| Respiratory infections with paramyxoviruses result in the establishment of acute and chronic lung inflammation and disease in susceptible individuals. Sendai virus (SeV) is a paramyxovirus that causes bronchiolitis and persistent airway inflammation in mice, providing an accepted experimental model for virus-induced chronic lung disease. This dissertation work focused on the study of the interaction of SeV with the host at two different levels: Fist, we evaluated the mechanisms involved in the stimulation of the antiviral response to SeV in vitro. Second, we explored the role of the cellular pattern recognition receptor MDA5 in the induction, progress, and resolution of SeV infection in vivo..;We have demonstrated that defective viral genomes (DVGs) present on Sendai virus (SeV) stocks provide strong immunostimulatory ability to the virus. Here, we show that the stimulatory activity of DVGs is mediated by robust and sustained activation of the transcription factors IRF3 and NF-kB, independently of type I IFN positive feedback. In addition, we show that other IRFs are not required for this potent cellular response to the virus, and that these responses are conserved in both hematopoietic and non-hematopoietic cells.;The intracellular pathogen recognition receptors RIG-I and MDA5 play a critical role in the cellular response to infecting viruses by signaling for the expression of antiviral and proinflammatory molecules. Here we show that while the replication and spread of SeV in the lung is controlled independently of MDA5 in vivo, deficiency of this molecule leads to sustained lung inflammation and enhanced disruption of the epithelial barrier upon infection. This phenotype is preceded by a striking shift in the early production of neutrophil- and monocyte/lymphocyteattracting chemokines in the lung and leads to the expression of a biased pro-inflammatory transcriptome in the lung that includes the expression of IL-10, IL-27 and IL-13. Notably, MDA5 deficiency results in exacerbated accumulation of alternatively activated macrophages in the lung and in chronic lung inflammation. |
