| Autor: |
Breidenbach JD; Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Dube P; Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Ghosh S; Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Abdullah BN; Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Modyanov NN; Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Malhotra D; Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Dworkin LD; Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Haller ST; Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA., Kennedy DJ; Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA. |
| Abstrakt: |
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. |
