Neuroimmunoendocrinology of SARS-CoV-2 Infection

Abstract

This review is aimed at illustrating and discussing the neuroimmune endocrinological aspects of the SARS-CoV-2 infection in light of the studies on this topic that have so far appeared in the literature. The most characteristic findings and pending controversies were derived by PubMed and Scopus databases. We included original and observational studies, reviews, meta-analysis, and case reports. The entry of the coronavirus into susceptible cells is allowed by the interaction with an ecto-enzyme located on human cells, the angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 also targets the central nervous system (CNS), including hypothalamic-pituitary structures, as their tissues express ACE2, and ACE2 mRNA expression in hypothalamus and pituitary gland cells has been confirmed in an autoptic study on patients who died of COVID 19. SARS-CoV-2 infection may cause central endocrine disorders in acute phase and in post-COVID period, particularly due to the effects of this virus at CNS level involving the hypothalamic-pituitary axis. The aggression to the hypothalamus-pituitary region may also elicit an autoimmune process involving this axis, responsible consequently for functional disorders of the satellite glands. Adrenal, thyroid and gonadal dysfunctions, as well as pituitary alterations involving GH and prolactin secretions, have so far been reported. However, the extent to which COVID-19 contributes to short- and long-term effects of infection to the endocrine system is currently being discussed and deserves further detailed research.

Increased neurovirulence of omicron BA.5 over BA.1 in human brain organoids and K18-hACE2 mice

“…Viral RNA/protein has been detected in the cortex of post-mortem COVID-patients 40,41 , with disruption of the hippocampus also reported 21,95 . The hypothalamus does not appear to be the site of infection in COVID-19 patients 96 , although the hypothalamic-pituitary axis does appear to be affected 97 . Viral antigen was also clearly evident in dendrites and axons (likely neural) (Fig.…”

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

“…Viral RNA/protein has been detected in the cortex of post-mortem COVID-patients 36,37 , with disruption of the hippocampus also reported 22,82 . The hypothalamus does not appear to be the site of infection in COVID-19 patients 83 , although the hypothalamic-pituitary axis does appear to be affected 84 . Viral antigen was also clearly evident in neural dendrites and axons (Fig.…”

COVID-19 vaccines and autoimmune disorders: A scoping review protocol

“…Thus, PNIE is critical to understand autoimmunity during the COVID-19 crisis because of the significant and widespread psychological stressors, such as social isolation, experienced by populations following public-health countermeasures like prolonged quarantines and mass lockdowns (23)(24)(25)(26). SARS-CoV-2 infections crossing the BBB and invading neurons and glia expressing angiotensin-converting enzyme 2 (ACE2) in the hypothalamic-pituitary region may cause autoimmune responses that can precipitate and/or exacerbate the hypothalamic-pituitary-adrenal (HPA) stress response system (22). Corticoids released in the stress response also play an important role in preventing damage to tissues through a negative feedback system that works to suppress the production and circulation of cytokines, including tumor necrosis factor α (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) involved in COVID-19 pathogenesis (22,27,28).…”

“…The proposed mechanism for HPA autoimmunity is a molecular mimicry of amino acid sequences of the host ACTH (22). SARS-CoV-2 can also induce mast cell activation which has been associated with neuroinflammation, neurodegeneration, and psychological stress (28).…”