Disease Tailored Therapeutic Strategies against Hyperinflammatory Viral Infections caused by Highly Pathogenic Respiratory Viruses

冠状病毒和流感病毒等高致病性呼吸道病毒在幼稚人群中的人畜传播构成了严重的大流行威胁，最近的SARS-CoV-2大流行令人印象深刻地证明了这一点。人类感染这种高致病性呼吸道病毒通常会导致威胁生命的全身性炎症性疾病，包括广泛的肺损伤和呼吸衰竭、血管功能障碍和多器官损害，作为病毒败血症的迹象。负责任的病毒诱导的免疫反应的特征是早期抗病毒先天免疫反应的延迟或扰动诱导，最终导致疾病后期炎性介质的不平衡和不成比例的高表达。为了揭示这些病毒特异性的免疫反应模式以及病毒特异性的触发因素，并在未来提供有效的抗病毒和抗炎治疗选择，我们的项目旨在通过使用相关高致病性和低致病性病毒的体内模型来剖析早期免疫反应的病毒和细胞类型特定的动态，并导致炎症性疾病的结局。此外，该项目建立在第一个资助期的结果基础上，旨在剖析MAPK p38信号通路在新冠肺炎期间的免疫反应和重点致病流感病毒感染中的关键参与，并揭示其作为抗炎以及使用两种预临床测试的p38抑制剂进行高级抗病毒治疗策略的潜在前景。利用先进的原始组织模型和人类肺的肺泡有机体，该项目的重点是将所获得的知识转化为现在和未来高致病性呼吸道病毒感染的新的和改进的临床治疗策略。

Zoonotic transmission of highly pathogenic respiratory viruses such as corona- and influenza viruses into a naïve human population poses a serious pandemic threat, which was impressively demonstrated by the recent SARS-CoV-2 pandemic. Human infections with such highly pathogenic respiratory viruses often result in life threatening systemic inflammatory diseases that include extensive pulmonary damage and respiratory failure, vascular dysfunction and multiple organ damage as signs of viral sepsis. The responsible virus-induced immune responses are characterized by delayed or perturbed induction of the early antiviral innate immune response, which culminates in imbalanced and unproportional high expression levels of inflammatory mediators in the later stages of the disease. To unravel these virus-specific immune response patterns as well as the virus-specific triggers, and provide effective antiviral as well as anti-inflammatory treatment options in the future, our project aims to dissect the virus- and cell type-specific dynamics of the early immune responses and lead to the inflammatory disease outcome by using in vivo models of related highly and low pathogenic viruses. Furthermore, this project builds up on the results of the first funding period and aims to dissect the crucial involvement of the MAPK p38 signaling pathway for the immune responses during COVID-19 and infections with highlight pathogenic influenza viruses as well as to unravel its promising potential as a target for anti-inflammatory as well as advanced antiviral treatment strategies using two pre-clinically tested p38 inhibitors. Employing advanced primary tissue models and alveolar organoids of the human lung, this project is strongly focused to convert the gained knowledge into new and improved clinical treatment strategies for infections with highly pathogenic respiratory viruses now and in the future.