Gut dysbiosis and neuroimmune responses to brain infection with Theiler's murine encephalomyelitis virus

Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4 + and CD8 + T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4 + and CD8 + T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mic

Gut dysbiosis and neuroimmune responses to brain infection with Theiler’s murine encephalomyelitis virus

Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4+ and CD8+ T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4+ and CD8+T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mice.This study was supported by the “Red Española de Esclerosis Múltiple” (REEM, RD 12/0008, RD16/0015/0021, F.J.C.S., L.M., M.M., A.F., C.G.; RD12/0032, RD16/0015/0001 L.M.V., J.C.A.C.; RD12/0017, RD16/0015/0004 C.E., X.M.), sponsored by the Fondo de Investigación Sanitaria (FIS) of the Instituto Nacional de Salud Carlos III, and the Spanish Ministry of Economy and Competitiveness and by the FIS PI12-00239, PI13/205 and SAF2013-42784R. CE and RdC are supported by the “Miguel Servet” program (CP07/00146; CP13/00028; CB05/00137) of the FIS of the Ministry of Economy and Competitiveness of Spain.Peer reviewe