SARS-CoV-2 requires acidic pH to infect cells

Area of Science:

• Virology
• Cell Biology
• Biochemistry

Background:

• SARS-CoV-2 infection initiates with the spike protein (S) mediating viral attachment and membrane fusion.
• Viral entry involves sequential proteolytic cleavage of the S protein, typically by furin and TMPRSS2, or endosomal cathepsins.

Approach:

• Utilized real-time 3D single virion tracking to visualize SARS-CoV-2 entry dynamics.
• Employed chemical and genetic perturbations to investigate the role of proteases and pH in viral uptake.
• Examined viral entry in multiple cell types, including TMPRSS2-overexpressing cells.

Key Points:

• Viral fusion and genome penetration necessitate exposure to an acidic environment (pH 6.2-6.8).
• S1 fragment dissociation, fusion, and content release occur sequentially and depend on acidic pH, even post-cleavage.
• An acidic milieu is essential for productive SARS-CoV-2 infection, found in endosomes and on the surface of TMPRSS2-expressing cells.

Conclusions:

• An acidic environment plays a critical, previously unappreciated role in SARS-CoV-2 cell entry.
• The findings elucidate the specific cellular uptake routes and the pH-dependent mechanisms governing productive infection.
• Understanding these entry mechanisms can inform therapeutic strategies targeting viral entry.