Research Project
10475402
PROJECT SUMMARY Recent levels of the bacterial disease pertussis are at their highest in 60 years. However, the currently used acellular pertussis vaccine is inadequate and no effective therapies exist for treatment of pertussis. Since antibiotic therapy is ineffective, host-targeted therapeutics are needed. However, we still have a very poor understanding of the pathogenesis of pertussis and therefore it is unclear which host targets are appropriate for therapeutic intervention. By RNAseq transcriptomics analysis, we found that the type I interferon (IFN) receptor subunit IFNAR1 was the most significant upstream activator of mouse lung genes differentially expressed in response to Bordetella pertussis infection. Type I IFNs are key cytokines in immune responses and antiviral defense, but they also exacerbate inflammation and pathogenesis in a variety of disease models. Type I IFNs have diverse effects on a variety of bacterial infections, being protective for some and deleterious for others. Our preliminary data indicate that expression of type I IFNs is upregulated in the lungs of B. pertussis-infected adult mice and that they exacerbate lung inflammatory pathology. However, in infant mice, in which the pathogenesis of pertussis is markedly different from that in adult mice (as in humans), our preliminary data suggest that type I IFN signaling is protective against B. pertussis disease, indicating age-dependence of type I IFN effects. We have also been studying sphingosine-1-phosphate (S1P) receptor ligands as candidate host- targeted therapeutics for pertussis. An S1P receptor ligand drug, FTY720, is used in humans as a therapy for relapsing-remitting multiple sclerosis, and other similar drugs are in clinical trials for various inflammatory disorders, demonstrating the translational potential of these drugs. In published studies, we found that administration of a single dose of S1P receptor ligands to B. pertussis-infected adult mice significantly reduced lung inflammatory pathology. Furthermore, our preliminary data suggest that S1P receptor ligand treatment reduces inflammation by downregulating type I IFN signaling in infected adult mice, consistent with the hypothesis that type I IFNs exacerbate lung inflammatory pathology. Therefore, the aims of this proposal are to test the hypotheses that (i) type I IFNs contribute to lung inflammatory pathology and pathogenesis of B. pertussis disease in adult mice but are protective in infant mice, and (ii) S1P receptor drugs attenuate lung inflammatory pathology in B. pertussis-infected adult mice by inhibiting type I IFN receptor signaling. We will use a combination of mouse infection and cell culture studies to test these hypotheses and investigate mechanisms, and we will take advantage of genetically altered mice that impact type I IFN receptor signaling. Identification of host targets and development of novel therapeutics for individuals suffering from debilitating and sometimes fatal pertussis will have a major public health impact on this disease.
