Mechanisms for post-COVID pituitary damage

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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.