The discovery of alternative viral entry mechanisms could reshape our understanding of severe COVID-19 progression and point toward new therapeutic targets beyond the well-established ACE2 pathway. This finding challenges the assumption that ACE2 represents the primary vulnerability point for SARS-CoV-2 infection.
Researchers identified CD147 as a secondary receptor protein that enables prolonged viral infection when ACE2 levels decline. In rhesus macaque studies, SARS-CoV-2 infection triggered upregulation of CD147 through the aryl hydrocarbon receptor transcription pathway, while simultaneously reducing membrane-bound ACE2 expression. This molecular switch allowed extended viral persistence and corresponded with more severe lung pathology. The team used cryo-electron microscopy to map five specific amino acid interactions between CD147 and the viral spike protein, revealing the structural basis for this alternative entry route.
The CD147 pathway appears particularly relevant for understanding why some patients develop prolonged, severe disease courses. Unlike ACE2-mediated entry, CD147 upregulation creates a positive feedback loop—more infection drives higher CD147 expression, enabling further viral spread. The researchers demonstrated that meplazumab, a humanized anti-CD147 antibody, could interrupt this cycle by blocking viral entry and restoring immune balance in infected lung tissue.
This mechanism offers a compelling explanation for the heterogeneity in COVID-19 severity and duration. While most therapeutic attention has focused on ACE2 inhibition, the CD147 pathway suggests that targeting alternative entry points could be crucial for managing severe cases. The finding that an existing antibody therapy can disrupt this process provides immediate therapeutic possibilities, though human trials would be necessary to confirm efficacy and safety profiles.