title: Human metapneumovirus M2-2 protein inhibits innate immune response in monocyte-derived dendritic cells.
abstract: Human metapneumovirus (hMPV) is a leading cause of lower respiratory infection in young children, the elderly and immunocompromised patients. Repeated hMPV infections occur throughout life. However, immune evasion mechanisms of hMPV infection are largely unknown. Recently, our group has demonstrated that hMPV M2-2 protein, an important virulence factor, contributes to immune evasion in airway epithelial cells by targeting the mitochondrial antiviral-signaling protein (MAVS). Whether M2-2 regulates the innate immunity in human dendritic cells (DC), an important family of immune cells controlling antigen presenting, is currently unknown. We found that human DC infected with a virus lacking M2-2 protein expression (rhMPV-ΔM2-2) produced higher levels of cytokines, chemokines and IFNs, compared to cells infected with wild-type virus (rhMPV-WT), suggesting that M2-2 protein inhibits innate immunity in human DC. In parallel, we found that myeloid differentiation primary response gene 88 (MyD88), an essential adaptor for Toll-like receptors (TLRs), plays a critical role in inducing immune response of human DC, as downregulation of MyD88 by siRNA blocked the induction of immune regulatory molecules by hMPV. Since M2-2 is a cytoplasmic protein, we investigated whether M2-2 interferes with MyD88-mediated antiviral signaling. We found that indeed M2-2 protein associated with MyD88 and inhibited MyD88-dependent gene transcription. In this study, we also identified the domains of M2-2 responsible for its immune inhibitory function in human DC. In summary, our results demonstrate that M2-2 contributes to hMPV immune evasion by inhibiting MyD88-dependent cellular responses in human DC.
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Junping
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Otorhinolaryngology, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Guangliang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Go
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Kolli
authors.affiliation: Department of Otorhinolaryngology, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Guanping
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Bao
mesh_terms: D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D029121:Metapneumovirus / Q000235:genetics* / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D014764:Viral Proteins