Sindbis virus (SINV) infection of neurons in the brain and spinal cord in mice provides a model system for investigating recovery from encephalomyelitis and antibody-mediated clearance of virus from the central nervous system (CNS). To determine the roles of IgM and IgG in recovery, we compared the responses of immunoglobulin-deficient activation-induced adenosine deaminase-deficient (AID^−/−), secretory IgM-deficient (sIgM^−/−), and AID^−/− sIgM^−/− double-knockout (DKO) mice with those of wild-type (WT) C57BL/6 mice for disease, clearance of infectious virus and viral RNA from brain and spinal cord, antibody responses, and B cell infiltration into the CNS. Because AID is essential for immunoglobulin class switch recombination and somatic hypermutation, AID^−/− mice produce only germ line IgM, while sIgM^−/− mice secrete IgG but no IgM and DKO mice produce no secreted immunoglobulin. After intracerebral infection with the TE strain of SINV, most mice recovered. Development of neurologic disease occurred slightly later in sIgM^−/− mice, but disease severity, weight loss, and survival were similar between the groups. AID^−/− mice produced high levels of SINV-specific IgM, while sIgM^−/− mice produced no IgM and high levels of IgG2a compared to WT mice. All mice cleared infectious virus from the spinal cord, but DKO mice failed to clear infectious virus from brain and had higher levels of viral RNA in the CNS late after infection. The numbers of infected cells and the amount of cell death in brain were comparable. We conclude that antibody is required and that either germ line IgM or IgG is sufficient for clearance of virus from the CNS.

IMPORTANCE Mosquito-borne alphaviruses that infect neurons can cause fatal encephalomyelitis. Recovery requires a mechanism for the immune system to clear virus from infected neurons without harming the infected cells. Antiviral antibody has previously been shown to be a noncytolytic means for alphavirus clearance. Antibody-secreting cells enter the nervous system after infection and produce antiviral IgM before IgG. Clinical studies of human viral encephalomyelitis suggest that prompt production of IgM is associated with recovery, but it was not known whether IgM is effective for clearance. Our studies used mice deficient in production of IgM, IgG, or both to characterize the antibody necessary for alphavirus clearance. All mice developed similar signs of neurologic disease and recovered from infection. Antibody was necessary for virus clearance from the brain, and either early germ line IgM or IgG was sufficient. These studies support the clinical observation that prompt production of antiviral antibody is a determinant of outcome.

小鼠大脑和脊髓中神经元的辛德比斯病毒（SINV）感染提供了一个模型系统，用于研究从脑脊髓炎的恢复以及抗体介导的病毒从中枢神经系统（CNS）的清除。为了确定IgM和IgG在恢复中的作用，我们比较了免疫球蛋白缺陷激活诱导的腺苷脱氨酶缺陷（AID ^-/-），分泌型IgM缺陷（sIgM ^-/-）和AID ^-/- sIgM的响应^-/-双敲除（DKO）小鼠与野生型（WT）C57BL / 6小鼠的疾病，从脑和脊髓清除传染性病毒和病毒RNA，抗体反应以及B细胞向CNS的浸润。由于AID对于免疫球蛋白类别开关重组和体细胞超突变至关重要，因此AID ^-/-小鼠仅产生种系IgM，而sIgM ^-/-小鼠分泌IgG，而IgM和DKO小鼠则不分泌免疫球蛋白。在脑内感染了SINV的TE株后，大多数小鼠得以康复。在sIgM ^-/-小鼠中，神经系统疾病的发生稍晚一些，但两组之间疾病的严重程度，体重减轻和存活率相似。AID ^-/-小鼠产生高水平的SINV特异性IgM，而sIgM与WT小鼠相比，^-/-小鼠不产生IgM和高水平的IgG2a。所有小鼠均从脊髓清除了感染性病毒，但是DKO小鼠未能从大脑清除感染性病毒，并且感染后中枢神经系统中的病毒RNA含量较高。大脑中被感染细胞的数量和细胞死亡的数量是可比的。我们得出结论，需要抗体，并且种系IgM或IgG足以从CNS中清除病毒。

重要性感染神经元的蚊媒甲病毒可导致致命性脑脊髓炎。康复需要一种免疫系统从受感染的神经元清除病毒而不损害受感染细胞的机制。先前已显示抗病毒抗体是清除α病毒的非细胞溶解手段。分泌抗体的细胞在感染后进入神经系统，并在IgG之前产生抗病毒IgM。人类病毒性脑脊髓炎的临床研究表明，IgM的迅速产生与恢复有关，但尚不清楚IgM是否对清除有效。我们的研究使用了缺乏IgM和/或IgG产生的小鼠来表征清除甲型病毒所需的抗体。所有小鼠均出现类似的神经系统疾病迹象，并从感染中恢复过来。抗体对于从大脑清除病毒是必不可少的，而且早期种系IgM或IgG都足够。这些研究支持临床观察，即抗病毒抗体的迅速产生是结果的决定因素。