COVID‑19 and SARS‑CoV‑2 host cell entry mediators: Expression profiling of TMRSS4 in health and disease

Abstract

Severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2), the causative viral agent for the ongoing COVID-19 pandemic, enters its host cells primarily via the binding of the SARS-CoV-2 spike (S) proteins to the angiotensin-converting enzyme 2 (ACE2). A number of other cell entry mediators have also been identified, including neuropilin-1 (NRP1) and transmembrane protease serine 2 (TMPRSS2). More recently, it has been demonstrated that transmembrane protease serine 4 (TMPRSS4) along with TMPRSS2 activate the SARS-CoV-2 S proteins, and enhance the viral infection of human small intestinal enterocytes. To date, a systematic analysis of TMPRSS4 in health and disease is lacking. In the present study, using in silico tools, the gene expression and genetic alteration of TMPRSS4 were analysed across numerous tumours and compared to controls. The observations were also expanded to the level of the central nervous system (CNS). The findings revealed that TMPRSS4 was overexpressed in 11 types of cancer, including lung adenocarcinoma, lung squamous cell carcinoma, cervical squamous cell carcinoma, thyroid carcinoma, ovarian cancer, cancer of the rectum, pancreatic cancer, colon and stomach adenocarcinoma, uterine carcinosarcoma and uterine corpus endometrial carcinoma, whilst it was significantly downregulated in kidney carcinomas, acute myeloid leukaemia, skin cutaneous melanoma and testicular germ cell tumours. Finally, a high TMPRSS4 expression was documented in the olfactory tubercle, paraolfactory gyrus and frontal operculum, all brain regions which are associated with the sense of smell and taste. Collectively, these data suggest that TMPRSS4 may play a role in COVID-19 symptomatology as another SARS-CoV-2 host cell entry mediator responsible for the tropism of this coronavirus both in the periphery and the CNS.

Current and innovative methods for the diagnosis of COVID‑19 infection (Review)

“…Of note, a significant fraction (~50-75%) of COVID-19 patients is asymptomatic or paucisymptomatic, presenting mild symptoms for a limited period of time, while other patients (~10%) present severe respiratory symptoms resulting in acute respiratory distress syndrome (ARdS) responsible for dyspnea, interstitial pneumonitis, multiorgan dysfunctions and in some cases, even death (120,121). Such severe manifestations are often observed in patients with pre-existing comorbidities, such as diabetes, cardiovascular diseases, hypertension and cancer, and are mediated by specific host cell entry mediators (122)(123)(124)(125)(126).…”

The Role of Neuropilin-1 (NRP-1) in SARS-CoV-2 Infection: Review

“…Typically, the receptorbinding domain (RBD), which is found on the surface of SARS-CoV-2, binds to human angiotensin-converting enzyme 2 (ACE2), whereas transmembrane serine protease 2 (TM-PRSS2) is a protease important for S proteolytic processing and priming during infection. Additionally, it has been indicated that neuropilins are co-receptors that promote the entry of SARS-CoV-2 into the cell [14][15][16]. The Neuropilin family consists of two membersneuropilin-1 (NRP-1) and neuropilin-2 (NRP-2)-which exert an important impact on lymphangiogenesis, angiogenesis or axon guidance [17].…”

Network Pharmacology analysis of orally bioavailable SARS-COV2 protease inhibitor shows synergistic targets to improve clinical efficacy

“…Besides ACE, several other proteases were also overserved to have pharmacologically relevant a nity with PF32. Although the clinical relevance of these interactions are unclear at present, considering the systemic in ammation evinced by SARS-COV2, [23][24][25] the broader protease inhibitory potential of PF32 observed in this study may facilitate synergistic clinical bene ts.…”