Pneumonia Biology

项目摘要：新冠肺炎是迫在眉睫的危机。负责的冠状病毒SARS-CoV-2具有高度传染性，传播迅速，并导致需要住院、重症护理或机械通风的严重疾病。然而，即使是SARS-CoV-2，也只有少数病例是严重的。决定谁得了重病的生物学因素需要更好地了解。重症新冠肺炎表现为弥漫性肺泡损伤、透明膜、含有T细胞和巨噬细胞的炎性浸润物。虽然T细胞在病变肺中占主导地位，但循环中的T细胞减少与预后不良有关。以前的严重冠状病毒疾病，SARS和MERS，提供了机械论观点。SARS和MERS也有淋巴细胞减少和含有T细胞和巨噬细胞的受损肺，对于这些感染，抑制T细胞、抗体或单核巨噬细胞可以减轻疾病的严重性。免疫活动是否、何时、哪些以及为什么可能导致新冠肺炎患者亚群的肺损伤尚不清楚。对于许多呼吸道病原体来说，异型免疫记忆对感染的结果至关重要，但没有数据表明这是否适用于冠状病毒。四种冠状病毒(OC43、HKU1、229E和NL63)定期传播，是感冒和肺炎的最常见原因之一。感染这些病毒后产生的免疫记忆的类型尚不确定，以及异型免疫记忆是否或如何影响SARS-CoV-2感染构成了一个关键的知识鸿沟。异型免疫记忆有助于对抗流感病毒、呼吸道合胞病毒和肺炎球菌。然而，根据冠状病毒流行病学、免疫学和病理生理学，先前存在的免疫反而可能是有害的，并会导致疾病，这对新冠肺炎来说似乎是可行的。我们推测，最近的一次冠状病毒感染使个人对更严重的新冠肺炎易感。我们也认识到相反的情况可能是真的，最近先前的人类冠状病毒感染可能相反地提供针对SARS-CoV-2的异型保护，从而使新冠肺炎不那么严重。无论哪种方式，这个问题都需要一个答案。在随后的感染中，先前存在的异型免疫对免疫反应和肺防御的影响是“肺炎生物学”NHLBI R35奖的焦点。为了有效和快速地研究围堵设施中的SARS-CoV-2，包括先前人类冠状病毒挑战的影响，我们建立了新的合作伙伴关系，并提议进行研究，这些研究将在范围上发生变化，并导致对R35的这次竞争性修订。个人最近是否以及何时感染了其他冠状病毒可能是新冠肺炎严重程度的主要决定因素。我们建议回答这个问题，研究明确旨在最大限度地减少所需的时间，同时最大化相关性和影响。我们的目标是迅速提供这个答案，为新冠肺炎的医疗和公共卫生方法提供信息和改进。

Project Summary COVID-19 is a pressing crisis. The responsible coronavirus, SARS-CoV-2, is highly infectious, spreads rapidly, and causes severe disease requiring hospitalization, critical care, or mechanical ventilation. However, even for SARS-CoV-2, only a minority of cases are severe. The biological factors determining who gets very ill need to be better understood. Severe COVID-19 involves pulmonary pathology demonstrating diffuse alveolar damage, hyaline membranes, and inflammatory infiltrates containing T cells and macrophages. While T cells are prominent in the diseased lung, diminished circulating T cells associates with poor outcome. Previous severe coronavirus diseases, SARS and MERS, provide mechanistic perspective. SARS and MERS also have lymphopenia and damaged lungs containing T cells and macrophages, and for these infections inhibiting T cells, antibodies, or monocyte-macrophages can diminish severity of disease. Whether, when, which, and why immune activities may be contributing to lung damage in subsets of COVID-19 patients are unclear. For many respiratory pathogens, heterotypic immunological memory is pivotal to the outcome of infection, but there are no data about whether this applies to coronaviruses. Four coronaviruses (OC43, HKU1, 229E, and NL63) circulate regularly and are among the most common causes of colds and pneumonias. The types of immune memory arising after infections with these viruses is uncertain, and whether or how heterotypic immune memory influences SARS-CoV-2 infections constitute a crucial knowledge gap. Heterotypic immune memory is helpful for fighting influenza viruses, RSV, and pneumococcus. However, pre-existing immunity could be detrimental instead and drive disease, which seems plausible for COVID-19 based on coronavirus epidemiology, immunology, and pathophysiology. We hypothesize that a recent coronavirus infection makes an individual susceptible to more severe COVID-19. We also recognize that the opposite may be true, and recent prior human coronavirus infection might instead provide heterotypic protection against SARS-CoV-2 and thereby make COVID-19 less severe. Either way, the question demands an answer. The effects of pre-existing heterotypic immunity on immune responses and lung defense during subsequent infections is the focus of the “Pneumonia Biology” NHLBI R35 award. To effectively and expeditiously study SARS-CoV-2 in containment facilities, including effects of a prior human coronavirus challenge, we created new collaborations and propose to perform studies that will be a change in scope and lead to this Competitive Revision to the R35. Whether and when an individual has been recently infected by other coronaviruses may be a major determinant of COVID-19 severity. We propose to answer this question, with studies expressly designed to minimize time needed while maximizing relevance and impact. Our goal is to provide this answer quickly, for informing and improving the medical and public health approaches to COVID-19.