Abstract
Antiviral defense in the liver during acute infection with the hepatotropic virus murine cytomegalovirus (MCMV) involves complex cytokine and cellular interactions. However, the mechanism of viral sensing in the liver that promotes these cytokine and cellular responses has remained unclear. Studies here were undertaken to investigate the role of nucleic acid-sensing Toll-like receptors (TLRs) in initiating antiviral immunity in the liver during infection with MCMV. We examined the host response of UNC93B1 mutant mice, which do not signal properly through TLR3, TLR7 and TLR9, to acute MCMV infection to determine whether liver antiviral defense depends on signaling through these molecules. Infection of UNC93B1 mutant mice revealed reduced production of systemic and liver proinflammatory cytokines including IFN-α, IFN-γ, IL-12 and TNF-α when compared to wild-type. UNC93B1 deficiency also contributed to a transient hepatitis later in acute infection, evidenced by augmented liver pathology and elevated systemic alanine aminotransferase levels. Moreover, viral clearance was impaired in UNC93B1 mutant mice, despite intact virus-specific CD8+ T cell responses in the liver. Altogether, these results suggest a combined role for nucleic acid-sensing TLRs in promoting early liver antiviral defense during MCMV infection.
Highlights
Initiation of inflammation following infection requires recognition of the invading microbe by innate immune pattern recognition receptors (PRRs) that signal in response to pathogen-associated molecular patterns (PAMPs)
TLR3 responses require signaling through the adaptor molecule Toll/IL-1R domain-containing adapter-inducing interferon-b (TRIF), while TLR7 and TLR9 are dependent on the adaptor molecule myeloid differentiation primary response gene 88 (MyD88) to activate transcription factors and induce gene transcription [1,12,13,14]
Considering the potential of endosomal Toll-like receptors (TLRs) signals to induce proinflammatory cytokine expression, UNC93B1 deficient 3d mice were first assessed for systemic IFN-a, IFN-c, IL-12 and TNF-a production during early infection with a moderate (56104 PFU) dose of MCMV
Summary
Initiation of inflammation following infection requires recognition of the invading microbe by innate immune pattern recognition receptors (PRRs) that signal in response to pathogen-associated molecular patterns (PAMPs). Members of the Toll-like receptor (TLR) family of PRRs are transmembrane receptors that are expressed either on the cell surface or within the endosomal compartment and respond to a variety of PAMPs [1]. TLR3 responses require signaling through the adaptor molecule Toll/IL-1R domain-containing adapter-inducing interferon-b (TRIF), while TLR7 and TLR9 are dependent on the adaptor molecule myeloid differentiation primary response gene 88 (MyD88) to activate transcription factors and induce gene transcription [1,12,13,14]
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