The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

Abstract

Most patients with COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), display neurological symptoms, and respiratory failure in certain cases could be of extrapulmonary origin. Hypothalamic neural circuits play key roles in sex differences, diabetes, hypertension, obesity and aging, all risk factors for severe COVID-19, besides being connected to olfactory/gustative and brainstem cardiorespiratory centers. Here, human brain gene-expression analyses and immunohistochemistry reveal that the hypothalamus and associated regions express angiotensin-converting enzyme 2 and transmembrane proteinase, serine 2, which mediate SARS-CoV-2 cellular entry, in correlation with genes or pathways involved in physiological functions or viral pathogenesis. A post-mortem patient brain shows viral invasion and replication in both the olfactory bulb and the hypothalamus, while animal studies indicate that sex hormones and metabolic diseases influence this susceptibility. Main textSARS-CoV-2 infection is increasingly associated with a wide range of neurological symptomsheadaches, dizziness, nausea, loss of consciousness, seizures, encephalitis etc., as well as anosmia or ageusia -in the majority of patients (1,2). Additionally, many COVID-19 patients with severe disease do not respond well to artificial ventilation or display "silent hypoxia" (3), suggesting an extrapulmonary component to respiratory dysfunction, and cardiorespiratory function and fluid homeostasis are themselves subject to central nervous system (CNS) control. However, despite emerging reports of the post-mortem detection of the virus in the cerebrospinal fluid (CSF) (see for example (4)) or brain parenchyma of patients (5), little is known about how and under what circumstances SARS-CoV-2 infects the brain.While the possibility of CNS infection has been largely underestimated due to the common view that angiotensin converting enzyme 2 (ACE2), the only confirmed cellular receptor for SARS-CoV-2 so far (6), is absent or expressed only at very low levels in the brain (7,8), and that too exclusively in vascular cells (He et al., bioRxiv 2020; doi: https://doi.org/10.1101.088500) the majority of these studies have focused on the cerebral cortex, ignoring the fact that other regions such as the hypothalamus, are rich in ACE2 (9). Intriguingly, most major risk factors for severe COVID-19 (male sex, age, obesity, hypertension, diabetes); reviewed by (10,11); could be mediated by normal or dysfunctional hypothalamic neural networks that regulate a variety of physiological processes: sexual differentiation and gonadal hormone production, energy homeostasis, fluid homeostasis/osmoregulation and even ageing (12)(13)(14). The hypothalamus is also directly linked to other parts of the CNS involved in functions affected in COVID-19 patients, including brainstem nuclei that control fluid homeostasis, cardiac function and respiration, as well as regions implicated in the perception or integration of odor and taste (12,(14)(15)(16)(17)(18).Here, we inves...

Effects of COVID-19 on the Nervous System

“…The virus could be internalized in nerve terminals by endocytosis, transported retrogradely, and spread trans -synaptically to other brain regions, as described for other coronaviruses ( Dubé et al., 2018 ). ACE2 and TMPRSS2 have been detected in the nasal mucosa at the RNA and protein levels, but they seem to be localized to epithelial cells (sustentacular cells), not olfactory neurons ( Brann et al., 2020 ), although another report suggests neuronal involvement ( Nampoothiri et al., 2020 ). Therefore, it is unclear if the virus is restricted to the olfactory epithelium or reaches olfactory neurons.…”

“…SARS-CoV-2 could also enter the brain through the median eminence of the hypothalamus and other circumventricular organs, brain regions with a leaky BBB due to openings (fenestrae) in the capillary wall ( Kaur and Ling, 2017 ). Although the size of the viral particle (80–120 nm) is larger than endothelial fenestrae ( Sarin, 2010 ), preliminary data suggest that median eminence capillaries and tanycytes express ACE2 and TMPRSS, which could allow virus entry into the hypothalamus ( Nampoothiri et al., 2020 ). Owing to its widespread connection, the hypothalamus could serve as a gateway to the entire brain.…”

Identification of Novel Hypothalamic MicroRNAs as Promising Therapeutics for SARS-CoV-2 by Regulating ACE2 and TMPRSS2 Expression: An In Silico Analysis

“…The CNS is a prominent site of miRNA expression and several miRNAs are expressed and enriched in different regions within the hypothalamus [ 30 ]. miRNAs have recently been shown to be important regulators of various hypothalamic functions [ 31 , 32 , 33 , 34 ]. In addition, a recent study has revealed that the hypothalamus is a pivot for understanding the nature of SARS-CoV-2 brain infection [ 35 ].…”

Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms

“…SARS-CoV-2 patients present with elevated plasma levels of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP), which are known as biochemical indicators of neuronal injury and glial activation, respectively [9]. Also, postmortem brain autopsies demonstrate virus invasion to different brain regions, including the hypothalamus and olfactory bulb, accompanied by neural death and demyelination [10,11].…”