Mechanisms for post-COVID pituitary damage

项目摘要 COVID-19相关的肺外损害很常见，甚至可能在轻度COVID-19患者中观察到。 19症状目前迫切需要建立最佳的感染后保健战略 对于这些患者，但其外观背后的机制仍然没有得到研究。例如，新冠肺炎后， 据报道，54%的COVID-19幸存者患有慢性疲劳综合征，包括那些没有严重 急性感染期间的症状;然而，其原因尚未得到解决。COVID-19后慢性 疲劳综合征的症状与脑垂体激素异常患者的症状相似 缺乏，支持COVID-19患者的垂体功能障碍可能与 COVID-19后的健康并发症。几条证据支持SARS-CoV-2感染 会损伤脑垂体导致脑垂体功能紊乱首先，我们检测了SARS-CoV-2的表达 SARS-CoV-2可直接与人垂体ACE 2受体结合， 损伤垂体内分泌细胞。第二，据报道，非典在东南亚流行， 2002年，由SARS-CoV-1感染后引起垂体功能下降，虽然对垂体有直接损害 没有被调查。第三，临床观察表明，COVID-19患者表现出异常的免疫反应， 活动，并可能发生细胞因子风暴，特别是IL-6和TNFα急性升高。细胞因子风暴， 其可作为例如癌症免疫疗法治疗的结果而发生， 与垂体炎症和功能障碍有关，尽管详细的发病机制尚不清楚 知道的这表明免疫系统的异常激活也可能间接损害垂体， COVID-19患者阐明直接和间接垂体损伤的机制， SARS-CoV-2感染对于建立及时诊断和管理垂体腺瘤的指南至关重要 COVID-19幸存者的功能障碍。在目标1中，我们将确定SARS-CoV-2是否直接侵入 垂体并导致垂体结构损伤。我们将研究尸检获得的垂体组织， COVID-19死亡患者和正常对照垂体组织。此外，使用新的空间基因组学， 技术，我们将确定五个垂体中与COVID-19相关的基因表达的变化 内分泌谱系和基质细胞。在目标2中，我们将确定垂体的关联和时间轴 功能障碍和症状的患者谁感染了SARS-CoV-2。通过结合细节和创新 细胞和分子分析，以及临床研究，我们将确定负责垂体 COVID-19患者的垂体功能障碍，并确定COVID-19中垂体功能障碍的过程。这些 创新的研究将反过来促进制定循证临床评估指南， 管理地球仪广大COVID-19人群的激素缺乏症。

PROJECT SUMMARY COVID-19–related extra-pulmonary damage is common and may even be observed in patients with mild COVID- 19 symptoms. There is an urgent and immediate need to establish optimal post-infection health care strategies for these patients, yet mechanisms underlying their appearance remain unexamined. For example, post-COVID- 19 chronic fatigue syndrome has been reported in 54% of COVID-19 survivors, including those without severe symptoms during the acute infection; however, its cause has not been addressed. Post-COVID-19 chronic fatigue syndrome’s symptoms mimic those experienced by patients with well-described pituitary hormone deficiencies, supporting the concept that pituitary dysfunction in patients with COVID-19 may be implicated in post–COVID-19 health complications. Several lines of evidence support the premise that SARS-CoV-2 infection damages the pituitary, leading to disrupted pituitary function. First, we detected expression of the SARS-CoV-2 receptor ACE2 in the normal human pituitary by immunofluorescence, suggesting that SARS-CoV-2 may directly damage pituitary endocrine cells. Second, it has been reported that the SARS pandemic in Southeast Asia in 2002, by SARS-CoV-1, caused post-infection pituitary function decline, although direct damage to the pituitary was not investigated. Third, clinical observations suggest that patients with COVID-19 show aberrant immune activity and may develop cytokine storm, with particularly acute elevations of IL-6 and TNFα. Cytokine storm, which can occur as a consequence of with cancer immunotherapy treatment, for example, is frequently associated with pituitary inflammation and dysfunction, although the detailed pathogenetic mechanisms are not known. This suggests that aberrant activation of the immune system may also indirectly damage the pituitary in patients with COVID-19. Elucidating the mechanisms underlying direct and indirect pituitary damage related to SARS-CoV-2 infection is critical to establishing guidelines for timely diagnosis and management of pituitary dysfunction in COVID-19 survivors. In Aim 1, we will determine whether SARS-CoV-2 directly invades the pituitary and causes pituitary structural damage. We will study autopsy-derived pituitary tissues obtained from COVID-19 deceased patients and normal control pituitary tissues. Moreover, using a novel spatial genomics technology, we will determine changes in gene expression associated with COVID-19 in each of the five pituitary endocrine lineages and stroma cells. In Aim 2, we will determine the association and the timeline of pituitary dysfunction and symptoms in patients who were infected by SARS-CoV-2. By combining detailed and innovative cellular and molecular analyses, and clinical studies, we will identify the mechanisms responsible for pituitary dysfunction in COVID-19 patients and determine the course of pituitary dysfunction in COVID-19. These innovative studies will, in turn, enable the development of an evidence-based clinical guide for evaluation and management of hormone deficiencies in the vast COVID-19 population across the globe.