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Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed by Glycosylation and Other Complex Determinants.
J Virol. 2017 10 01; 91(19)JV

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes dipeptidyl peptidase 4 (DPP4) as an entry receptor. While bat, camel, and human DPP4 support MERS-CoV infection, several DPP4 orthologs, including mouse, ferret, hamster, and guinea pig DPP4, do not. Previous work revealed that glycosylation of mouse DPP4 plays a role in blocking MERS-CoV infection. Here, we tested whether glycosylation also acts as a determinant of permissivity for ferret, hamster, and guinea pig DPP4. We found that, while glycosylation plays an important role in these orthologs, additional sequence and structural determinants impact their ability to act as functional receptors for MERS-CoV. These results provide insight into DPP4 species-specific differences impacting MERS-CoV host range and better inform our understanding of virus-receptor interactions associated with disease emergence and host susceptibility.IMPORTANCE MERS-CoV is a recently emerged zoonotic virus that is still circulating in the human population with an ∼35% mortality rate. With no available vaccines or therapeutics, the study of MERS-CoV pathogenesis is crucial for its control and prevention. However, in vivo studies are limited because MERS-CoV cannot infect wild-type mice due to incompatibilities between the virus spike and the mouse host cell receptor, mouse DPP4 (mDPP4). Specifically, mDPP4 has a nonconserved glycosylation site that acts as a barrier to MERS-CoV infection. Thus, one mouse model strategy has been to modify the mouse genome to remove this glycosylation site. Here, we investigated whether glycosylation acts as a barrier to infection for other nonpermissive small-animal species, namely, ferret, guinea pig, and hamster. Understanding the virus-receptor interactions for these DPP4 orthologs will help in the development of additional animal models while also revealing species-specific differences impacting MERS-CoV host range.

Authors+Show Affiliations

Department of Biology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.Department of Biology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA rbaric@email.unc.edu mark_heisem@med.unc.edu. Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA rbaric@email.unc.edu mark_heisem@med.unc.edu. Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28747502

Citation

Peck, Kayla M., et al. "Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed By Glycosylation and Other Complex Determinants." Journal of Virology, vol. 91, no. 19, 2017.
Peck KM, Scobey T, Swanstrom J, et al. Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed by Glycosylation and Other Complex Determinants. J Virol. 2017;91(19).
Peck, K. M., Scobey, T., Swanstrom, J., Jensen, K. L., Burch, C. L., Baric, R. S., & Heise, M. T. (2017). Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed by Glycosylation and Other Complex Determinants. Journal of Virology, 91(19). https://doi.org/10.1128/JVI.00534-17
Peck KM, et al. Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed By Glycosylation and Other Complex Determinants. J Virol. 2017 10 1;91(19) PubMed PMID: 28747502.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed by Glycosylation and Other Complex Determinants. AU - Peck,Kayla M, AU - Scobey,Trevor, AU - Swanstrom,Jesica, AU - Jensen,Kara L, AU - Burch,Christina L, AU - Baric,Ralph S, AU - Heise,Mark T, Y1 - 2017/09/12/ PY - 2017/03/30/received PY - 2017/07/13/accepted PY - 2017/7/28/pubmed PY - 2017/9/28/medline PY - 2017/7/28/entrez KW - DPP4 KW - MERS-coronavirus KW - animal models KW - glycosylation KW - host range KW - host range expansion KW - orthologs JF - Journal of virology JO - J Virol VL - 91 IS - 19 N2 - Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes dipeptidyl peptidase 4 (DPP4) as an entry receptor. While bat, camel, and human DPP4 support MERS-CoV infection, several DPP4 orthologs, including mouse, ferret, hamster, and guinea pig DPP4, do not. Previous work revealed that glycosylation of mouse DPP4 plays a role in blocking MERS-CoV infection. Here, we tested whether glycosylation also acts as a determinant of permissivity for ferret, hamster, and guinea pig DPP4. We found that, while glycosylation plays an important role in these orthologs, additional sequence and structural determinants impact their ability to act as functional receptors for MERS-CoV. These results provide insight into DPP4 species-specific differences impacting MERS-CoV host range and better inform our understanding of virus-receptor interactions associated with disease emergence and host susceptibility.IMPORTANCE MERS-CoV is a recently emerged zoonotic virus that is still circulating in the human population with an ∼35% mortality rate. With no available vaccines or therapeutics, the study of MERS-CoV pathogenesis is crucial for its control and prevention. However, in vivo studies are limited because MERS-CoV cannot infect wild-type mice due to incompatibilities between the virus spike and the mouse host cell receptor, mouse DPP4 (mDPP4). Specifically, mDPP4 has a nonconserved glycosylation site that acts as a barrier to MERS-CoV infection. Thus, one mouse model strategy has been to modify the mouse genome to remove this glycosylation site. Here, we investigated whether glycosylation acts as a barrier to infection for other nonpermissive small-animal species, namely, ferret, guinea pig, and hamster. Understanding the virus-receptor interactions for these DPP4 orthologs will help in the development of additional animal models while also revealing species-specific differences impacting MERS-CoV host range. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/28747502/Permissivity_of_Dipeptidyl_Peptidase_4_Orthologs_to_Middle_East_Respiratory_Syndrome_Coronavirus_Is_Governed_by_Glycosylation_and_Other_Complex_Determinants_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28747502/ DB - PRIME DP - Unbound Medicine ER -