title: Human metapneumovirus glycoprotein G inhibits TLR4-dependent signaling in monocyte-derived dendritic cells.
abstract: Human metapneumovirus (hMPV) is a major cause of upper and lower respiratory infections in children and adults. Recent work from our group demonstrated that hMPV G glycoprotein is an important virulence factor, responsible for inhibiting innate immune responses in airway epithelial cells. Myeloid dendritic cells (DCs) are potent APCs and play a major role in initiating and modulating the innate and adaptive immune responses. In this study, we found that TLR4 plays a major role in hMPV-induced activation of monocyte-derived DCs (moDCs), as downregulation of its expression by small interfering RNA significantly blocked hMPV-induced chemokine and type I IFN expression. Similar results were found in bone marrow-derived DCs from TLR4-deficient mice. moDCs infected with a virus lacking G protein expression produced higher levels of cytokines and chemokines compared with cells infected with wild-type virus, suggesting that G protein plays an inhibitory role in viral-induced cellular responses. Specifically, G protein affects TLR4-dependent signaling, as infection of moDCs with recombinant hMPV lacking G protein inhibited LPS-induced production of cytokine and chemokines significantly less than did wild-type virus, and treatment of moDCs with purified G protein resulted in a similar inhibition of LPS-dependent signaling. Our results demonstrate that hMPV G protein plays an important role in inhibiting host innate immune responses, likely affecting adaptive responses too.
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Kolli
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Bao
authors.forename: Tianshuang
authors.initials: T
authors.lastname: Liu
authors.forename: Chao
authors.initials: C
authors.lastname: Hong
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
authors.forename: Antonella
authors.initials: A
authors.lastname: Casola
mesh_terms: D056704:Adaptive Immunity; D000328:Adult; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008253:Macaca mulatta; D029121:Metapneumovirus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D018925:Chemokines; D016207:Cytokines; C484233:G glycoprotein, human metapneumovirus; D006023:Glycoproteins; D018836:Inflammation Mediators; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014764:Viral Proteins