Lung inflammation and type I interferons in Bordetella pertussis infection

University Of Maryland Baltimore, Baltimore MD

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Abstract

Bordetella pertussis causes prolonged severe cough and puts infants at risk of fatal disease. Cases of pertussis are at a 60 year high in the United States due to a combination of an ineffective vaccine, bacterial strain evolution, and a poorly understood mechanism of pathogenesis. To combat this, host targeted therapeutics must be developed to effectively treat patients. An RNAseq transcriptomic analysis identified type I interferon (IFN) receptor subunit, IFNAR1, as the single most significant upstream activator of gene expression in the lungs of B. pertussis-­infected mice. This suggests that type I IFN signaling plays a crucial role in pertussis pathogenesis and disease. Type I IFNs are classically considered the major antiviral cytokine class, however, they are also involved in inflammation and pathogenesis of several bacterial infection models. The role of type I IFNs in B. pertussis is an understudied area. Recently, a study was published in which IFN?-­producing plasmacytoid dendritic cells were found to be significantly upregulated in the lungs of B. pertussis-­infected mice. These data, in tandem with preliminary data that show a clear association between type I IFN levels and proinflammatory cytokine gene expression, indicate that these classically antiviral cytokines may function to exacerbate pertussis inflammatory pathology and disease. The role of type I IFN receptor signaling in lung inflammatory pathology during B. pertussis infection will be studied using genetically modified mice that either have no IFNAR1 receptor or have an altered IFNAR1 receptor that cannot be downregulated. Additionally, specific cell types involved in this signaling during B. pertussis infection and the role of TLR9 signaling in type I IFN induction will be investigated. The outcome of this research will elucidate the role of type I IFNs in B. pertussis infection and disease and provide a potential host target for future therapeutic testing in pertussis and possibly other respiratory infections.