{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T06:54:58Z","timestamp":1777618498142,"version":"3.51.4"},"reference-count":62,"publisher":"American Society for Microbiology","issue":"18","license":[{"start":{"date-parts":[[2015,9,15]],"date-time":"2015-09-15T00:00:00Z","timestamp":1442275200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2015,9,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Myd88 signaling is critical to the control of numerous central nervous system (CNS) infections by promoting both innate and adaptive immune responses. Nevertheless, the extent to which Myd88 regulates type I interferon (IFN) versus proinflammatory factors and T cell function, as well as the anatomical site of action, varies extensively with the pathogen. CNS infection by neurotropic coronavirus with replication confined to the brain and spinal cord induces protective IFN-\u03b1\/\u03b2 via Myd88-independent activation of melanoma differentiation-associated gene 5 (MDA5). However, a contribution of Myd88-dependent signals to CNS pathogenesis has not been assessed. Infected Myd88<jats:sup>\u2212\/\u2212<\/jats:sup>mice failed to control virus, exhibited enhanced clinical disease coincident with increased demyelination, and succumbed to infection within 3 weeks. The induction of IFN-\u03b1\/\u03b2, as well as of proinflammatory cytokines and chemokines, was impaired early during infection. However, defects in both IFN-\u03b1\/\u03b2 and select proinflammatory factors were rapidly overcome prior to T cell recruitment. Myd88 deficiency also specifically blunted myeloid and CD4 T cell recruitment into the CNS without affecting CD8 T cells. Moreover, CD4 T cells but not CD8 T cells were impaired in IFN-\u03b3 production. Ineffective virus control indeed correlated most prominently with reduced antiviral IFN-\u03b3 in the CNS of Myd88<jats:sup>\u2212\/\u2212<\/jats:sup>mice. The results demonstrate a crucial role for Myd88 both in early induction of innate immune responses during coronavirus-induced encephalomyelitis and in specifically promoting protective CD4 T cell activation. In the absence of these responses, functional CD8 T cells are insufficient to control viral spread within the CNS, resulting in severe demyelination.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>During central nervous system (CNS) infections, signaling through the adaptor protein Myd88 promotes both innate and adaptive immune responses. The extent to which Myd88 regulates antiviral type I IFN, proinflammatory factors, adaptive immunity, and pathology is pathogen dependent. These results reveal that Myd88 protects from lethal neurotropic coronavirus-induced encephalomyelitis by accelerating but not enhancing the induction of IFN-\u03b1\/\u03b2, as well as by promoting peripheral activation and CNS accumulation of virus-specific CD4 T cells secreting IFN-\u03b3. By controlling both early innate immune responses and CD4 T cell-mediated antiviral IFN-\u03b3, Myd88 signaling limits the initial viral dissemination and is vital for T cell-mediated control of viral loads. Uncontrolled viral replication in the absence of Myd88 leads to severe demyelination and pathology despite overall reduced inflammatory responses. These data support a vital role of Myd88 signaling in protective antimicrobial functions in the CNS by promoting proinflammatory mediators and T cell-mediated IFN-\u03b3 production.<\/jats:p>","DOI":"10.1128\/jvi.01199-15","type":"journal-article","created":{"date-parts":[[2015,7,2]],"date-time":"2015-07-02T03:51:00Z","timestamp":1435809060000},"page":"9299-9312","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Myd88 Initiates Early Innate Immune Responses and Promotes CD4 T Cells during Coronavirus Encephalomyelitis"],"prefix":"10.1128","volume":"89","author":[{"given":"Niranjan","family":"Butchi","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parul","family":"Kapil","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shweta","family":"Puntambekar","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen A.","family":"Stohlman","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Hinton","sequence":"additional","affiliation":[{"name":"Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelia C.","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.022"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/v3060920"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2013.10.012"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2012.00201"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01026-10"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3108"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22375"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2007.02.009"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200737310"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62359-0"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.12.8604"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-19"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308057100"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01305-07"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000757"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.11.012"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02272-13"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-023770"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01794-07"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01199-08"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.5.2506-2514.2006"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1343"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.1.383-391.1997"},{"key":"e_1_3_2_25_2","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.4049\/jimmunol.162.3.1641","article-title":"IFN-gamma is required for viral clearance from central nervous system oligodendroglia","volume":"162","author":"Parra B","year":"1999","unstructured":"Parra B, Hinton DR, Marten NW, Bergmann CC, Lin MT, Yang CS, Stohlman SA. 1999. IFN-gamma is required for viral clearance from central nervous system oligodendroglia. J Immunol 162:1641\u20131647.","journal-title":"J Immunol"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.58.3.869-875.1986"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2014.02.012"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001984"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00051-10"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2006.01.027"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000602"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803557"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-269"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.4.2775-2778.2003"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050496"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-5728(90)90050-W"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.9.6481"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000937"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21222"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2013.07.019"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06797-11"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00200-11"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.6.3204"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20625"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.4.2278"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1979"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00016-10"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.4.1739-1750.2004"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.4.1547"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.10.6760"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31816fc975"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.11.7985"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00222"},{"key":"e_1_3_2_54_2","first-page":"744","article-title":"Sequential infection of glial cells by the murine hepatitis virus JHM strain (MHV-4) leads to a characteristic distribution of demyelination","volume":"66","author":"Wang FI","year":"1992","unstructured":"Wang FI, Hinton DR, Gilmore W, Trousdale MD, Fleming JO. 1992. Sequential infection of glial cells by the murine hepatitis virus JHM strain (MHV-4) leads to a characteristic distribution of demyelination. Lab Invest 66:744\u2013754.","journal-title":"Lab Invest"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.7.4091"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00202-11"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401192"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20121897"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12167"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201142052"},{"key":"e_1_3_2_61_2","first-page":"37","article-title":"Interaction of immune and central nervous systems: contribution of anti-viral Thy-1+ cells to demyelination induced by coronavirus JHM","volume":"5","author":"Fleming JO","year":"1993","unstructured":"Fleming JO, Wang FI, Trousdale MD, Hinton DR, Stohlman SA. 1993. Interaction of immune and central nervous systems: contribution of anti-viral Thy-1+ cells to demyelination induced by coronavirus JHM. Reg Immunol 5:37\u201343.","journal-title":"Reg Immunol"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2012.11.004"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001992"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.01199-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.01199-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T23:05:26Z","timestamp":1691795126000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.01199-15"}},"subtitle":[],"editor":[{"given":"S.","family":"Perlman","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2015,9,15]]},"references-count":62,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2015,9,15]]}},"alternative-id":["10.1128\/JVI.01199-15"],"URL":"https:\/\/doi.org\/10.1128\/jvi.01199-15","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9,15]]},"assertion":[{"value":"2015-05-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-06-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-08-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}