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.
Highlights
Comorbidities such as diabetes, chronic lung disease, and cardiovascular disease are highly prevalent in patients with COVID-19 and are associated with worse outcomes [1,2]
We examined the expression levels of SARS-CoV-2 entry-related genes in target organ systems including pulmonary, renal, cardiac, and peripheral blood mononuclear cells (PBMCs) from 1968 patients across a variety of common comorbidities including hypertension (n = 94 hypertensives vs. n = 61 normotensives), diabetes (n = 131 diabetic vs. n = 101 normoglycemic), obesity (n = 56 obese vs. n = 58 healthy weight), chronic lung disease (n = 200 asthmatic vs. n = 106 non-asthmatic and Chronic Obstructive Pulmonary Disease (COPD) n = 94 vs. healthy tissue n = 42) and cardiovascular disease, as well as other common pathologies such as chronic kidney disease (CKD) and cancer
Differential gene expression was curated from genetic data deposited in the National Center for Biotechnology Information (NCBI), U.S National Library of Medicine, Gene Expression Omnibus (GEO) DataSets and the European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI)
Summary
Comorbidities such as diabetes, chronic lung disease, and cardiovascular disease are highly prevalent in patients with COVID-19 and are associated with worse outcomes [1,2]. Whether these conditions contribute directly to SARS-CoV-2 virulence or worsen outcomes through independent mechanisms and reflect the general disease burden of the population remain unclear [2,3]. In addition to the widely reported ACE2, host cell membrane bound HSPGs, such as syndecans 1-4 (SDC1-4), glycosylphosphatidylinositol-anchored proteoglycans (glypicans 1-6 (GPC1-6)), betaglycan (TGFBR3), neuropilin-1 (NRP1) and CD44 may serve as alternative or complementary binding molecules [9]. Downstream effector molecules such as those involved in the bradykinin system have important intersections with the renin-angiotensin-aldosterone system and its metabolites and have been suggested as potential drivers of a “Bradykinin Storm” which may drive adverse outcomes in COVID-19 patients [10]
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