Untersuchungen zur Rolle von TMPRSS2 bei der Aktivierung zoonotischer und pandemischer Corona- und Influenzaviren in humanen Atemwegsepithelzellen und darüber hinaus
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Philipps-Universität Marburg
Abstract
The proteolytic activation of the viral surface glycoproteins influenza A virus (IAV) hemagglutinin (HA) and coronavirus (CoV) spike protein (S) is essential for the fusion of the viral and the host membrane and thus infectivity. The transmembrane protease serine subtype 2 (TMPRSS2) was identified as the main activating protease of HA of human IAV in the respiratory tract. Bacterial co-infections are the major risk factor for severe complications in IAV infections. Not only is the virus-damaged airway epithelium more prone to bacterial infection, but the bacteria can also contribute to viral replication, particularly by enhancing surface glycoprotein cleavage. Furthermore, TMPRSS2 is essential for the activation of the Severe Acute Respiratory Syndrome (SARS)-CoV-2 S in human airway cells.
In the first part of this work, the upregulation of TMPRSS2 expression in (primary) airway epithelial cells by bacterial factors, particularly flagellin, was investigated on mRNA- and protein-level. Moreover, a slight enhancement of the viral titers and of HA-cleavage was observed upon infection of flagellin-stimulated cells with IAV. This indicates that enhanced virus activation due to increased TMPRSS2 expression could be relevant in the context of viral-bacterial co-infections in the human respiratory tract in vivo. Additionally, the data suggest a potential physiological function of TMPRSS2 in the antimicrobial immune response.
Furthermore, the present study demonstrates differences in the TMPRSS2-dependency of the zoonotic CoV SARS-CoV and Middle-East Respiratory Syndrome (MERS)-CoV in human respiratory epithelial cells. While the viral replication of SARS-CoV was only marginally reduced in the absence of TMPRSS2, MERS-CoV was much more dependent on the protease. It was shown that S activation of SARS-CoV could alternatively be performed by endosomal cathepsins. In contrast to that, furin was essential for MERS-CoV S activation in addition to TMPRSS2. The HA activation and the viral replication of the pandemic H1N1/1918 was strongly dependent on TMPRSS2 as well. Avian H12, on the other hand, used other so far unidentified serine proteases for its activation. Interestingly, the monobasic H17 relied on furin. In sum, the presented data indicate that an efficient activation by TMPRSS2 is associated with efficient transmission to and spread among the human host. Therefore, TMPRSS2 is a promising target for a broad antiviral therapy against IAV and CoV.
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This item has been published with the following license: In Copyright