Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry

Area of Science:

• Virology
• Cell Biology
• Respiratory Medicine

Background:

• Human coronaviruses (HCoVs) utilize distinct cellular entry pathways.
• These pathways involve either endosomal cathepsins or cell-surface proteases like TMPRSS2.
• Previous studies showed HCoV-229E prefers TMPRSS2 for entry.

Purpose of the Study:

• To investigate the preferred cell entry pathway for HCoV-OC43 and HCoV-HKU1.
• To compare the entry mechanisms of clinical HCoV isolates with cell-culture-adapted strains.
• To understand the implications of altered entry pathways for viral infectivity in relevant cell models.

Main Methods:

• Infection of human bronchial tracheal epithelial cells with HCoV-OC43 and HCoV-HKU1 clinical isolates.
• Assessment of viral entry via endosomal cathepsins versus cell-surface TMPRSS2.
• Evaluation of viral replication in air-liquid interface cultures of human bronchial tracheal epithelial cells.

Main Results:

• Clinical isolates of HCoV-OC43 and HCoV-HKU1 preferentially used cell-surface TMPRSS2 for cell entry.
• This preference mirrors that of HCoV-229E.
• Cell-culture-adapted HCoV-OC43 demonstrated reduced infectivity and replication in human airway epithelial cell cultures.

Conclusions:

• Circulating HCoVs in humans predominantly employ the cell-surface TMPRSS2 pathway for entry into airway epithelial cells.
• Endosomal cathepsin-dependent entry is less common for naturally circulating strains.
• Cell culture adaptation can lead to a loss of TMPRSS2 dependence and reduced infectivity in relevant human airway models.