Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Department of Molecular and Comparative Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
Sci Transl Med. 2020 Apr 1;12(537). doi: 10.1126/scitranslmed.aax7799.
Infection with wild-type (WT) measles virus (MeV) is an important cause of childhood mortality that leads to lifelong protective immunity in survivors. WT MeV and the live-attenuated MeV used in the measles vaccine (LAMV) are antigenically similar, but the determinants of attenuation are unknown, and protective immunity induced by LAMV is less robust than that induced by WT MeV. To identify factors that contribute to these differences, we compared virologic and immunologic responses after respiratory infection of rhesus macaques with WT MeV or LAMV. In infected macaques, WT MeV replicated efficiently in B and T lymphocytes with spreading throughout lymphoid tissues resulting in prolonged persistence of viral RNA. In contrast, LAMV replicated efficiently in the respiratory tract but displayed limited spread to lymphoid tissue or peripheral blood mononuclear cells. In vitro, WT MeV and LAMV replicated similarly in macaque primary respiratory epithelial cells and human lymphocytes, but LAMV-infected lymphocytes produced little virus. Plasma concentrations of interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), CCL2, CCL11, CXCL9, and CXCL11 increased in macaques after WT MeV but not LAMV infection. WT MeV infection induced more protective neutralizing, hemagglutinin-specific antibodies and bone marrow plasma cells than did LAMV infection, although numbers of MeV-specific IFN-γ- and IL-4-producing T cells were comparable. Therefore, MeV attenuation may involve altered viral replication in lymphoid tissue that limited spread and decreased the host antibody response, suggesting a link between lifelong protective immunity and the ability of WT MeV, but not LAMV, to spread in lymphocytes.
野生型（WT）麻疹病毒（MeV）感染是导致儿童死亡的一个重要原因，但其幸存者会产生终身保护免疫力。WT MeV 和用于麻疹疫苗的减毒 MeV（LAMV）在抗原上相似，但减毒的决定因素尚不清楚，并且 LAMV 诱导的保护性免疫不如 WT MeV 诱导的那样强大。为了确定导致这些差异的因素，我们比较了 WT MeV 或 LAMV 呼吸道感染恒河猴后的病毒学和免疫学反应。在感染的猕猴中，WT MeV 在 B 和 T 淋巴细胞中有效复制，并且在淋巴组织中广泛传播，导致病毒 RNA 持续存在。相比之下，LAMV 在呼吸道中有效复制，但在淋巴组织或外周血单核细胞中的传播有限。在体外，WT MeV 和 LAMV 在猕猴原代呼吸道上皮细胞和人淋巴细胞中复制相似，但 LAMV 感染的淋巴细胞产生的病毒很少。WT MeV 感染后猕猴的白细胞介素-1β（IL-1β）、IL-12、干扰素-γ（IFN-γ）、CCL2、CCL11、CXCL9 和 CXCL11 的血浆浓度增加，但 LAMV 感染后则没有。与 LAMV 感染相比，WT MeV 感染诱导了更多保护性的中和、血凝素特异性抗体和骨髓浆细胞，但 MeV 特异性 IFN-γ和 IL-4 产生 T 细胞的数量相当。因此，MeV 衰减可能涉及在淋巴组织中改变病毒复制，从而限制了传播并降低了宿主抗体反应，这表明终身保护免疫力与 WT MeV（而不是 LAMV）在淋巴细胞中传播的能力之间存在联系。
