Non-human primate orthologues of TMPRSS2 cleave and activate the influenza virus hemagglutinin

Zmora, Paweł; Molau-Blazejewska, Paulina; Bertram, Stephanie; Walendy-Gnirß, Kerstin; Nehlmeier, Inga; Hartleib, Anika; Moldenhauer, Anna-Sophie; Konzok, Sebastian; Dehmel, Susann; Sewald, Katherina; Brinkmann, Constantin; Curths, Christoph; Knauf, Sascha; Gruber, Jens; Mätz‐Rensing, Kerstin; Dahlmann, Franziska; Braun, Armin; Pöhlmann, Stefan

doi:10.1371/journal.pone.0176597

Cited by 17 publications

(20 citation statements)

References 43 publications

(62 reference statements)

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“…Padj and FC values were generated by GEO2R. Figures were prepared using GraphPad Prism v.8.4.2 and are both implicated in the activation and cell entry of H3N2 influenza A and influenza B viruses, so that TMPRSS4 allows cell infection in the albescence of the host TMPRSS2 gene (Bertram et al, 2010;Chaipan et al, 2009;Harbig et al, 2020;Hayashi et al, 2018;Kühn et al, 2016;Zmora et al, 2017). Both TMPRSS2 and TMPRSS4 play a role in lung cancer metastasis (Martin & List, 2019); high levels of TMPRSS4 were observed in several malignancies and were associated with epithelial to mesenchymal cell transition, invasion and metastasis (de Aberasturi & Calvo, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, TMPRSS4 (transmembrane serine protease 4) was recently shown to similarly recognize the SARS‐Cov‐2 spike protein and prime it for cell entry (Zang et al, 2020). Remarkably, both TMPRSS2 and TMPRSS4 are co‐expressed in numerous tissues, including the entire digestive tract, kidney, and bladder, and are both implicated in the activation and cell entry of H3N2 influenza A and influenza B viruses, so that TMPRSS4 allows cell infection in the albescence of the host TMPRSS2 gene (Bertram et al, 2010; Chaipan et al, 2009; Harbig et al, 2020; Hayashi et al, 2018; Kühn et al, 2016; Zmora et al, 2017). Both TMPRSS2 and TMPRSS4 play a role in lung cancer metastasis (Martin & List, 2019); high levels of TMPRSS4 were observed in several malignancies and were associated with epithelial to mesenchymal cell transition, invasion and metastasis (de Aberasturi & Calvo, 2015).…”

Section: Resultsmentioning

confidence: 99%

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Smoking and COVID‐19: Similar bronchial ACE2 and TMPRSS2 expression and higher TMPRSS4 expression in current versus never smokers

Voinsky

Genevieve

2020

Drug Development Research

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Uncertainties remain concerning the pathophysiology, epidemiology, and potential therapeutics for COVID‐19. Among unsettled controversies is whether tobacco smoking increases or protects from severe COVID‐19. Several epidemiological studies reported reduced COVID‐19 hospitalizations among smokers, while other studies reported the opposite trend. Some authors assumed that smokers have elevated airway expression of ACE2, the cell recognition site of the SARS‐Cov‐2 spike protein, but this suggestion remains unverified. We therefore performed data mining of two independent NCBI GEO genome‐wide RNA expression files (GSE7894 and GSE994) and report that in both data sets, current smokers and never smokers have, on average, closely similar bronchial epithelial cell mRNA levels of ACE2 , as well as TMPRSS2 , coding for a serine protease priming SARS‐Cov‐2 for cell entry, and ADAM17 , coding for a protease implicated in ACE2 membrane shedding. In contrast, the expression levels of TMPRSS4 , coding for a protease that primes SARS‐CoV‐2 for cell entry similarly to TMPRSS2 , were elevated in bronchial epithelial cells from current smokers compared with never smokers, suggesting that higher bronchial TMPRSS4 levels in smokers might put them at higher SARS‐Cov‐2 infection risk. The effects of smoking on COVID‐19 severity need clarification with larger studies. Additionally, the postulated protective effects of nicotine and nitric oxide, which may presumably reduce the risk of a “cytokine storm” in infected individuals, deserve assessment by controlled clinical trials.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Smoking and COVID‐19: Similar bronchial ACE2 and TMPRSS2 expression and higher TMPRSS4 expression in current versus never smokers

Voinsky

Genevieve

2020

Drug Development Research

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“…Orthologues of TMPRSS2 have been cloned from chicken, swine, and nonhuman primates and have been shown to be capable of activating IAV with a monobasic HA cleavage site, indicating that TMPRSS2 can support HA activation in various species (32)(33)(34). The characteristic role of TMPRSS2 in IAV activation in these hosts, however, remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

