title: Middle east respiratory syndrome corona virus spike glycoprotein suppresses macrophage responses via DPP4-mediated induction of IRAK-M and PPARγ.
abstract: Middle East Respiratory Syndrome Corona Virus (MERS-CoV) is transmitted via the respiratory tract and causes severe Acute Respiratory Distress Syndrome by infecting lung epithelial cells and macrophages. Macrophages can readily recognize the virus and eliminate it. MERS-CoV infects cells via its Spike (S) glycoprotein that binds on Dipeptidyl-Peptidase 4 (DPP4) receptor present on macrophages. Whether this Spike/DPP4 association affects macrophage responses remains unknown. Herein we demonstrated that infection of macrophages with lentiviral particles pseudotyped with MERS-CoV S glycoprotein results in suppression of macrophage responses since it reduced the capacity of macrophages to produce TNFα and IL-6 in naive and LPS-activated THP-1 macrophages and augmented LPS-induced production of the immunosuppressive cytokine IL-10. MERS-CoV S glycoprotein induced the expression of the negative regulator of TLR signaling IRAK-M as well as of the transcriptional repressor PPARγ. Inhibition of DPP4 by its inhibitor sitagliptin or siRNA abrogated the effects of MERS-CoV S glycoprotein on IRAK-M, PPARγ and IL-10, confirming that its immunosuppressive effects were mediated by DPP4 receptor. The effect was observed both in THP-1 macrophages and human primary peripheral blood monocytes. These findings support a DPP4-mediated suppressive action of MERS-CoV in macrophages and suggest a potential target for effective elimination of its pathogenicity.
authors.affiliation: Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Saudi Arabia.|Department of Microbiology and Immunology, School of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Al-Qahtani
authors.affiliation: Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Lyroni
authors.affiliation: Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece.
authors.forename: Marina
authors.initials: M
authors.lastname: Aznaourova
authors.affiliation: Laboratory of Virology, Medical School, University of Crete, Heraklion, Greece.
authors.forename: Melpomeni
authors.initials: M
authors.lastname: Tseliou
authors.affiliation: Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Saudi Arabia.
authors.forename: Mashael R
authors.initials: MR
authors.lastname: Al-Anazi
authors.affiliation: Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Saudi Arabia.|Department of Microbiology and Immunology, School of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Al-Ahdal
authors.affiliation: Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Saad
authors.initials: S
authors.lastname: Alkahtani
authors.affiliation: Laboratory of Virology, Medical School, University of Crete, Heraklion, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Sourvinos
authors.affiliation: Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
mesh_terms: D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D054884:Host-Pathogen Interactions; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D065207:Middle East Respiratory Syndrome Coronavirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D064370:Spike Glycoprotein, Coronavirus / Q000235:genetics / Q000378:metabolism*; D000074084:THP-1 Cells; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D047495:PPAR gamma; D064370:Spike Glycoprotein, Coronavirus; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: DPP4; IRAK-M; Immune response; Immunity; Immunology and Microbiology Section; MERS CoV; cytokines; macrophages