title: Human metapneumovirus M2-2 protein inhibits innate cellular signaling by targeting MAVS.
abstract: Human metapneumovirus (hMPV) is a leading cause of respiratory infections in pediatric populations globally, with no prophylactic or therapeutic measures. Recently, a recombinant hMPV lacking the M2-2 protein (rhMPV-ΔM2-2) demonstrated reduced replication in the respiratory tract of animal models, making it a promising live vaccine candidate. However, the exact nature of the interaction between the M2-2 protein and host cells that regulates viral infection/propagation is largely unknown. By taking advantage of the available reverse genetics system and ectopic expression system for viral protein, we found that M2-2 not only promotes viral gene transcription and replication but subverts host innate immunity, therefore identifying M2-2 as a novel virulence factor, in addition to the previously described hMPV G protein. Since we have shown that the RIG-I/MAVS pathway plays an important role in hMPV-induced signaling in airway epithelial cells, we investigated whether M2-2 antagonizes the host cellular responses by targeting this pathway. Reporter gene assays and coimmunoprecipitation studies indicated that M2-2 targets MAVS, an inhibitory mechanism different from what we previously reported for hMPV G, which affects RIG-I- but not MAVS-dependent gene transcription. In addition, we found that the domains of M2-2 responsible for the regulation of viral gene transcription and antiviral signaling are different. Our findings collectively demonstrate that M2-2 contributes to hMPV immune evasion through the inhibition of MAVS-dependent cellular responses.
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Junping
authors.initials: J
authors.lastname: Ren
authors.forename: Qingrong
authors.initials: Q
authors.lastname: Wang
authors.forename: Deepthi
authors.initials: D
authors.lastname: Kolli
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Prusak
authors.forename: Chien-Te K
authors.initials: CT
authors.lastname: Tseng
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: Kui
authors.initials: K
authors.lastname: Li
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Wood
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Bao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D057131:Immune Evasion / Q000235:genetics*; D047468:Immunoprecipitation; D029121:Metapneumovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C505371:MAVS protein, human; D014764:Viral Proteins; D037521:Virulence Factors