. IFN = interferon. (Figure courtesy of DC Bloom.)

Toll-like receptors

Elements of the innate immune response were first identified in Drosophila mutants (Toll) that were observed to be especially susceptible to fungal infections. These mutants lacked a key protein that has since been shown to be involved in cell-signaling response that promotes a nonspecific antifungal response. Years later a mouse strain that was particularly susceptible to gram-negative bacterial infections was found to lack a receptor protein that was related to the Drosophila protein. In normal mice, when this receptor protein encounters LPS it initiates a cell-signaling response that causes a nonspecific inflammatory process. This inflammatory process alters the local cellular environment in a manner that slows down bacterial growth, until an antigen-specific immune response has been mounted. The LPS-specific mouse receptor was termed "toll-like" receptor (TLR) after the name of the original Drosophila mutant.

It is now known that vertebrates possess a number of different TLRs (at least 10 in humans) that bind to different types of molecules that are associated with bacterial, fungal, viral, and protozoan pathogens. TLR3 and TLR9 play a particularly important role in the innate antiviral defense; for example, TLR3 recognizes and binds to dsRNA, which is formed during the replication cycles of many viruses (RNA and DNA viruses alike).

Once TLRs are activated they activate adaptor proteins which in turn induce proinflammatory cytokines. Each of the TLRs induces specific pathways through the activation of different adaptor proteins. For example, TLR3 (activated by dsRNA) induces type 1 interferons, described in Chapter 8, below. Interestingly, in addition to the antiviral effects mediated by the interferon and inflammatory responses induced by the specific TLRs, the cytokines induced by the innate immune response also play a key role in helping to directly activate and augment the development of specific cellular and humoral immune responses. For example in response to LPS activation, TRL4 produces cytokines that specifically activate helper T cells that have been stimulated by specific antigens. Moreover, the type of cytokines produced by TLR innate responses are now believed to be an important determinant of the type of helper T response that is mediated in response to a given pathogen. As discussed below, the selectivity of the T-helper response plays a critical role in dictating whether an antiviral response is primarily humoral or cellular; a process that no doubt has helped drive viral evolution.

Defensins

Another recently discovered component of innate immunity is mediated by cellular proteins known collectively as defensins. These small (30—50 amino acid) proteins are secreted by a number of cells of the respiratory and gastrointestinal systems and bind to many pathogens including bacteria, fungi, and some viruses. Such binding enhances elimination of bacteria and fungi. Defensins have been shown to interfere with the entry of influenza virus and HIV into human cells by cross-linking cellular membrane proteins. This cross-linking blocks the virus-induced clearance of cellular membrane proteins from the region juxtaposed to the viral envelope, thus blocking membrane fusion (see Fig. 6.3b for an illustration of the normal process of membrane fusion).

Like TLRs, defensins also enhance the stimulation of both cellular and humoral immunity. In addition, defensins appear to play a role in helping generate immune responses to tumor cells in the host. This is further illustration of the complex interactions between the different arms of the immune system and the continuing evolution of components of these arms towards cooperative interactions.

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