Endocrine Abstracts

JOINT3887

Background: The COVID-19 pandemic, induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2), resulted in a significant health burden worldwide. Previously, we demonstrated that SARS–CoV-2 could target human adrenal glands, increasing parenchymal inflammation and necrosis. However, little is known about the mechanisms that facilitate SARS–CoV-2 infection of adrenocortical cells and whether this coronavirus can directly affect the function of these cells.

Objectives: The current study examined the mechanisms involved in SARS–CoV-2 infection of adrenal cells. Furthermore, we investigate the hypothesis that COVID-19 conditions may alter the susceptibility of individual human adrenocortical cells to SARS–CoV-2 infection by affecting their entry receptors.

Methods: To this end, we infected the human adrenocortical cell line, NCI-H295R, with various strains of SARS–CoV-2 and compared the efficiency of infection through nucleocapsid staining and ultrastructural analysis of the infected cells. Moreover, we sought evidence of active replication and production of new viral particles in the adrenal cells using an additional plaque-forming assay. Finally, we induced steroidogenesis in the adrenal cells with forskolin (FSK) and examined its effects on the expression of SARS–CoV-2 receptors, infection efficiency, and coronavirus replication.

Results: Our results demonstrated that human adrenal cells are susceptible to coronavirus infection and support its replication. FSK activation of adrenal glucocorticoid production enhanced susceptibility, replication, and SARS–CoV-2 production in NCI-H295R cells. The latter was associated with increased expression of the primary SARS–CoV-2 entry receptor, ACE2, which involved the cAMP-PKA pathway. Furthermore, we observed that SARS–CoV-2 infection induced necroptosis and apoptosis in both infected and bystander cells.

Conclusions: To summarise, our results indicate that human adrenocortical cells are differentially affected by SARS–CoV-2 and that alterations in ACE2 expression, as demonstrated in the case of FSK-mediated steroidogenesis, may influence their susceptibility to coronavirus infection. Moreover, when supported by clinical evidence, this finding could elucidate the increased risk of complications in patients with GC overproduction, including those suffering from Cushing’s syndrome.