Expression of SARS-CoV-2 entry receptors in the respiratory tract of healthy individuals, smokers and asthmatics

Abstract

SARS-CoV-2 is causing a pandemic with currently > 29 million confirmed cases and > 900,000 deaths worldwide. The locations and mechanisms of virus entry into the human respiratory tract are incompletely characterized. We analyzed publicly available RNA microarray datasets for SARS-CoV-2 entry receptors and cofactors ACE2, TMPRSS2, BSG (CD147) and FURIN. We found that ACE2 and TMPRSS2 are upregulated in the airways of smokers. In asthmatics, ACE2 tended to be downregulated in nasal epithelium, and TMPRSS2 was upregulated in the bronchi. Furthermore, respiratory epithelia were negative for ACE-2 and TMPRSS2 protein expression while positive for BSG and furin, suggesting a possible alternative entry route for SARS-CoV-2.

Expression and co-expression analyses of TMPRSS2, a key element in COVID-19

“…In nasal epithelium samples (GSE8987), cigarette smoking significantly increases TMPRSS2 expression (p = 0.014). Recently, this expression increase in smoker subjects as compared to non-smokers has also been observed by western blots analysis in the lung [10] and by microarray analysis in small airway epithelium [11]. Since TMPRSS2 expression seems unexpectedly to decrease with increasing age, other factors, including diabetes, lower levels of androgens, pollutants or a genetic predisposition, could be relevant to explain the observed epidemiological trends in this outbreak ( Supplementary Table S1).…”

“…Notably, TMPRSS2 is highly and positively co-expressed with CD147 receptor and FURIN, CD209, cathepsin L (CTSL) and B (CTSB) proteases in men, but not in women, while the co-expression with ACE2 is similarly high in both males and females. These results indicate that, in males, the co-expression of these proteases and CD147, a newly discovered SARS-CoV-2 receptor [11], may enhance the host priming activity on SARS-CoV spike proteins. In turn, it may result in a higher viral entry, which explains the higher infection risk and illness severity in men than women.…”

SARS-CoV-2 leads to a small vessel endotheliitis in the heart

“…The pathogenetic mechanism in COVID-19 disease is complex and involves also the activation of several pro-inflammatory factors such as IL-1, Il-6 [ 13 , 56 , 57 ]. In addition to ACE2, further receptors such as TMPRSS2, cathepsins, furin and CD147 (EMMPRIN) play a role in the initiation and progression of SARS CoV2 infection [ 13 , 56 ]. CD147 has been shown to be closely involved in cardial inflammation [ 13 , 56 ].…”

“…In addition to ACE2, further receptors such as TMPRSS2, cathepsins, furin and CD147 (EMMPRIN) play a role in the initiation and progression of SARS CoV2 infection [ 13 , 56 ]. CD147 has been shown to be closely involved in cardial inflammation [ 13 , 56 ]. Blocking CD147 can inhibit SARS-Cov-2 replication and thus invasion of host cells [ 13 , 56 ].…”

“…Recently, ACE2 was unequivocally established as the functional host receptor for SARSCoV-2 [ 13 , 14 ]. Its expression varies between different organs/tissues, also in association with individual factors such as age, gender, genetic background, life style, medications and comorbidities [14] .…”