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Mouse dipeptidyl peptidase 4 is not a functional receptor for Middle East respiratory syndrome coronavirus infection
Adam S Cockrell1, Kayla M Peck, Boyd L Yount
1Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
Abstract:
Human dipeptidyl peptidase 4 (hDPP4) was recently identified as the receptor for Middle East respiratory syndrome coronavirus (MERS-CoV) infection, suggesting that other mammalian DPP4 orthologs may also support infection. We demonstrate that mouse DPP4 cannot support MERS-CoV infection. However, employing mouse DPP4 as a scaffold, we identified two critical amino acids (A288L and T330R) that regulate species specificity in the mouse. This knowledge can support the rational design of a mouse-adapted MERS-CoV for rapid assessment of therapeutics.
Insights
Mouse cells do not support Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Researchers identified key amino acid changes in mouse dipeptidyl peptidase 4 (DPP4) to enable MERS-CoV adaptation for therapeutic studies.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Human dipeptidyl peptidase 4 (hDPP4) is the known receptor for Middle East respiratory syndrome coronavirus (MERS-CoV).
- The potential for other mammalian DPP4 orthologs to mediate MERS-CoV infection remains largely unexplored.
- Understanding DPP4-CoV interactions is crucial for developing antiviral strategies.
Purpose of the Study:
- To investigate the susceptibility of mouse DPP4 to MERS-CoV infection.
- To identify specific amino acid residues in mouse DPP4 that confer species specificity.
- To provide a basis for developing a mouse-adapted MERS-CoV model for therapeutic evaluation.
Main Methods:
- Infection assays using MERS-CoV and cells expressing mouse DPP4.
- Site-directed mutagenesis to alter amino acid residues in mouse DPP4.
- Comparative analysis of MERS-CoV binding and entry mediated by wild-type and mutant mouse DPP4.
Main Results:
- Mouse DPP4 does not support MERS-CoV infection.
- Two critical amino acid substitutions (A288L and T330R) in mouse DPP4 were identified as key determinants of species specificity.
- These mutations enable MERS-CoV to utilize mouse DPP4 for infection.
Conclusions:
- Mouse DPP4 is not a functional receptor for MERS-CoV.
- Specific amino acid residues regulate the species tropism of MERS-CoV entry via DPP4.
- The identified mutations provide a foundation for engineering a mouse-adapted MERS-CoV for preclinical drug screening.
