MDA5 participates in the detection of paramyxovirus infection and is essential for the early activation of dendritic cells in response to Sendai Virus defective interfering particles.
Defective interfering (DI) particles are byproducts of virus replication that potently enhance dendritic cell (DC) maturation by virus infection. DI particles have been reported for many different viruses and are strong inducers of type I IFNs. The cellular mechanisms involved in the response to DI particles are not known. In this study, we show that 1) DI particles are recognized by more than one viral sensor independently of TLRs and type I IFN signaling; 2) The helicase MDA5 participates in the detection of DI genomes as MDA5-deficient DCs respond inefficiently to Sendai virus stocks containing DI particles; 3) DI particles stimulate the expression of IRF3-responsive genes by a uniquely potent mechanism when compared with other prototypic viral stimulus; and 4) the efficient detection of DI particles overcomes virus immune antagonism. These data highlight the outstanding adjuvant capacity of DI particles in stimulating mouse and human DCs. They also offer biological relevance to the previously reported inhibition of MDA5 by different paramyxovirus V proteins. The unique mechanism by which DI particles trigger the maturation of DCs represents a novel strategy that could be further exploited for the development of potent adjuvant molecules.
Yount
Jacob S
JS
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Gitlin
Leonid
L
Moran
Thomas M
TM
López
Carolina B
CB
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D003673:Defective Viruses / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D010253:Respirovirus Infections / Q000378:metabolism*; D029082:Sendai virus / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013997:Time Factors; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D051193:Toll-Like Receptors; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1