[Protease-dependent virus tropism and pathogenicity: The role for TMPRSS2]

Area of Science:

• Virology
• Biochemistry
• Molecular Biology

Context:

• Host proteases and their cleavage specificity for viral fusion glycoproteins are critical for viral tissue tropism and pathogenicity.
• Early studies by Homma et al. in the 1970s highlighted host-induced virus modification, later explained by protease activation of viral fusion glycoproteins.

Purpose:

• To elucidate the host proteases responsible for cleaving viral fusion glycoproteins, particularly the mono-basic hemagglutinin (HA) of low pathogenic avian influenza viruses (LPAIVs) and human influenza viruses.
• To identify the specific protease responsible for in vivo cleavage of mono-basic HA, a long-standing question in influenza research.

Summary:

• Highly pathogenic avian influenza viruses (HPAIVs) possess a multi-basic HA cleavage motif activated by ubiquitous furin, enabling systemic infection.
• Low pathogenic and human influenza viruses have mono-basic HA sites, requiring organ-specific proteases for cleavage.
• Recent studies identified TMPRSS2 (a type II transmembrane serine protease) as the protease responsible for cleaving mono-basic HA in influenza viruses in vivo.
• TMPRSS2 also plays a role in the replication and pathology of SARS and MERS coronaviruses.

Impact:

• Identifies TMPRSS2 as a key host factor determining influenza virus tropism and pathogenicity.
• Provides a molecular explanation for the distinct pathogenicity of different influenza virus strains.
• Highlights TMPRSS2 as a potential target for antiviral therapies against influenza and other viral infections like SARS and MERS.