MAVS and MyD88 Are Essential for Innate Immunity but Not Cytotoxic T Lymphocyte Response against Respiratory Syncytial Virus

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (37), p.14046-14051
• Main Authors: Bhoj, Vijay G., Sun, Qinmiao, Bhoj, Elizabeth J., Somers, Cynthia, Chen, Xiang, Torres, Juan-Pablo, Mejias, Asuncion, Gomez, Ana M., Jafri, Hasan, Ramilo, Octavio, Chen, Zhijian J.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antibody Formation - immunology; Antivirals; Biological Sciences; Cytokines; Cytokines - immunology; Gene Expression Regulation; Genomics; Genotypes; Human respiratory syncytial virus; Immunity, Innate - immunology; Infections; Lung Diseases - genetics; Lung Diseases - immunology; Lung Diseases - metabolism; Lung Diseases - physiopathology; Lungs; Lymphocytes; Mice; Mice, Knockout; Molecules; Myeloid Differentiation Factor 88 - deficiency; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Respiratory syncytial virus; Respiratory syncytial virus infections; Respiratory Syncytial Virus Infections - genetics; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Virus Infections - metabolism; Respiratory Syncytial Virus Infections - physiopathology; Respiratory syncytial viruses; Respiratory Syncytial Viruses - immunology; Ribonucleic acid; RNA; Rodents; Signal Transduction - immunology; T cell receptors; T lymphocytes; T-Lymphocytes, Cytotoxic - immunology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0804717105

Infection by RNA viruses is detected by the host through Toll-like receptors or RIG-I-like receptors. Toll-like receptors and RIG-I-like receptors signal through the adaptors MyD88 and MAVS, respectively, to induce type I IFNs (IFN-I) and other antiviral molecules, which are thought to be essential for activating the adaptive immune system. We investigated the role of these adaptors in innate and adaptive immune responses against respiratory syncytial virus (RSV), a common human pathogen. Deletion of Mavs abolished the induction of IFN-I and other proinflammatory cytokines by RSV. Genome-wide expression profiling in the lung showed that the vast majority of RSV-induced genes depended on MAVS. Although Myd88 deficiency did not affect most RSV-induced genes, mice lacking both adaptors harbored a higher and more prolonged viral load and exhibited more severe pulmonary disease than those lacking either adaptor alone. Surprisingly, $Myd88^{-/-}Mavs^{-/-}$ mice were able to activate a subset of pulmonary dendritic cells that traffic to the draining lymph node in response to RSV. These mice subsequently mounted a normal cytotoxic T-lymphocyte response and demonstrated delayed but effective viral clearance. These results provide an example of a normal and effective adaptive immune response in the absence of innate immunity mediated by MAVS and MyD88.