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Clade C MERS-CoV camel strains vary in protease utilization during viral entry

Helena Winstone1,2, Helen Stillwell1,2, Li Hui Tan3

  • 1Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Proceedings of the National Academy of Sciences of the United States of America
|April 1, 2026
PubMed

Insights

Middle East Respiratory Syndrome coronavirus (MERS-CoV) clade C spikes show reduced cleavage and syncytium formation. This may explain lower human spillover potential for MERS-CoV clade C strains.

Area of Science:

  • Virology
  • Infectious Diseases
  • Epidemiology

Background:

  • Middle East Respiratory Syndrome coronavirus (MERS-CoV) poses a pandemic threat, with clades A and B causing outbreaks since 2012.
  • Clade C MERS-CoV strains are found in African camels, with lower apparent spillover potential than clades A/B, requiring further investigation.

Purpose of the Study:

  • To investigate the molecular and cellular basis for the reduced human spillover potential of MERS-CoV clade C strains.
  • To compare the viral entry mechanisms and spike protein characteristics of MERS-CoV clade C strains with clades A and B.

Main Methods:

  • Analysis of MERS-CoV spike protein cleavage at the S1/S2 boundary.
  • Assessment of syncytium formation induced by different MERS-CoV clades.
  • Evaluation of viral entry utilizing the TMPRSS2 pathway in cell lines and primary nasal epithelial cultures.
  • Mapping the molecular determinants of TMPRSS2 usage in clade C MERS-CoV.

Main Results:

  • Clade C MERS-CoV spikes exhibit less efficient cleavage at the S1/S2 boundary compared to clades A and B.
  • Most clade C spikes induce reduced syncytium formation.
  • East African clade C MERS-CoV strains show diminished utilization of the TMPRSS2-mediated entry pathway.
  • Reduced TMPRSS2 usage is linked to the N-terminal domain and subdomain 2 of East African clade C MERS-CoV.

Conclusions:

  • Reduced TMPRSS2 pathway usage may explain the lower replication of East African clade C MERS-CoV in humans.
  • Differential protease usage suggests geographically distinct selection pressures on MERS-CoV spike proteins.
  • Further research is needed to understand the reduced replication of West African clade C strains.
Keywords:
MERS-CoV camel reservoircoronavirusespandemic potentialviral entryvirus–host interaction

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