The pathogenic effects of epithelial cells surviving direct influenza virus infection

甲型流感病毒(IAV)给人类健康造成了巨大的负担，尽管接种了疫苗，但全球每年仍有20%的人口感染。虽然流感疾病通常与低死亡率有关，但这种疾病还有更严重的表现，其特征是一种称为高细胞分裂素血症的促炎正反馈循环。人们对这种疾病的发病机制知之甚少。为了确定病毒诱导的炎症来源，我们利用重组流感病毒和转基因动物系统来监测直接感染IAV的细胞的命运。使用这项技术，我们鉴定了一组直接感染后存活并在病毒清除后持续存在的肺上皮细胞。这是一个意想不到的发现，因为该领域的教条长期以来一直认为IAV是一种专门的细胞病变病毒，即所有被感染的细胞都会被杀死。这些“幸存者”细胞表现出高度炎症的转录特征，我们已经证明它们可以影响病毒感染引起的免疫病理。然而，这些细胞如何影响病毒疾病仍不清楚。在这里，我们建议研究存活细胞在IAV发病机制中的三个核心机制。在目标1中，我们将定义一种新的抗病毒信号通路，使上皮俱乐部细胞能够在直接病毒感染下存活。在目标2中，我们将确定Survior细胞如何在去除刺激配体后仍保持炎症基因的表达。在目标3中，我们将研究存活细胞的存在如何影响病毒复制动力学和病毒清除后炎症的消退。这项拟议的研究不仅将揭示病毒发病机制的新方面，而且还可能揭示新的分子靶点，这些靶点可用于治疗，以防止IAV或其他病毒感染期间的过度炎症。

Influenza A virus (IAV) causes a significant burden to human health, with an estimated 20% of the global population infected every year despite vaccination. While influenza disease is generally associated with low mortality, there are more severe manifestations of the disease that are characterized by a pro-inflammatory positive feedback loop known as hypercytokinemia. The mechanisms underlying this disease are poorly understood. To identify virally induced sources of inflammation, we utilized recombinant influenza viruses and transgenic animal systems to monitor the fates of cells that are directly infected by IAV. Using this technology, we identified a population of lung epithelial cells that survived direct infection and persisted in the lung after viral clearance. This was an unexpected discovery, because the dogma in the field has long held that IAV is an exclusively cytopathic virus, i.e. all infected cells are killed. These “survivor” cells exhibit a highly inflammatory transcriptional profile, and we have shown that they can influence the immunopathology caused by viral infection. How these cells influence viral disease however, has remained unknown. Here, we propose to study three central mechanisms that underlie survivor cell effects on IAV pathogenesis. In aim 1, we will define a novel anti-viral signaling pathway that allows epithelial club cells to survive direct viral infection. In aim 2, we will determine how survivor cells maintain expression of inflammatory genes even after the stimulating ligands are removed. And in aim 3, we will study how the presence of survivor cells influences both viral replication kinetics and the resolution of inflammation after viral clearance. The proposed research will reveal not only novel aspects of viral pathogenesis, but also potentially reveal new molecular targets which can be therapeutically exploited to prevent excessive inflammation during IAV or other viral infections.