Activation of the Innate Signaling Molecule MAVS by Bunyavirus Infection Upregulates the Adaptor Protein SARM1, Leading to Neuronal Death

Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 S. 4(th) Street, Hamilton, MT 59840, USA.
Immunity (Impact Factor: 21.56). 03/2013; 38(4). DOI: 10.1016/j.immuni.2013.02.013
Source: PubMed


La Crosse virus (LACV), a zoonotic Bunyavirus, is a major cause of pediatric viral encephalitis in the United States. A hallmark of neurological diseases caused by LACV and other encephalitic viruses is the induction of neuronal cell death. Innate immune responses have been implicated in neuronal damage, but no mechanism has been elucidated. By using in vitro studies in primary neurons and in vivo studies in mice, we have shown that LACV infection induced the RNA helicase, RIG-I, and mitochondrial antiviral signaling protein (MAVS) signaling pathway, resulting in upregulation of the sterile alpha and TIR-containing motif 1 (SARM1), an adaptor molecule that we found to be directly involved in neuronal damage. SARM1-mediated cell death was associated with induced oxidative stress response and mitochondrial damage. These studies provide an innate-immune signaling mechanism for virus-induced neuronal death and reveal potential targets for development of therapeutics to treat encephalitic viral infections.

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Available from: Piyali Mukherjee, Dec 18, 2015
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    • "Engineered SARM1 fragments induce cell death in primary neurons as well as immortalized cell lines (Gerdts et al., 2013Gerdts et al., , 2015), with the site of activation within the cell determining whether this leads to selective axon loss or cell death. Moreover, endogenous SARM1 promotes neuronal cell death in response to various insults, including mitochondrial poisons, oxygen-glucose deprivation, and neurotropic viruses (Kim et al., 2007; Mukherjee et al., 2013; Summers et al., 2014 ). This function is conserved in C. elegans: the SARM1 ortholog tir-1 promotes non-apoptotic developmental cell death, death triggered by anoxia, and motor neuron degeneration in an ALS model (Blum et al., 2012; Hayakawa et al., 2011; Vé riè pe et al., 2015). "
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    ABSTRACT: Wallerian axon degeneration is a form of programmed subcellular death that promotes axon breakdown in disease and injury. Active degeneration requires SARM1 and MAP kinases, including DLK, while the NAD+ synthetic enzyme NMNAT2 prevents degeneration. New studies reveal that these pathways cooperate in a locally mediated axon destruction program, with NAD+ metabolism playing a central role. Here, we review the biology of Wallerian-type axon degeneration and discuss the most recent findings, with special emphasis on critical signaling events and their potential as therapeutic targets for axonopathy.
    Preview · Article · Feb 2016 · Neuron
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    • "Recently, studies on mouse demonstrate that SARM1 contributes to T cell death, neuronal injury and cytokine production following infection (Hou et al., 2013; Lin et al., 2014; Panneerselvam et al., 2013). In addition, SARM1 mediates neuronal apoptosis following activating IPS-1 by virus infection (Mukherjee et al., 2013). "
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    ABSTRACT: Sterile alpha and Toll/IL-1R motif containing 1 (SARM1) negatively regulates TRIF-dependent TLR signaling in mammals. However, its immune function remains unclear in teleost. Here, a grass carp Ctenopharyngodon idella SARM1 (CiSARM1) gene and its two novel splice variants (CiSARM1s1 and CiSARM1s2) were identified. CiSARM1s1 and CiSARM1s2 are generated by intron retention mechanism, and they only retain N-terminal HEAT/armadillo motifs. In C. idella kidney (CIK) cells, CiSARM1 and CiSARM1s1 are located in mitochondria, whereas CiSARM1s2 distributes in the whole cell. All the three transcripts are ubiquitously expressed in 15 investigated tissues. They were responsive to GCRV in vivo and in vitro and to viral/bacterial PAMPs in vitro, implying they participate in both antiviral and antibacterial immune responses. By overexpression experiment, CiSARM1 and its two isoforms affected each other's expression in CIK cells. CiSARM1 inhibited GCRV-triggered IFN-I response by affecting the expressions of CiTRIF, CiMyD88, CiIPS-1, CiTRAF6, CiTBK1, CiIRF3 and CiIRF7 in TRIF-, MyD88- and IPS-1-dependent pathways; CiSARM1s1 and CiSARM1s2 inhibited GCRV-triggered IFN-I production through suppressing the expressions of CiMyD88, CiIPS-1, CiTRAF6, CiTBK1, CiIRF3 and CiIRF7 in MyD88- and IPS-1-dependent pathways. Moreover, antiviral activity assays indicated that all the three genes promote GCRV-induced cell death. These results were further verified by RNAi experiments. Thus, CiSARM1 and its two splice variants jointly prevent excessive activation of the host immune response. These findings uncover the regulatory mechanisms of SARM1 in teleost and lay a foundation for further functional and evolutionary researches on SARM1.
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    • "SARM1 functions as a negative regulator of TRIF-dependent TLR signaling and inhibits MAPK activation [21]. Upregulation of SARM1 has been reported in bunyavirus infection leading to neuronal death associated with oxidative stress response and mitochondrial damage [22]. Therefore, role of this adaptor in HEV super-infection of chronic HBV infection warrants further investigation. "
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