Research ArticleVIRAL INFECTIONS

A durable protective immune response to wild-type measles virus infection of macaques is due to viral replication and spread in lymphoid tissues

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Science Translational Medicine  01 Apr 2020:
Vol. 12, Issue 537, eaax7799
DOI: 10.1126/scitranslmed.aax7799

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Finding clues to life-long immunity

Natural infection with wild-type (WT) measles virus (MeV) induces lifelong immunity, but immunity induced by infection with the live-attenuated measles strain used in the measles vaccine (LAMV) is less durable. To identify differences between WT MeV and LAMV, Lin et al. studied virus replication and immune responses in infected rhesus macaques. Both WT MeV and LAMV replicated well in respiratory epithelial cells. However, although WT MeV replicated well in lymphocytes and spread efficiently through the blood, LAMV did not. WT MeV induced more serum antiviral antibody and bone marrow antibody–secreting cells than did LAMV, suggesting that more efficient virus replication in lymphoid tissue led to a more vigorous immune response.

Abstract

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.

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