Pneumonia Biology

项目摘要 COVID-19 是一场紧迫的危机。负责的冠状病毒 SARS-CoV-2 具有高度传染性，传播迅速，并引起需要住院治疗、重症监护或机械通气的严重疾病。然而，即使对于 SARS-CoV-2，也只有少数病例病情严重。需要更好地了解决定谁得重病的生物学因素。严重的 COVID-19 涉及肺部病理学，表现为弥漫性肺泡损伤、透明膜以及含有 T 细胞和巨噬细胞的炎症浸润。虽然 T 细胞在患病肺部很突出，但循环 T 细胞的减少与不良预后相关。此前严重的冠状病毒疾病，SARS 和 MERS，提供了机制视角。 SARS 和 MERS 还存在淋巴细胞减少和含有 T 细胞和巨噬细胞的肺部受损，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程度。目前尚不清楚免疫活动是否、何时、哪些以及为何可能导致部分 COVID-19 患者的肺损伤。对于许多呼吸道病原体来说，异型免疫记忆对于感染结果至关重要，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，是引起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类型尚不确定，异型免疫记忆是否或如何影响 SARS-CoV-2 感染构成了关键的知识空白。异型免疫记忆有助于对抗流感病毒、RSV和肺炎球菌。然而，预先存在的免疫力反而可能有害并引发疾病，根据冠状病毒流行病学、免疫学和病理生理学，这对于 COVID-19 来说似乎是合理的。我们假设最近的冠状病毒感染使个人容易感染更严重的 COVID-19。我们还认识到，事实可能恰恰相反，最近的人类冠状病毒感染可能反而提供针对 SARS-CoV-2 的异型保护，从而使 COVID-19 的严重程度减轻。不管怎样，这个问题需要一个答案。先前存在的异型免疫对后续感染期间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、迅速地研究遏制设施中的 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关系，并提议进行研究，这些研究将改变范围，并导致对 R35 的竞争性修订。一个人最近是否以及何时感染过其他冠状病毒可能是 COVID-19 严重程度的主要决定因素。我们建议通过专门设计的研究来回答这个问题，以最大限度地减少所需时间，同时最大限度地提高相关性和影响力。我们的目标是快速提供这一答案，以告知和改进针对 COVID-19 的医疗和公共卫生方法。

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.