Abstract
Human metapneumovirus (hMPV) is a leading cause of lower respiratory infection in pediatric populations globally. This study examined proteomic profile changes in A549 cells infected with hMPV and two attenuated mutants with deleted PDZ domain-binding motif(s) in the M2-2 protein. These motifs are involved in the interruption of antiviral signaling, namely the interaction between the TNF receptor associated factor (TRAF) and mitochondrial antiviral-signaling (MAVS) proteins. The aim of this study was to provide insight into the overall and novel impact of M2-2 motifs on cellular responses via an unbiased comparison. Tandem mass tagging, stable isotope labeling, and high-resolution mass spectrometry were used for quantitative proteomic analysis. Using quantitative proteomics and Venn analysis, 1248 common proteins were detected in all infected samples of both technical sets. Hierarchical clustering of the differentiated proteome displayed distinct proteomic signatures that were controlled by the motif(s). Bioinformatics and experimental analysis confirmed the differentiated proteomes, revealed novel cellular biological events, and implicated key pathways controlled by hMPV M2-2 PDZ domain-binding motif(s). This provides further insight for evaluating M2-2 mutants as potent vaccine candidates.
Highlights
Human metapneumovirus, a negative-sense single-stranded RNA virus, belongs to the Pneumoviridae family, the same virus family that causes mumps and parainfluenza [1,2,3]
In terms of M2-2, we have recently shown that it contributes to the immune evasion of infected human dendritic cells and airway epithelial cells by targeting myeloid differentiation primary response gene 88 (MyD88) and the mitochondrial antiviral-signaling (MAVS)
We have previously shown that Human metapneumovirus (hMPV) activates one of the most important innate immune pathways, namely the RIG-I-MAVS-TNF receptor associated factor (TRAF) pathway, in infected airway epithelial cells [12,16,36,37,38,39,40], and M2-2 uses its two putative PDZ motifs to counteract host antiviral responses [13]
Summary
Human metapneumovirus (hMPV), a negative-sense single-stranded RNA virus, belongs to the Pneumoviridae family, the same virus family that causes mumps and parainfluenza [1,2,3]. Several viral protein-based vaccine candidates have been developed recently, with some inducing a strong humoral immune response against both homologous and heterologous strains. Such response diminishes rapidly over time, which might result from the lack of other viral protein(s) contributing to the immunogenicity and immune balance [7]. A wild-type recombinant hMPV was approved as a suitable parent virus for the development of live attenuated hMPV vaccine candidates in experimental human infection trials [8], providing a promising vaccine study direction for hMPV. Live attenuated vaccines offer several advantages for the immunization of infants and young children, including no vaccine-associated enhanced viral disease, the induction of both humoral and mucosal immunity, intranasal vaccine delivery, and viral replication in the upper respiratory tract of young infants despite the presence of passively acquired maternally-derived respiratory syncytial virus (RSV) neutralizing antibodies [14]
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