ABSTRACT
In addition to the angiotensinconverting enzyme 2 (ACE2), a number of host cell entry mediators have been identified for severe acute respiratory syndrome coronavirus2 (SARSCoV2), including transmembrane protease serine 4 (TMPRSS4). The authors have recently demonstrated the upregulation of TMPRSS4 in 11 different cancers, as well as its specific expression within the central nervous system using in silico tools. The present study aimed to expand the initial observations and, using immunohistochemistry, TMPRSS4 protein expression in the gastrointestinal (GI) tract and lungs was further mapped. Immunohistochemistry was performed on tissue arrays and lung tissues of patients with nonsmall cell lung cancer with concurrent coronavirus disease 2019 (COVID19) infection using TMPRSS4 antibody. The results revealed that TMPRSS4 was abundantly expressed in the oesophagus, stomach, small intestine, jejunum, ileum, colon, liver and pancreas. Moreover, the extensive TMPRSS4 protein expression in the lungs of a deceased patient with COVID19 with chronic obstructive pulmonary disease and bronchial carcinoma, as well in the adjacent normal tissue, was demonstrated for the first time, at least to the best of our knowledge. On the whole, the immunohistochemistry data of the present study suggest that TMPRSS4 may be implicated in the broader (pulmonary and extrapulmonary) COVID19 symptomatology; thus, it may be responsible for the tropism of this coronavirus both in the GI tract and lungs.
Subject(s)
COVID-19/pathology , Gastrointestinal Tract/pathology , Lung Neoplasms/pathology , Lung/pathology , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/virology , Gastrointestinal Tract/virology , Humans , Immunohistochemistry , Lung/virology , Lung Neoplasms/complications , Male , Membrane Proteins/analysis , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/analysis , Virus InternalizationABSTRACT
The pathophysiology of coronavirus disease 2019 (COVID19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARSCoV2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a widerepertoire of possible cell entry mediators that appear to colocalise in a cell and tissuespecific manner. The present study provides an overview of the 'canonical' SARSCoV2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin1, expanding on the involvement of novel candidates, including glucoseregulated protein 78, basigin, kidney injury molecule1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factorα convertase) and Tolllike receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARSCoV2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID19 warrants further investigation.
Subject(s)
COVID-19/metabolism , MicroRNAs/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/virology , Endoplasmic Reticulum Chaperone BiP/genetics , Endoplasmic Reticulum Chaperone BiP/metabolism , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/genetics , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Virus/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Viral TropismABSTRACT
Severe acute respiratory syndrome (SARS) coronavirus2 (SARSCoV2), the causative viral agent for the ongoing COVID19 pandemic, enters its host cells primarily via the binding of the SARSCoV2 spike (S) proteins to the angiotensinconverting enzyme 2 (ACE2). A number of other cell entry mediators have also been identified, including neuropilin1 (NRP1) and transmembrane protease serine 2 (TMPRSS2). More recently, it has been demonstrated that transmembrane protease serine 4 (TMPRSS4) along with TMPRSS2 activate the SARSCoV2 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 COVID19 symptomatology as another SARSCoV2 host cell entry mediator responsible for the tropism of this coronavirus both in the periphery and the CNS.
Subject(s)
COVID-19/enzymology , COVID-19/genetics , Membrane Proteins/genetics , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics , Virus Internalization , Brain/enzymology , COVID-19/virology , Central Nervous System/enzymology , Computer Simulation , Databases, Genetic , Female , Gastrointestinal Tract/enzymology , Gene Expression Profiling , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Male , Membrane Proteins/physiology , Neoplasms/enzymology , Neoplasms/genetics , Pandemics , Serine Endopeptidases/physiologyABSTRACT
Severe acute respiratory syndrome (SARS) coronavirus2 (SARSCoV2) is the cause of a new disease (COVID19) which has evolved into a pandemic during the first half of 2020. Older age, male sex and certain underlying diseases, including cancer, appear to significantly increase the risk for severe COVID19. SARSCoV2 infection of host cells is facilitated by the angiotensinconverting enzyme 2 (ACE2), and by transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL). With the exception of ACE2, a systematic analysis of these two other SARSCoV2 infection mediators in malignancies is lacking. Here, we analysed genetic alteration, RNA expression, and DNA methylation of TMPRSS2 and CTSL across a wide spectrum of tumors and controls. TMPRSS2 was overexpressed in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), uterine corpus endometrial carcinoma and uterine carcinosarcoma, with PRAD and READ exhibiting the highest expression of all cancers. CTSL was upregulated in lymphoid neoplasm diffuse large Bcell lymphoma, oesophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, lower grade glioma, pancreatic adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, and thymoma. Hypomethylation of both genes was evident in most cases where they have been highly upregulated. We have expanded on our observations by including data relating to mutations and copy number alterations at pancancer level. The novel hypotheses that are stemming out of these data need to be further investigated and validated in large clinical studies.