Neurotropic SARS-CoV-2: Causalities and Realities

Abstract

Evidences for the dysfunctions of central nervous system (CNS) caused by SARS-CoV-2 infection have accumulated since the beginning of pandemic. The clinical and experimental evidences on viral entry routes to CNS lead to several open questions. While the neurological impairments caused by the virus stay as a reality under Long COVID, dissecting the causality underlying these problems continues to be an intensely studied topic. Extensive reports of olfactory dysfunctions including anosmia, hyposmia, and parosmia due to infections during 2020–2021, led to the hypothesis of virus’ CNS invasion through the olfactory nerve. Some of the investigations using animal models of cellular factors mediating the viral entry also suggest potential neurotropism. Conversely, recent studies proved the absence of viral particles in olfactory sensory neurons and olfactory bulb, hence leading to the deliberation on viral entry route. Here, we summarize the findings on the debated neurotropic characteristics of the virus, including clinical observations and the results from animal models. Further, we emphasize on the need of tracking olfactory and cognitive fitness in the post-COVID-19 era.

Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell

“…Neurological complications of long-COVID may challenge the global health for many more years ( Kay, 2022 ). Various olfactory problems including hyposmia, anosmia, and parosmia have been reported during infection and under long-COVID conditions ( Bhattacharjee et al, 2020 ; Pardasani and Abraham, 2022 ; Bhowmik et al, 2023 ). While infection at the olfactory periphery and the neuronal loss may explain the transient hyposmic and anosmic conditions, parosmia may result from the mis-targeting of regenerating OSNs during the recovery period ( Costanzo, 2000 ; John and Key, 2003 ; Cooper et al, 2020 ).…”

“…After the viral glycoprotein binds to the ACE2 receptor, the TMPRSS2 protein cleaves the virus’ S2 site, causing the internalization of the virus ( Glowacka et al, 2011 ; Jackson et al, 2022 ). The widespread expression of ACE2 receptors indicates toward number of possible entry points for the invasion of virus ( Mainland et al, 2015 ; Sungnak et al, 2020 ; Zhou et al, 2020 ; Boldrini et al, 2021 ; Casagrande et al, 2021 ; Huang N. et al, 2021 ; Pardasani and Abraham, 2022 ). Additionally, the virus can also enter the body through a breach of the blood–brain barrier (BBB), which is caused by the instability of the barrier by an increase in inflammatory cytokines following infection ( Huang X. et al, 2021 ).…”

“…Brain imaging data further confirmed the structural abnormalities caused by the viral infection ( Douaud et al, 2022 ). Moreover, long-lasting brain dysfunctions have become a serious challenge in post-COVID-19 conditions ( Pardasani and Abraham, 2022 ; Bhowmik et al, 2023 ). Therefore, probing the mechanisms underlying these deficits using animal models is a pressing need of global health.…”

“…This is assisted by the priming of spike protein by host cell transmembrane protease, serine 2 (TMPRSS2) ( Shang et al, 2020 ; Jackson et al, 2022 ). Although the routes of viral entry to the central nervous system (CNS) and the neurotropism of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) remain as debated topics, various cellular factors mediating virus entry are expressed in neuronal and non-neuronal cells in the brain ( Pardasani and Abraham, 2022 ). ACE2 receptors are expressed in the non-neuronal supporting (sustentacular) cells of olfactory epithelium.…”

Perceptual learning deficits mediated by somatostatin releasing inhibitory interneurons of olfactory bulb in an early life stress mouse model

“…Therefore, quantifying olfactory fitness of the ELA-affected population using precise methods may help in identifying and characterizing sensory and cognitive deficits at early stages and help in designing better treatment strategies [54][55][56][57].…”