A post-mortem study towards the pathophysiology underlying SARS-CoV-2 neurotropism: ACE2 receptor and cytokine expression within the human brainstem.

BACKGROUND: Angiotensin Converting Enzyme 2 Receptor (ACE2R) represents the major cell entry receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus causing Coronavirus Disease 2019 (COVID-19). Despite being a respiratory virus, SARS-CoV-2 may directly access the central nervous system and infect neurons and glial cells alike. However, even though numerous studies have assessed SARS-CoV-2 neurotropism, very little information is available concerning the distribution of ACE2 Receptors in the human brain, with particular regard to its topographical expression in the brainstem. Furthermore, following viral infection, the immune response conveys the release of interleukins known as cytokines, molecules involved in neurodegenerative processes subsequently to their long-term expression. AIM: Assess the topography and expression pattern of ACE2 Receptor and TMPRSS2 in the human brainstem, in order to identify possible entry sites more susceptible to SARS-CoV-2 infection. Identify the presence and extent of cytokines within the human brainstem. MATERIALS AND METHODS: The brains of 24 COVID-19 patients and 18 matched controls underwent immunoperoxidase and immunofluorescent staining to determine ACE2R, TMPRSS2 topography, and expression of cytokines within standardized sections of the medulla, pons, and midbrain. Semi-quantitative morphometrical assessment was performed to compare protein expression within the structure. RESULTS AND DISCUSSION: ACE2R and TMPRSS2 appear to be expressed in neuronal and oligodendroglial cells of the brainstem, particularly at the level of the medullary and midbrain tegmentum of control subjects. These sites coincide with the most frequent sites of reported SARS-CoV-2 tropism. Higher cytokine expression within the brainstem is noted following viral infection. CONCLUSIONS: This study helps to define anatomically susceptible regions to SARS-CoV-2 infection in the brainstem, advancing knowledge on the neuropathological underpinnings of neurological manifestations in COIVD-19, additionally addressing the cytokine over-expression within the neural parenchyma.