Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes

Abstract

Viral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2), type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase Cathepsin L (CTSL), subtilisin-like proprotein peptidase furin (FURIN), and even potentially membrane bound heparan sulfate proteoglycans. The distribution and expression of many of these genes across cell types representing multiple organ systems in healthy individuals has recently been demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and are associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remains unclear. Here, we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes, as well as potential downstream effector genes such as bradykinin receptors, are modulated in the target organs of select disease states. In tissues, such as the heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities compared to healthy individuals. Additionally, we found the increased expression of viral entry-related genes in the settings of hypertension, cancer, or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and we suggest new therapeutic targets to improve outcomes in vulnerable patient populations.

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

“…Animal models indicate that ACE2 and Ang-(1-7) are protective in asthma ( El-Hashim et al, 2012 ). In recent studies, ACE2 expression was not altered ( Breidenbach et al, 2020 ; G. Li et al, 2020 ; Peters et al, 2020 ; Radzikowska et al, 2020 ) or reduced ( Jackson et al, 2020 ; Kimura et al, 2020 ) in asthmatic patients; but increased expression of TMPRSS2, the enzyme facilitating SARS-CoV-2 entry into host cells, has been reported ( Kimura et al, 2020 ; Radzikowska et al, 2020 ). However, in a large cohort study, increased ACE2 gene expression was reported in a sub-group of type 2 asthmatic patients ( Camiolo, Gauthier, Kaminski, Ray, & Wenzel, 2020 ).…”

Body Localization of ACE-2: On the Trail of the Keyhole of SARS-CoV-2

“…Different cardiovascular complications, such as myocarditis, acute coronary syndrome, decompensated heart failure, pulmonary embolism, cardiogenic shock, and infection of a heart transplant recipient, accompanied by altered levels of creatine kinase isoenzyme-MB, myohemoglobin, cardiac troponin I, and N-terminal pro-brain natriuretic peptide were currently reported ( 1 , 149 – 155 ). In addition, a high prevalence of pre-existing cardiovascular morbidities, including hypertension, and coronary artery diseases, has been detected among patients with severe SARS-CoV-2 ( 1 , 149 , 156 ). In COVID-19 patients, the highest mortality rates were also observed in case of pre-existing cardiovascular disease and elevated cardiac troponin levels ( 137 , 157 ).…”

Cardiovascular protective properties of oxytocin against COVID-19

“…SARS-CoV-2 entry of host cells could involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase cathepsin L, and membrane bound heparan sulphate proteoglycans (HSPGs) and others [ 21 ]. As the receptor for SARS-CoV-2, ACE2 is present on the surface of lung alveolar epithelial cells, enterocytes of the small intestine, renal tubules, heart, arterial and venous endothelial cells, arterial smooth muscle cells, cerebral neurons and monocytes/macrophages [ 22 , 23 ].…”

“…Among patients with diabetes and CV disease, the expression levels of TMPRSS2 are elevated significantly in comparison to healthy individuals. Additionally, expression of viral entry-related genes is increased in the settings of hypertension across target organ systems [ 21 ]. Thus, if infected by the virus, these patients may have higher risk of CV complications and progression to critically-ill condition.…”