Middle east respiratory syndrome corona virus spike glycoprotein suppresses macrophage responses via DPP4-mediated induction of IRAK-M and PPARγ

// Ahmed A. Al-Qahtani 1,2 , Konstantina Lyroni 3 , Marina Aznaourova 3 , Melpomeni Tseliou 4 , Mashael R. Al-Anazi 1 , Mohammed N. Al-Ahdal 1,2 , Saad Alkahtani 5 , George Sourvinos 4,* and Christos Tsatsanis 3,* 1 Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Saudi Arabia 2 Department of Microbiology and Immunology, School of Medicine, Alfaisal University, Riyadh, Saudi Arabia 3 Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece 4 Laboratory of Virology, Medical School, University of Crete, Heraklion, Greece 5 Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia * These authors have contributed equally to this work Correspondence to: Christos Tsatsanis, email: // George Sourvinos, email: // Keywords : MERS CoV, macrophages, DPP4, IRAK-M, cytokines, Immunology and Microbiology Section, Immune response, Immunity Received : July 22, 2016 Accepted : January 10, 2017 Published : January 19, 2017 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.