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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    • "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.
    Developmental & Comparative Immunology 09/2014; 48(1). DOI:10.1016/j.dci.2014.09.009 · 2.82 Impact Factor
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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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    ABSTRACT: Pathogenesis of hepatitis B virus (HBV) and hepatitis E virus (HEV) infection is as varied as they appear similar; while HBV causes an acute and/or chronic liver disease and hepatocellular carcinoma, HEV mostly causes an acute self-limiting disease. In both infections, host responses are crucial in disease establishment and/or virus clearance. In the wake of worsening prognosis described during HEV super-infection over chronic HBV hepatitis, we investigated the host responses by studying alterations in gene expression in liver cells (Huh-7 cell line) by transfection with HEV replicon only (HEV-only), HBV replicon only (HBV-only) and both HBV and HEV replicons (HBV+HEV). Virus replication was validated by strand-specific real-time RT-PCR for HEV and HBsAg ELISA of the culture supernatants for HBV. Indirect immunofluorescence for the respective viral proteins confirmed infection. Transcription profiling was carried out by RNA Sequencing (RNA-Seq) analysis of the poly-A enriched RNA from the transfected cells. Averages of 600 million bases within 5.6 million reads were sequenced in each sample and ∼15,800 genes were mapped with at least one or more reads. A total of 461 genes in HBV+HEV, 408 in HBV-only and 306 in HEV-only groups were differentially expressed as compared to mock transfection control by two folds (p<0.05) or more. Majority of the significant genes with altered expression clustered into immune-associated, signal transduction, and metabolic process categories. Differential gene expression of functionally important genes in these categories was also validated by real-time RT-PCR based relative gene-expression analysis. To our knowledge, this is the first report of in vitro replicon transfected RNA-Seq based transcriptome analysis to understand the host responses against HEV and HBV.
    PLoS ONE 02/2014; 9(2):e87835. DOI:10.1371/journal.pone.0087835 · 3.23 Impact Factor
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    • "Following West Nile virus infection, which invokes signaling through TLR pathways, SARM deficiency resulted in increased neuronal cell death [38]. In contrast, a zoonotic Bunyavirus, known as La Crosse virus, caused neuronal cell death mediated by SARM through mitochondrial damage [39]. SARM deficiency in the brains of another strain of sarm−/− mice resulted in decreased neuronal cell death following oxygen and glucose deprivation [40] or infection with Vesicular Stomatitis Virus [41]. "
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    ABSTRACT: Sterile alpha and armadillo-motif containing protein (SARM), a highly conserved and structurally unique member of the MyD88 family of Toll-like receptor adaptors, plays an important role in innate immunity signaling and apoptosis. Its exact mechanism of intracellular action remains unclear. Apoptosis is an ancient and ubiquitous process of programmed cell death that results in disruption of the nuclear lamina and, ultimately, dismantling of the nucleus. In addition to supporting the nuclear membrane, lamins serve important roles in chromatin organization, epigenetic regulation, transcription, nuclear transport, and mitosis. Mutations and other damage that destabilize nuclear lamins (laminopathies) underlie a number of intractable human diseases. Here, we report that SARM translocates to the nucleus of human embryonic kidney cells by using its amino-terminal Armadillo repeat region. Within the nucleus, SARM forms a previously unreported lattice akin to the nuclear lamina scaffold. Moreover, we show that SARM protects lamins from apoptotic degradation and reduces internucleosomal DNA fragmentation in response to signaling induced by the proinflammatory cytokine Tumor Necrosis Factor alpha. These findings indicate an important link between the innate immunity adaptor SARM and stabilization of nuclear lamins during inflammation-driven apoptosis in human cells.
    PLoS ONE 07/2013; 8(7):e70994. DOI:10.1371/journal.pone.0070994 · 3.23 Impact Factor
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