Viral infection: an evolving insight into the signal transduction pathways responsible for the innate immune response

Abstract

The innate immune response is initiated by the interaction of stereotypical pathogen components with genetically conserved receptors for extracytosolic pathogen-associated molecular patterns (PAMPs) or intracytosolic nucleic acids. In multicellular organisms, this interaction typically clusters signal transduction molecules and leads to their activations, thereby initiating signals that activate innate immune effector mechanisms to protect the host. In some cases programmed cell death-a fundamental form of innate immunity-is initiated in response to genotoxic or biochemical stress that is associated with viral infection. In this paper we will summarize innate immune mechanisms that are relevant to viral pathogenesis and outline the continuing evolution of viral mechanisms that suppress the innate immunity in mammalian hosts. These mechanisms of viral innate immune evasion provide significant insight into the pathways of the antiviral innate immune response of many organisms. Examples of relevant mammalian innate immune defenses host defenses include signaling to interferon and cytokine response pathways as well as signaling to the inflammasome. Understanding which viral innate immune evasion mechanisms are linked to pathogenesis may translate into therapies and vaccines that are truly effective in eliminating the morbidity and mortality associated with viral infections in individuals.

Figure 1

Signaling by the innate immune system that is inhibited by several viral proteins. This model depicts the salient features of TLR-induced NF-κB and IRF3 induction. Several poxviral proteins N1, C6, A14 A46, and A52 inhibit the activation of NF-κB and/or IRF3 signaling pathways, by interacting with and inhibiting the activity of the classical IKK complex (IKKα/β/γ) as well as the nonclassical IKKε/TBK1 complex. HCV protein NS5A inhibits TIR signaling by MyD88, its NS3/4A digests MAVS to inhibit RLR signaling, and its core protein inhibits Jak/Stat signaling. Finally, HIV Vif and Vpr degrade IRF3.

Figure 2

Viral proteins inhibit nucleic acid receptors of the intracytosolic innate immune response. Viruses inhibit each of the two signals that initiate the inflammasome activation process. The first signal—IL-1β and/or IL-18 binding and activation of the TLR/IL-1β receptor pathway—is inhibited by soluble IL-1β and IL-18 (from VACV); downstream, inhibitors of signaling to NF-κB (from VACV or HCV) repeatedly target this important antiviral pathway that optimally requires NF-κB translocation leading to the production of pro-IL-1β and pro-IL-18. Second, the inflammasome processes these pro-IL-1β and pro-IL-18 proteins via caspase-1 that is itself processed upon clustering mediated at the NLRP3 inflammasome upon detection of intracytosolic pathogens. This leads to IL-1β and IL-18 production and release that activates the IL-1β/IL-18 pathway in an autocrine manner, as well as the innate and adaptive immune response. Inflammasome activation is inhibited by myxoma virus M013, measles viruses V protein, and KSHV vNLR. Finally signaling to IRF3 by intracytosolic DNA or RNA is inhibited at the level of MAVS by HCV's NS3/4A and at the level of TBK1 by VACV C6 and N1 (Figure 1).