SARS-CoV-2 infects human GnRH neurons and tanycytes, disrupting hypothalamic-pituitary hormonal axes

Abstract

Neuroinvasion by SARS-CoV-2 is now accepted. To investigate whether low testosterone levels observed in men with severe COVID-19 could be of central origin, we retrospectively analyzed blood samples from 60 male intensive-care patients and explored SARS-CoV-2 brain entry using animal and cellular models as well as adult COVID-19 patient and fetal human brains. Most hypotestosteronemic patients displayed hypogonadotropic hypogonadism or abnormal hypothalamic-pituitary-gonadal axis regulation. Neurons producing gonadotropin-releasing hormone (GnRH), the master molecule controlling fertility, expressed angiotensin-converting enzyme 2 and neuropilin-1, two host-cell factors mediating infection, and were infected and dying in all COVID-19 patient brains. Tanycytes - hypothalamic glia that regulate GnRH secretion - were also infected. Additionally, human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, richly expressed both the above host-cell susceptibility factors and formyl peptide receptor 2, a putative vomeronasal receptor that also appeared involved in SARS-CoV-2 pathogenesis in humans and mice. Finally, a fetal human GnRH cell line expressing all these receptors could be infected by a SARS-CoV-2-like pseudovirus. Together, our findings suggest that GnRH neurons, which may be implicated in brain development and aging in addition to reproduction, are particularly vulnerable to SARS-CoV-2 in both adults and fetuses/newborns, with potentially devastating long-term consequences.

The polygamous GnRH neuron: Astrocytic and tanycytic communication with a neuroendocrine neuronal population

“…While SARS‐CoV‐2 is now accepted as being capable of infecting the brain 202‐205 and to cause microvascular brain pathology, 202 number of scientific studies and popular reports have suggested that the virus could interfere with reproductive function 206 . Studying post mortem COVID‐19 patient brains, we have seen immunoreactivity for both the spike (S) and nucleocapsid (N) viral proteins in the processes and endfeet of tanycytes in the median eminence, 205 as well as the infection of GnRH neurons themselves by SARS‐CoV‐2 207 207 .…”

“…206 Studying post mortem COVID-19 patient brains, we have seen immunoreactivity for both the spike (S) and nucleocapsid (N) viral proteins in the processes and endfeet of tanycytes in the median eminence, 205 as well as the infection of GnRH neurons themselves by SARS-CoV-2. 207 The infection of either GnRH neurons or tanycytes could -play in these mechanisms? NG2 glial cells (also known as oligodendrocyte precursors) have recently been shown to play a role in the maintenance of neuronal processes in the median eminence 208,209 ; whether these cells could also regulate neuroendocrine axon dynamics is another intriguing question.…”

“…Studying post mortem COVID‐19 patient brains, we have seen immunoreactivity for both the spike (S) and nucleocapsid (N) viral proteins in the processes and endfeet of tanycytes in the median eminence, 205 as well as the infection of GnRH neurons themselves by SARS‐CoV‐2 207 207 . Such alterations in the neuroglial network regulating reproduction evoke the very real possibility of long‐term repercussions from SARS‐CoV‐2 infection on fertility in patients who survive infection, and thus the need for longitudinal studies on reproductive parameters in cohorts of individuals who were adolescents or young adults during the pandemic.…”

A role for GnRH in olfaction and cognition: Implications for veterinary medicine

“…On the other hand, the findings discussed in this section also raise the provocative idea that well-aging could be programmed at minipuberty and that intervention during this critical window of postnatal development could improve cognitive and neurodegenerative disorders in specific conditions such as Huntington's disease (Braz et al, 2022), minipuberty-altering gene mutations (Chachlaki et al, 2022), but also possibly in cases of preterm birth (https:// minino-proje ct.com). Neonatal viral infection targeting GnRH neurons, which have access to the olfactory epithelium even after birth (Chachlaki et al, 2022;Sauvé et al, 2021), including infections by the SARS-CoV2 virus known to infect both humans (Sauvé et al, 2021) and animals (de Melo et al, 2021;Koeppel et al, 2022;Mastutik et al, 2022), could be one of the risk factors altering the course of minipuberty and thus predisposing the infected subjects to fertility, sensory and cognitive disorders later in life.…”