TMPRSS2 Is the Major Activating Protease of Influenza A Virus in Primary Human Airway Cells and Influenza B Virus in Human Type II Pneumocytes

Limburg

Harbig

Bestle

et al. 2019

J Virol

120

118

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Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is essential for virus infectivity and spread. We previously demonstrated in vitro that the transmembrane protease TMPRSS2 cleaves influenza A virus (IAV) and influenza B virus (IBV) HA possessing a monobasic cleavage site. Subsequent studies revealed that TMPRSS2 is crucial for the activation and pathogenesis of H1N1pdm and H7N9 IAV in mice. In contrast, activation of H3N2 IAV and IBV was found to be independent of TMPRSS2 expression and supported by an as-yet-undetermined protease(s). Here, we investigated the role of TMPRSS2 in proteolytic activation of IAV and IBV in three human airway cell culture systems: primary human bronchial epithelial cells (HBEC), primary type II alveolar epithelial cells (AECII), and Calu-3 cells. Knockdown of TMPRSS2 expression was performed using a previously described antisense peptideconjugated phosphorodiamidate morpholino oligomer, T-ex5, that interferes with splicing of TMPRSS2 pre-mRNA, resulting in the expression of enzymatically inactive TMPRSS2. T-ex5 treatment produced efficient knockdown of active TMPRSS2 in all three airway cell culture models and prevented proteolytic activation and multiplication of H7N9 IAV in Calu-3 cells and H1N1pdm, H7N9, and H3N2 IAV in HBEC and AECII. T-ex5 treatment also inhibited the activation and spread of IBV in AECII but did not affect IBV activation in HBEC and Calu-3 cells. This study identifies TMPRSS2 as the major HA-activating protease of IAV in human airway cells and IBV in type II pneumocytes and as a potential target for the development of novel drugs to treat influenza infections. IMPORTANCE Influenza A viruses (IAV) and influenza B viruses (IBV) cause significant morbidity and mortality during seasonal outbreaks. Cleavage of the viral surface glycoprotein hemagglutinin (HA) by host proteases is a prerequisite for membrane fusion and essential for virus infectivity. Inhibition of relevant proteases provides a promising therapeutic approach that may avoid the development of drug resistance. HA of most influenza viruses is cleaved at a monobasic cleavage site, and a number of proteases have been shown to cleave HA in vitro. This study demonstrates that the transmembrane protease TMPRSS2 is the major HA-activating protease of IAV in primary human bronchial cells and of both IAV and IBV in primary human type II pneumocytes. It further reveals that human and murine airway cells can differ in their HA-cleaving protease repertoires. Our data will help drive the development of potent and selective protease inhibitors as novel drugs for influenza treatment.

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“…Moreover, in basic research, PCLS have been used to elucidate calcium signaling 16 , early allergic responses 17 , and viral infection responses 18 19 . Technical progress is ongoing and further advances are being explored.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Cytotoxic and Immunomodulatory Effects of Substances in Human Precision-cut Lung Slices

Neuhaus

Danov

Konzok

et al. 2018

JoVE

Self Cite

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Respiratory diseases in their broad diversity need appropriate model systems to understand the underlying mechanisms and enable development of new therapeutics. Additionally, registration of new substances requires appropriate risk assessment with adequate testing systems to avoid the risk of individuals being harmed, for example, in the working environment. Such risk assessments are usually conducted in animal studies. In view of the 3Rs principle and public skepticism against animal experiments, human alternative methods, such as precision-cut lung slices (PCLS), have been evolving. The present paper describes the ex vivo technique of human PCLS to study the immunomodulatory potential of low-molecular-weight substances, such as ammonium hexachloroplatinate (HClPt). Measured endpoints include viability and local respiratory inflammation, marked by altered secretion of cytokines and chemokines. Pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α), and interleukin 1 alpha (IL-1α) were significantly increased in human PCLS after exposure to a sub-toxic concentration of HClPt. Even though the technique of PCLS has been substantially optimized over the past decades, its applicability for the testing of immunomodulation is still in development. Therefore, the results presented here are preliminary, even though they show the potential of human PCLS as a valuable tool in respiratory research.

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Non-human primate orthologues of TMPRSS2 cleave and activate the influenza virus hemagglutinin

Cited by 17 publications

References 43 publications

Smoking and COVID‐19: Similar bronchial ACE2 and TMPRSS2 expression and higher TMPRSS4 expression in current versus never smokers

Smoking and COVID‐19: Similar bronchial ACE2 and TMPRSS2 expression and higher TMPRSS4 expression in current versus never smokers

TMPRSS2 Is the Major Activating Protease of Influenza A Virus in Primary Human Airway Cells and Influenza B Virus in Human Type II Pneumocytes

Assessment of the Cytotoxic and Immunomodulatory Effects of Substances in Human Precision-cut Lung Slices

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