TMPRSS2 in Influenza Virus and Coronavirus Infections

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 4676

Special Issue Editors


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Guest Editor
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
Interests: hepatocellular carcinoma; extracellular vesicles; tumor microenvironment

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Guest Editor
Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
Interests: TMPRSS2; SARS-CoV-2; extracellular vesicles; tumor microenvironment; cancer metastasis; tumor biology

Special Issue Information

Dear Colleagues,

Since the early 21st century, epidemics or pandemics of influenza virus and coronavirus, both of which are highly contagious viral pathogens, have occurred and imposed a significant impact on global healthcare systems. Indeed, the co-infection of SARS-CoV-2, the most recently discovered coronavirus that is responsible for the COVID-19 pandemic, with influenza viruses and even other respiratory pathogens has been reported, which may cause an even more significant threat to humankind. Emerging evidence has supported the unequivocal role of TMPRSS2 in influenza virus and coronavirus infections. Although the physiological role remains largely elusive, TMPRSS2 serves as a major player in SARS-CoV-2 entry as well as priming glycoproteins of other respiratory viruses. Therefore, targeting TMPRSS2 has been proposed as a promising anti-viral approach. The aim of this Special Issue is to highlight the latest studies on the role of TMPRSS2 in influenza virus and coronavirus infections, providing great insight into the mechanistic pathway, transmission and epidemiology.

We welcome the submission of original research, brief research reports, reviews and communication articles that address these issues.

Prof. Dr. Judy Wai Ping Yam
Dr. Sze Keong Tey
Guest Editors

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Keywords

  • TMPRSS2
  • influenza virus
  • coronavirus
  • viral infection
  • treatment of viral diseases

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Published Papers (2 papers)

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Research

23 pages, 3398 KiB  
Article
Unveiling the Role of TMPRSS2 in the Proteolytic Activation of Pandemic and Zoonotic Influenza Viruses and Coronaviruses in Human Airway Cells
by Marie Schwerdtner, Luna C. Schmacke, Julia Nave, Hannah Limburg, Torsten Steinmetzer, David A. Stein, Hong M. Moulton and Eva Böttcher-Friebertshäuser
Viruses 2024, 16(11), 1798; https://doi.org/10.3390/v16111798 - 20 Nov 2024
Cited by 1 | Viewed by 1512
Abstract
The zoonotic transmission of influenza A viruses (IAVs) and coronaviruses (CoVs) may result in severe disease. Cleavage of the surface glycoproteins hemagglutinin (HA) and spike protein (S), respectively, is essential for viral infectivity. The transmembrane serine protease 2 (TMPRSS2) is crucial for cleaving [...] Read more.
The zoonotic transmission of influenza A viruses (IAVs) and coronaviruses (CoVs) may result in severe disease. Cleavage of the surface glycoproteins hemagglutinin (HA) and spike protein (S), respectively, is essential for viral infectivity. The transmembrane serine protease 2 (TMPRSS2) is crucial for cleaving IAV HAs containing monobasic cleavage sites and severe acute respiratory syndrome (SARS)-CoV-2 S in human airway cells. Here, we analysed and compared the TMPRSS2-dependency of SARS-CoV, Middle East respiratory syndrome (MERS)-CoV, the 1918 pandemic H1N1 IAV and IAV H12, H13 and H17 subtypes in human airway cells. We used the peptide-conjugated morpholino oligomer (PPMO) T-ex5 to knockdown the expression of active TMPRSS2 and determine the impact on virus activation and replication in Calu-3 cells. The activation of H1N1/1918 and H13 relied on TMPRSS2, whereas recombinant IAVs carrying H12 or H17 were not affected by TMPRSS2 knockdown. MERS-CoV replication was strongly suppressed in T-ex5 treated cells, while SARS-CoV was less dependent on TMPRSS2. Our data underline the importance of TMPRSS2 for certain (potentially) pandemic respiratory viruses, including H1N1/1918 and MERS-CoV, in human airways, further suggesting a promising drug target. However, our findings also highlight that IAVs and CoVs differ in TMPRSS2 dependency and that other proteases are involved in virus activation. Full article
(This article belongs to the Special Issue TMPRSS2 in Influenza Virus and Coronavirus Infections)
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16 pages, 6480 KiB  
Article
The Transmembrane Protease Serine 2 (TMPRSS2) Non-Protease Domains Regulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike-Mediated Virus Entry
by Romano Strobelt, Julia Adler and Yosef Shaul
Viruses 2023, 15(10), 2124; https://doi.org/10.3390/v15102124 - 19 Oct 2023
Cited by 7 | Viewed by 2425
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells by binding to the angiotensin-converting enzyme 2 (hACE2) receptor. This process is aided by the transmembrane protease serine 2 (TMPRSS2), which enhances entry efficiency and infectiousness by cleaving the SARS-CoV-2 surface glycoprotein (Spike). [...] Read more.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells by binding to the angiotensin-converting enzyme 2 (hACE2) receptor. This process is aided by the transmembrane protease serine 2 (TMPRSS2), which enhances entry efficiency and infectiousness by cleaving the SARS-CoV-2 surface glycoprotein (Spike). The cleavage primes the Spike protein, promoting membrane fusion instead of receptor-mediated endocytosis. Despite the pivotal role played by TMPRSS2, our understanding of its non-protease distinct domains remains limited. In this report, we present evidence indicating the potential phosphorylation of a minimum of six tyrosine residues within the cytosolic tail (CT) of TMPRSS2. Via the use of TMPRSS2 CT phospho-mimetic mutants, we observed a reduction in TMPRSS2 protease activity, accompanied by a decrease in SARS-CoV-2 pseudovirus transduction, which was found to occur mainly via the endosomal pathway. We expanded our investigation beyond TMPRSS2 CT and discovered the involvement of other non-protease domains in regulating infection. Our co-immunoprecipitation experiments demonstrated a strong interaction between TMPRSS2 and Spike. We revealed a 21 amino acid long TMPRSS2-Spike-binding region (TSBR) within the TMPRSS2 scavenger receptor cysteine-rich (SRCR) domain that contributes to this interaction. Our study sheds light on novel functionalities associated with TMPRSS2’s cytosolic tail and SRCR region. Both of these regions have the capability to regulate SARS-CoV-2 entry pathways. These findings contribute to a deeper understanding of the complex interplay between viral entry and host factors, opening new avenues for potential therapeutic interventions. Full article
(This article belongs to the Special Issue TMPRSS2 in Influenza Virus and Coronavirus Infections)
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