COVID-19 researchGene: DPP4
PMID: 31883094 - Leist et al 2020 - describe the generation of the 288-330+/+ MERS-CoV mouse model in which mice were made susceptible to MERS-CoV by modifying two amino acids on mDPP4 (A288 and T330).
Created: 13 May 2020, 7 p.m. | Last Modified: 13 May 2020, 7 p.m.
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PMID: 31964246 - Kleine-Weber et al 2020- looked at naturally-occurring polymorphisms in DPP4 from public databases, that alter amino acid residues required for MERS-CoV S binding to see if they influence cellular entry of MERS-CoV. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication.
Created: 13 May 2020, 6:53 p.m. | Last Modified: 13 May 2020, 6:53 p.m.
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Comment on phenotypes: This is not an official phenotype, just the observation from the literature
Created: 12 Jun 2020, 10:21 a.m. | Last Modified: 12 Jun 2020, 10:21 a.m.
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DPP4 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA). "Illumina review: Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. DPP4 acts as a receptor for MERS-CoV - PMID: 24554656 - Barlan et al. (2014). MERS virus cell entry begins with the receptor-binding domains (RBDs) of the MERS-CoV protein virus spike (S) protein binding to blades 4 and 5 of the 8-blade propeller domain of DPP4. PMID:23486063 - Raj et al. (2013) - identified DPP4 as a functional receptor for hCoV-EMS (MERS CoV). Evidence from mouse models of involvment in susceptibility to MERS-CoV infection. PMID:24599590 - Zhao et al. (2014) - noted that rodents are not susceptible to MERS-CoV. They used an adenovirus vector expressing human DPP4 to generate mice sensitized to infection with MERS-CoV. These mice developed pneumonia characterized by extensive inflammatory cell infiltration with virus clearance after 6 to 8 days in a type I IFN- and T cell-dependent manner. Treatment with poly(I:C) was also efficacious in this model. PMID: 25589660 - Agrawal et al. (2015) developed a transgenic mouse model expressing human DPP4 that was susceptible to MERS-CoV infection, with high titers of virus detectable in brain and lung and later in other organs. PMID: 26124093 - Pascal et al. (2015) - obtained a mouse model susceptible to intranasal infection with MERS-CoV. Human monoclonal antibodies binding to the MERS-CoV S protein neutralized all variants of the virus and prevented entry into target cells. The antibodies could both prevent and treat mice humanized for DPP4. Pascal et al. (2015) concluded that the model will be valuable for assessing treatments for MERS-CoV infection and disease. PMID:31883094 - Leist et al. (2020) - generated a mouse model susceptible to MERS-CoV infection - used C57BL/6J mice and CRISPR/Cas9 to substitute human residues at positions 288 and 330 (A288L and T330R). Strollo et al. (2020) and Bassedine et al. (2020) suggested that DPP4 could affect severity of infection and also be a therapeutic target: PMID:32336077 - Strollo et al. (2020) - propose a role for DDP4 as a functional receptor for SARS-CoV-2 and ask the question if DPP4 is directly involved in SARS-CoV-2 cell adhesion/virulence, and whether DPP4 inhibition might be a therapeutic strategy for preventing infection. PMID:32394639 - Bassedine et al. (2020) - modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. Notes that increased DPP4 expression and activity are associated with diabetes, obesity, and metabolic syndrome, all of which have been reported to influence COVID‐19 severity. DPP4 inhibitors (gliptins), which vary in their interactions with the active site of the enzyme, may have immunomodulatory and cardioprotective effects that could be beneficial in COVID‐19 cases. PMID:31964246 - Keline-Weber at al. (2020) - Identified 14 polymorphisms in DPP4 from public databases that alter amino acid residus required for MERS-CoV S binding. Introduction of the respective variants into DPP4 revealed that all except one (Δ346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients.
Created: 11 Jun 2020, 6:10 p.m. | Last Modified: 12 Jun 2020, 10:24 a.m.
Panel Version: 1.23
DPP4 is a functional receptor for human coronavirus-Erasmus Medical Center (hCoV-EMC), also known as Middle East respiratory syndrome coronavirus (MERS-CoV). Blades 4 and 5 of the 8-blade beta-propeller region of DPP4 confer binding and susceptibility to MERS-CoV (PMID 24554656). Rhodants are not susceptible to MERS-CoV, however, a mouse models expressing human DPP4 became infected with MERS-CoV (PMID 24599590; 25589660; 26124093).
Created: 12 May 2020, 4:20 p.m.
Mode of inheritance
Phenotypes for gene: DPP4 were changed from to Susceptiblity to MERS-CoV infection
Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093; https://doi.org/10.1101/2020.04.30.071274; 31883094; 31964246
Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093; https://doi.org/10.1101/2020.04.30.071274
Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093
Gene: dpp4 has been classified as Amber List (Moderate Evidence).
gene: DPP4 was added gene: DPP4 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: DPP4 was set to Unknown Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093 Review for gene: DPP4 was set to AMBER