Research ArticleInnate Immunity

TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection

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Science Signaling  29 Oct 2019:
Vol. 12, Issue 605, eaaw1347
DOI: 10.1126/scisignal.aaw1347

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TLRing the antiviral response

Monocytes are critical orchestrators of immunity that both sense pathogens and produce cytokines. When comparing a range of RNA viruses, de Marcken et al. found that the human monocyte response to infection was virus specific and influenced by Toll-like receptor 7 (TLR7) and TLR8, which sense single-stranded RNA. Whereas TLR8 signaling stimulated monocytes to express type I interferon and cytokines involved in CD4+ T helper 1 (TH1) cell differentiation, TLR7 signaling promoted production of cytokines involved in TH17 cell differentiation. Only TLR7 activated monocyte Ca2+ flux, which suppressed antiviral interferon production. Thus, these receptors activate distinct pathways in monocytes, which can tailor the immune response to viral infection.

Abstract

Human blood CD14+ monocytes are bone marrow–derived white blood cells that sense and respond to pathogens. Although innate immune activation by RNA viruses preferentially occurs through intracellular RIG-I–like receptors, other nucleic acid recognition receptors, such as Toll-like receptors (TLRs), play a role in finely programming the final outcome of virus infection. Here, we dissected how human monocytes respond to infection with either Coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), or vesicular stomatitis (VSV) virus. We found that in monocytes, type I interferon (IFN) and cytokine responses to infection were RNA virus specific and differentially involved TLR7 and TLR8, which sense single-stranded RNA. These TLRs activated distinct signaling cascades in monocytes, which correlated with differences in the production of cytokines involved in the polarization of CD4+ T helper cells. Furthermore, we found that TLR7 signaling specifically increased expression of the transcription factor FOSL1, which reduced IL-27 and TNFα production by monocytes. TLR7, but not TLR8, activation of monocytes also stimulated Ca2+ flux that prevented type I IFN responses. Our work demonstrates that in human monocytes, TLR7 and TLR8 triggered different signaling pathways that contribute to distinct phenotypes during RNA virus infection. In addition, we defined individual targets within these pathways that promoted specific T helper and antiviral responses.

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