Abstract
The cellular protease TMPRSS2 cleaves and activates the influenza virus hemagglutinin (HA) and TMPRSS2 expression is essential for viral spread and pathogenesis in mice. Moreover, severe acute respiratory syndrome coronavirus (SARS-CoV) and other respiratory viruses are activated by TMPRSS2. However, previous studies on viral activation by TMPRSS2 focused on a 492 amino acids comprising form of the protein (isoform 2) while other TMPRSS2 isoforms, generated upon alternative splicing of the tmprss2 mRNA, have not been characterized. Here, we show that the mRNA encoding a TMPRSS2 isoform with an extended N-terminal cytoplasmic domain (isoform 1) is expressed in lung-derived cell lines and tissues. Moreover, we demonstrate that TMPRSS2 isoform 1 colocalizes with HA and cleaves and activates HA. Finally, we show that isoform 1 activates the SARS-CoV spike protein for cathepsin L-independent entry into target cells. Our results indicate that TMPRSS2 isoform 1 is expressed in viral target cells and might contribute to viral activation in the host.
Highlights
IntroductionAnnual influenza epidemics are associated with several hundred thousand deaths every year, and interspersed pandemics may wreck even greater havoc [1], as documented by the 1918 Spanish influenza, which caused 30 to 50 million deaths [2]
Respiratory viruses pose a significant threat to human health
Several host cell proteases can activate FLUAV HA in cell culture and it has been assumed that respiratory viruses can employ redundant proteolytic systems to ensure their activation in the host [4]
Summary
Annual influenza epidemics are associated with several hundred thousand deaths every year, and interspersed pandemics may wreck even greater havoc [1], as documented by the 1918 Spanish influenza, which caused 30 to 50 million deaths [2]. Antiviral drugs against influenza are available but their effectiveness is compromised by frequent acquisition of viral resistance. No drugs with broad antiviral activity are available to combat emerging and highly virulent respiratory viruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS) CoV. In order to close this gap, novel antiviral strategies are being sought, which allow inhibition of a broad spectrum of viruses and which are associated with a high barrier against resistance development. Host cell factors which are essential for viral spread but dispensable for cellular survival are attractive targets for such approaches to antiviral therapy
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