Chapter 11 : Innate Immunity and Viral Infections

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This chapter reviews the current understanding of the induction and function of innate immune responses to viral infections. The focus is on the characteristics unique to or best characterized in the context of viral rather than nonviral infections. This chapter is organized into six sections. The first reviews the literature on induction of innate cytokine proteins during in vivo infections. The second presents the known molecular pathways to cytokine induction. The third is an overview of biochemical pathways activated by key innate cytokines. The last three sections integrate this information to examine functions of innate cytokines in regulating endogenous immune responses, the accessing of innate cytokines by adaptive immune responses, and the contributions of innate cytokines to viral pathogenesis. The ability of IL-6 to induce secretion of glucocorticoids (GCs) and therefore limit the extent of the pathologic inflammatory reactions, as demonstrated in mice infected with murine cytomegalovirus (MCMV), may contribute to such a protective effect. In MCMV infections, MIP-1α is required for induction of an early natural killer (NK)-cell infiltration into livers. It is now clear that systemic proinflammatory cytokines can be part of acute primary responses to some viruses and are likely to contribute to disease during adaptive responses to a number of viral infections.

Citation: Biron C, Dalod M, Salazar-Mather T. 2002. Innate Immunity and Viral Infections, p 139-160. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch11
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Figure 1

Distinguishing features of general pathways of innate to adaptive immune responses during infections with viruses, bacteria and intracellular protozoa, and parasites. Initial host cytokine responses to infectious agents are induced as a result of recognition, by specific receptors expressed in or on host cells, of unique microbial structures. Many viral infections induce innate cytokine responses overlapping with those seen during infections with bacteria or intracellular protozoa. These include IL-12 and NK-cell IFN- production, responses important for promoting downstream Th1-type responses with CD4 T-cell IFN- production. Responses to viruses can have dominant early IFN-/ production induced by unique viral products. This response is associated with NK cell cytotoxicity but not IFN- production. There are prominent downstream CD8 T-cell responses including IFN- production and cytotoxic T-lymphocyte (CTL) function during many viral infections. Challenges with certain organisms of the viral, bacterial, or protozoan parasite classes also induce the proinflammatory cytokine cascade including TNF. Responses to extracellular parasites fail to elicit an early IL-12 production and are linked to Th2 responses with CD4 T-cell IL-4 and IL-5 production. The patterns are idealized, and there can be overlap. Ig, immunoglobulin. Adapted from Biron and Sen, 2001.

Citation: Biron C, Dalod M, Salazar-Mather T. 2002. Innate Immunity and Viral Infections, p 139-160. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch11
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Figure 2

Simplified model of the pathways for signaling through the IFN-/ and IFN- receptors to reach major target responses. There are specific heterodimeric receptors for these cytokines. These are linked to particular but overlapping kinases and STAT molecules to transmit the signal from cytokine exposure to the nucleus of the cell. IFN-/ are particularly effective at activating a number of well-characterized biochemical pathways blocking viral replication. These include the 2-5(A) synthetase /RNase L system, ADAR, and Mx proteins. A variety of immunoregulatory effects also appear to be preferentially elicited in response to IFN-/ compared to IFN-. These include up-regulation of other IFN-/ genes. IFN- appears to be particularly effective at inducing NOS2 and a family of GTPases with antimicrobial functions. It also has unique function for promoting antigen-processing and presentation pathways to both class I and class II MHC molecules and inducing the expression of a variety of chemokines including Mig.

Citation: Biron C, Dalod M, Salazar-Mather T. 2002. Innate Immunity and Viral Infections, p 139-160. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch11
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Figure 3

Chemokine-to-cytokine-to-chemokine cascade using innate NK-cell responses to direct localization of downstream adaptive responses. The model is based on studies of MCMV infections in livers. In the first step, NK cells are activated, in response to IL-12, to produce IFN- in a variety of host compartments. This production subsides rapidly in the periphery. In the second step, the expression of the chemokine MIP-1 is induced in response to viral challenge signals in the liver and promotes the recruitment of NK cells from the blood to the liver. In the third step, NK cells surround and sequester MCMV-infected cells, forming distinctive clusters of inflammatory foci. These events also serve to localize and sustain the production of IFN-. In the fourth step, there is induction of the -inducible chemokine Mig in response to localized production of IFN-. In the last step, Mig may be involved in the downstream recruitment of activated T cells into liver.

Citation: Biron C, Dalod M, Salazar-Mather T. 2002. Innate Immunity and Viral Infections, p 139-160. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch11
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Table 1

In vivo induction of innate cytokine protein expression early during viral infections.

Citation: Biron C, Dalod M, Salazar-Mather T. 2002. Innate Immunity and Viral Infections, p 139-160. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch11

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