STAT activation during viral infection in vivo: where's the interferon?

Abstract

In this issue of Cell Host & Microbe, O'Gorman et al. (2010) identify a key role for early TLR2-mediated IL-6 production and STAT3 activation in generating protective immunity against poxviruses. These findings highlight the importance of early inflammatory cytokine production in antiviral defense and have implications for enhancing vaccination efficacy.

Figure 1. Role of cytokines and STATs in antiviral responses

(A) Viral infection of cells leads to recognition and signaling by endosomal and cytoplasmic receptors such as TLRs and RLRs, with downstream induction of IFN and cytokine production. Type I IFNs activate their cognate IFNAR receptor in an autocrine, paracrine and possibly systemic manner. IFNAR signaling leads to activation of the STAT1-STAT2-IRF9-containing ISGF3 complex that binds to ISRE DNA elements and induces expression of IFN target genes that are important for an antiviral state and innate amd acquired immune responses. The role of other cytokines induced in the earliest stages of viral infection was not well appreciated. (B) IFNs were previously shown to play an important role in host defense against vaccinia virus. The current study shows that vaccinia also activates TLR2, which typically resides in plasma membranes, leading to production of IL-6 and downstream STAT3 activation. TLR2 and early IL-6-STAT3 signaling are important for generating protective antibody-mediated immunity against vaccinia virus in mice.