STING is required for host defense against neuropathological West Nile virus infection

Abstract

West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that ST imulator of IN terferon G ene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro . However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo , STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.

Innate Immune DNA Sensing of Flaviviruses

“…Most recently, the Gale group studied the role of STING played in controlling WNV infection using a murine model of infection [130]. First, they validated the observation that STING KO mice have higher morbidity and mortality rates when compared with WT mice during WNV infection [131].…”

“…West Nile fever develops in approximately one-fourth of the infected patients, with a wide range of clinical manifestations. Although WNV infection can be contained outside the CNS, it is still capable of evading the innate immune responses and invade the CNS to cause encephalitis, encephalomyelitis, or even death in some patient populations [5,[126][127][128][129][130].…”

The continued threat of emerging flaviviruses

“…Binding of single-and/or double-stranded viral RNA results in the downstream activation of adaptor molecules, such as mitochondrial antiviral signalling protein, MyD88, TIR domain-containing adaptor inducing IFN-β (TRIF), nuclear translocation of interferon (IFN) regulatory transcription factors 3 and 7 (IRF3 and IRF7) and NF-κB, which induce expression of type I and III IFNs. The cytoplasmic adaptor molecule stimulator of IFN genes (STING) also participates in immune responses generated against flaviviruses in the context of RIG-I recognition, by acting as a scaffold for the recruitment of signalling components required for IRF3 activation and IFN induction [82][83][84] . Type I interferons (IFN-α and β) promote an antiviral state by inducing IFN-stimulated genes (ISGs) with direct and indirect antiviral functions (reviewed in refs.…”

Amino acid 159 of the envelope protein affects viral replication and T-cell infiltration by West Nile virus in intracranial infection

“…Aberrant T-cell infiltration in brain was reported to be linked to the pathogenesis of WNV infection 23 . Amino acid 159 of the E protein may thus modulate T-cell infiltration and the immunopathogenic/immunoprotective balance in the brain during WNV infection.…”