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 TNFa 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.

MERS coronavirus outbreak: Implications for emerging viral infections

“…This could contribute to the level of pulmonary inflammation and tissue damage associated with MERS-CoV induced progressive pneumonia. On the other hand, recent studies in differentiated THP-1 macrophages infected with lentiviral particles pseudotyped with MERS-CoV S protein suggested that macrophage responses including IL-6 and TNF-α production were reduced, while LPS-induced production of the immunosuppressive IL-10 was increased (Al-Qahtani et al, 2017). This increase in IL-10 production was mediated by DPP4 binding and activation of IRAK-M, a negative regulator of TLR signaling and the transcriptional repressor PPARγ (Al-Qahtani et al, 2017).…”

“…The MERS-CoV S protein DPP4 receptor is widely expressed in human cells including lower respiratory tract non ciliated bronchial epithelium, kidney epithelial cells, small intestine cells, T lymphocytes and macrophages (Al-Qahtani et al, 2017;Boonacker and Van Noorden, 2003;Tang et al, 2017;Widagdo et al, 2016). There is limited expression of DPP4 in the upper respiratory tract epithelium in humans when compared to dromedary camels, which may contribute to the limited replication of MERS-CoV in the human upper respiratory tract and to restriction of human-to-human transmission (Widagdo et al, 2016).…”

“…There is limited expression of DPP4 in the upper respiratory tract epithelium in humans when compared to dromedary camels, which may contribute to the limited replication of MERS-CoV in the human upper respiratory tract and to restriction of human-to-human transmission (Widagdo et al, 2016). Infection of macrophages by lentiviral particles pseudotyped with MERS-CoV S protein resulted in attenuation of macrophage responses via expression of IRAK-M, a negative regulator of Toll-like receptor (TLR) signaling, and of the transcriptional repressor PPARγ (Al-Qahtani et al, 2017). Use of the DPP4 inhibitor sitagliptin or DPP4-siRNA reduced the effects of MERS-CoV S protein on IRAK-M, PPARγ and IL-10, indicating that the suppression of macrophage immune responses by MERS-CoV is mediated via DPP4 (Al-Qahtani et al, 2017).…”

“…Infection of macrophages by lentiviral particles pseudotyped with MERS-CoV S protein resulted in attenuation of macrophage responses via expression of IRAK-M, a negative regulator of Toll-like receptor (TLR) signaling, and of the transcriptional repressor PPARγ (Al-Qahtani et al, 2017). Use of the DPP4 inhibitor sitagliptin or DPP4-siRNA reduced the effects of MERS-CoV S protein on IRAK-M, PPARγ and IL-10, indicating that the suppression of macrophage immune responses by MERS-CoV is mediated via DPP4 (Al-Qahtani et al, 2017). Mathematical modeling suggests that reducing the rate of DPP4 expression would reduce MERS-CoV spread (Tang et al, 2017).…”

Human T-cell immunity against the emerging and re-emerging viruses

“…These data indicate that dysregulated immune response-associated lung immunopathology in MERS-CoV-infected patients might lead to deleterious clinical manifestations. In addition, recent evidence (Al-Qahtani et al, 2017) showed that the capture of the human CD26 by MERS-CoV S protein suppressed macrophage responses via CD26-mediated induction of Toll-like receptor (TLR) signaling. This discovery verified our previous observation about the potential impact of both MERS-CoV and SARS-CoV on the host immune responses through interaction with their receptors (Liu et al, 2017b).…”