Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA.
J Virol. 2018 Nov 12;92(23). doi: 10.1128/JVI.00826-18. Print 2018 Dec 1.
Noroviruses are enteric pathogens causing significant morbidity, mortality, and economic losses worldwide. Secretory immunoglobulins (sIg) are a first line of mucosal defense against enteric pathogens. They are secreted into the intestinal lumen via the polymeric immunoglobulin receptor (pIgR), where they bind to antigens. However, whether natural sIg protect against norovirus infection remains unknown. To determine if natural sIg alter murine norovirus (MNV) pathogenesis, we infected pIgR knockout (KO) mice, which lack sIg in mucosal secretions. Acute MNV infection was significantly reduced in pIgR KO mice compared to controls, despite increased MNV target cells in the Peyer's patch. Natural sIg did not alter MNV binding to the follicle-associated epithelium (FAE) or crossing of the FAE into the lymphoid follicle. Instead, naive pIgR KO mice had enhanced levels of the antiviral inflammatory molecules interferon gamma (IFN-γ) and inducible nitric oxide synthase (iNOS) in the ileum compared to controls. Strikingly, depletion of the intestinal microbiota in pIgR KO and control mice resulted in comparable IFN-γ and iNOS levels, as well as MNV infectious titers. IFN-γ treatment of wild-type (WT) mice and neutralization of IFN-γ in pIgR KO mice modulated MNV titers, implicating the antiviral cytokine in the phenotype. Reduced gastrointestinal infection in pIgR KO mice was also observed with another enteric virus, reovirus. Collectively, our findings suggest that natural sIg are not protective during enteric virus infection, but rather, that sIg promote enteric viral infection through alterations in microbial immune responses. Enteric virus, such as norovirus, infections cause significant morbidity and mortality worldwide. However, direct antiviral infection prevention strategies are limited. Blocking host entry and initiation of infection provides an established avenue for intervention. Here, we investigated the role of the polymeric immunoglobulin receptor (pIgR)-secretory immunoglobulin (sIg) cycle during enteric virus infections. The innate immune functions of sIg (agglutination, immune exclusion, neutralization, and expulsion) were not required during control of acute murine norovirus (MNV) infection. Instead, lack of pIgR resulted in increased IFN-γ levels, which contributed to reduced MNV titers. Another enteric virus, reovirus, also showed decreased infection in pIgR KO mice. Collectively, our data point to a model in which sIg-mediated microbial sensing promotes norovirus and reovirus infection. These data provide the first evidence of the proviral role of natural sIg during enteric virus infections and provide another example of how intestinal bacterial communities indirectly influence MNV pathogenesis.
诺如病毒是一种肠道病原体，在全球范围内导致发病率、死亡率和经济损失。分泌型免疫球蛋白（sIg）是抵御肠道病原体的第一道黏膜防御。它们通过多聚免疫球蛋白受体（pIgR）分泌到肠腔中，在那里与抗原结合。然而，天然 sIg 是否能预防诺如病毒感染尚不清楚。为了确定天然 sIg 是否改变鼠诺如病毒（MNV）的发病机制，我们感染了缺乏黏膜分泌物中 sIg 的 pIgR 敲除（KO）小鼠。与对照组相比，急性 MNV 感染在 pIgR KO 小鼠中明显减少，尽管派伊尔斑中的 MNV 靶细胞增加。天然 sIg 并未改变 MNV 与滤泡相关上皮（FAE）的结合或穿过 FAE 进入淋巴滤泡。相反，与对照组相比，幼稚的 pIgR KO 小鼠在回肠中具有更高水平的抗病毒炎症分子干扰素 γ（IFN-γ）和诱导型一氧化氮合酶（iNOS）。引人注目的是，pIgR KO 和对照组小鼠的肠道微生物组耗竭导致 IFN-γ 和 iNOS 水平以及 MNV 感染滴度相当。IFN-γ 处理野生型（WT）小鼠和 pIgR KO 小鼠中 IFN-γ 的中和调节了 MNV 滴度，表明抗病毒细胞因子在表型中起作用。pIgR KO 小鼠的胃肠道感染也减少了另一种肠道病毒，呼肠孤病毒。总的来说，我们的研究结果表明，天然 sIg 在肠道病毒感染过程中没有保护作用，而是通过改变微生物免疫反应来促进肠道病毒感染。肠道病毒，如诺如病毒，在全球范围内造成了严重的发病率和死亡率。然而，直接的抗病毒感染预防策略有限。阻断宿主进入和感染的启动为干预提供了一个既定的途径。在这里，我们研究了多聚免疫球蛋白受体（pIgR）-分泌型免疫球蛋白（sIg）循环在肠道病毒感染中的作用。sIg 的先天免疫功能（凝集、免疫排除、中和和排出）在控制急性鼠诺如病毒（MNV）感染时并不需要。相反，缺乏 pIgR 导致 IFN-γ 水平升高，从而降低 MNV 滴度。另一种肠道病毒，呼肠孤病毒，在 pIgR KO 小鼠中也表现出感染减少。总的来说，我们的数据表明，sIg 介导的微生物感应促进了诺如病毒和呼肠孤病毒的感染。这些数据首次证明了天然 sIg 在肠道病毒感染中的促病毒作用，并提供了另一个例子，说明肠道细菌群落如何间接影响 MNV 的发病机制。
