Abstract
Respiratory syncytial virus (RSV) infection can result in severe disease partially due to its ability to interfere with the initiation of Th1 responses targeting the production of type I interferons (IFN) and promoting a Th2 immune environment. Epigenetic modulation of gene transcription has been shown to be important in regulating inflammatory pathways. RSV-infected bone marrow-derived DCs (BMDCs) upregulated expression of Kdm5b/Jarid1b H3K4 demethylase. Kdm5b-specific siRNA inhibition in BMDC led to a 10-fold increase in IFN-β as well as increases in IL-6 and TNF-α compared to control-transfected cells. The generation of Kdm5b fl/fl-CD11c-Cre+ mice recapitulated the latter results during in vitro DC activation showing innate cytokine modulation. In vivo, infection of Kdm5b fl/fl-CD11c-Cre+ mice with RSV resulted in higher production of IFN-γ and reduced IL-4 and IL-5 compared to littermate controls, with significantly decreased inflammation, IL-13, and mucus production in the lungs. Sensitization with RSV-infected DCs into the airways of naïve mice led to an exacerbated response when mice were challenged with live RSV infection. When Kdm5b was blocked in DCs with siRNA or DCs from Kdm5b fl/fl-CD11c-CRE mice were used, the exacerbated response was abrogated. Importantly, human monocyte-derived DCs treated with a chemical inhibitor for KDM5B resulted in increased innate cytokine levels as well as elicited decreased Th2 cytokines when co-cultured with RSV reactivated CD4+ T cells. These results suggest that KDM5B acts to repress type I IFN and other innate cytokines to promote an altered immune response following RSV infection that contributes to development of chronic disease.
Highlights
Respiratory syncytial virus (RSV) is a significant burden to healthcare worldwide
We found that the protein KDM5B regulates an epigenetic mechanism that directs the immune response to RSV
Our results show that decreasing Kdm5b expression by siRNA, chemical inhibition or genetic deletion prior to RSV infection leads to an increase in the production of IFN-β and other inflammatory cytokines compared to uninfected controls, as well as decreased Th2 pathogenesis in vivo linking Kdm5b expression with disease exacerbation during RSV infection
Summary
Respiratory syncytial virus (RSV) is a significant burden to healthcare worldwide. In the United States most children have been infected by age two [1,2]. Severe infections are the leading cause of bronchiolitis in children, resulting in up to 125,000 hospitalizations in the US each year [3,4]. Infants who are hospitalized with severe disease are 3–4 times more likely to develop asthma later in life [5,6], as RSV interferes with the initiation of the adaptive immune response leading to an altered immune environment in the lungs. Attempts to create a formalin-inactivated vaccine resulted in more severe infection upon exposure to the virus in those children who were vaccinated compared to unvaccinated children [8]. The need to understand the immune response to RSV at the molecular level is critical to develop better therapeutics and aid in the development of effective vaccines
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