The pathogenic effects of epithelial cells surviving direct influenza virus infection

甲型流感病毒（IAV）对人类健康造成重大负担，尽管接种了疫苗，但估计每年仍有20%的全球人口受到感染。虽然流感疾病通常与低死亡率有关，但该疾病还有更严重的表现，其特征是促炎正反馈循环，即高细胞分裂血症。这种疾病背后的机制尚不清楚。为了确定病毒诱导的炎症源，我们利用重组流感病毒和转基因动物系统来监测直接被IAV感染的细胞的命运。利用这项技术，我们鉴定了一群肺上皮细胞，它们在直接感染后存活下来，并在病毒清除后在肺中持续存在。这是一个出乎意料的发现，因为该领域的教条长期以来一直认为IAV是一种完全的细胞病变病毒，即所有感染的细胞都被杀死。这些“幸存者”细胞表现出高度炎症性转录谱，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性疾病仍然未知。在这里，我们建议研究存活细胞对IAV发病机制的影响的三个核心机制。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中存活。在目标2中，我们将确定即使在刺激配体被移除后，存活细胞如何维持炎症基因的表达。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解决。这项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，这些靶点可以在治疗上被利用来防止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.