OmniVira

Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed by Glycosylation and Other Complex Determinants.

Kayla M Peck1 Trevor Scobey2 Jesica Swanstrom2 Kara L Jensen2 Christina L Burch1 Ralph S Baric3,4 Mark T Heise5,4
Affiliations 5 institutions
  1. Department of Biology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
  2. Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
  3. Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA [email protected] [email protected].
  4. Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
  5. Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA [email protected] [email protected].
PMID28747502 DOI10.1128/JVI.00534-17 Year2017 Journal Journal of virology J Virol Languageeng Statusepublish

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.

Supporting text Virus Host Location
animal models 3 DPP4 3 glycosylation 23 host range 29 host range expansion 1 MERS-coronavirus 1 orthologs 1 Virus Attachment 55 Amino Acid Sequence 128 Animals 1948 Cell Line 158 Chlorocebus aethiops 70 Coronavirus Infections 171 Cricetinae 41 Dipeptidyl Peptidase 4 32 Ferrets 79 Glycosylation 22 Guinea Pigs 21 HEK293 Cells 61 Host Specificity 132 Humans 1440 Middle East Respiratory Syndrome Coronavirus 68 Receptors, Virus 204 Sequence Alignment 51

Evidence records

2 total
Experimental Infection
1 records · 1 evidence types
Evidence type Host Range Experiment
1 records
OVE2664 Host Range Experiment
Key finding

Glycosylation and additional sequence or structural determinants in ferret, hamster, and guinea pig DPP4 orthologs influence their ability to act as functional receptors for MERS-CoV, affecting host range.

Virus
Middle East Respiratory Syndrome Coronavirus
Host
domestic ferret Mustela putorius furo Experimental system domestic guinea pig Cavia porcellus Experimental system hamsters Cricetinae Experimental system
Location
Not specified
Supporting text

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.

Method
receptor expression | virus entry assay | glycosylation analysis | sequence and structural analysis
Sample type
DPP4 ortholog proteins | cells expressing DPP4 orthologs
Experimental system
cell-culture receptor-expression system assessing DPP4 ortholog-mediated viral entry
Functional Mechanism
1 records · 1 evidence types
Evidence type Receptor Usage
1 records
OVE2662 Receptor Usage
Key finding

Bat, camel, and human DPP4 act as functional receptors permitting MERS-CoV infection, whereas mouse, ferret, hamster, and guinea pig DPP4 do not support viral entry, demonstrating species-specific DPP4 usage.

Virus
Middle East Respiratory Syndrome Coronavirus
Host
bats Chiroptera Experimental system Camelus Experimental system human Homo sapiens Experimental system house mouse Mus musculus Experimental system domestic ferret Mustela putorius furo Experimental system hamsters Cricetinae Experimental system domestic guinea pig Cavia porcellus Experimental system
Location
Not specified
Supporting text

While bat, camel, and human DPP4 support MERS-CoV infection, several DPP4 orthologs, including mouse, ferret, hamster, and guinea pig DPP4, do not.

Method
infection assay | receptor compatibility testing | ortholog expression system
Receptors
DPP4 | dipeptidyl peptidase 4
Host factors
glycosylation