Abstract
The distribution pattern of host proteases and their cleavage specificity for viral fusion glycoproteins are key determinants for viral tissue tropism and pathogenicity. The discovery of this protease-dependent virus tropism and pathogenicity has been triggered by the leading studies of the host-induced or -controlled modification of viruses by Homma et al. in 1970s. With the introduction of advanced protein analysis method, the observations by Homma et al. have been clearly explained by the cleavage activation of viral fusion glycoproteins by proteases. The molecular biological features of viruses, which show distinct protease specificity or dependency, have been also revealed by newly introduced nucleotide and molecular analysis method. Highly pathogenic avian influenza viruses (HPAIVs) have multi-basic cleavage motif in the hemagglutinin (HA) protein and are activated proteolytically by furin. Furin is ubiquitously expressed in eukaryotic cells and thereby HPAIVs have the potential to cause a systemic infection in infected animals. On the other hand, the HA cleavage site of low pathogenic avian influenza viruses (LPAIVs) and seasonal human influenza viruses is mono-basic and thus not recognized by furin. They are likely cleaved by protease(s) localized in specific organs or tissues. However, the protease(s), which cleaves mono-basic HA in vivo, has long been undetermined, although many proteases have been shown as candidates. Finally, recent studies using gene knocked out mice revealed that TMPRSS2, a member of type II transmembrane serine proteases, is responsible for the cleavage of influenza viruses with a mono-basic HA in vivo. A subsequent study further demonstrated that TMPRSS2 contributes to replication and pathology of emerging SARS- and MERS coronaviruses in vivo.
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