Repurposing S1P receptor drugs as therapeutics for pertussis in the baboon model

University Of Maryland Baltimore, Baltimore MD

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Abstract

PROJECT SUMMARY   The hallmark pathophysiology of typical pertussis is severe paroxysmal coughing (whooping cough) persisting for weeks after initial onset. In young infants, the disease can be more severe and sometimes fatal. Neither antibiotics nor anti-tussive cough medications have any beneficial effect for individuals suffering from pertussis, and in the face of increasing pertussis epidemics, novel therapies are needed. In the mouse model, Bordetella pertussis infection is characterized by marked lung inflammatory pathology peaking at 2-3 weeks post-inoculation, but overt pertussis symptomology cannot be studied in this model since mice do not cough (to any stimulus). In a recently developed non-human primate model of pertussis, young baboons experimentally infected with B. pertussis develop classic symptoms of pertussis, including prolonged paroxysmal coughing. The baboon model therefore provides the possibility to test hypotheses on disease etiologies and identify potential therapies related to the pathophysiology of pertussis. In our recent work in mice, we have investigated sphingosine-1-phosphate (S1P) receptor- targeting drugs for their anti-inflammatory effects in B. pertussis-infected lungs. S1P is a phosphorylated sphingolipid that binds and signals through five receptors. Treatment with exogenously administered S1P receptor-targeting drugs can attenuate pulmonary inflammatory pathology in mouse models of LPS- induced acute lung injury and influenza virus infection. We found that intranasal treatment of B. pertussis-infected adult mice with S1P receptor-targeting drugs at therapeutic time points significantly reduced lung inflammatory pathology, the best measure of pertussis disease in these animals. In this proposal, we aim to investigate the therapeutic potential of the S1P receptor-targeting drug FTY720 for treatment of pertussis in experimentally infected baboons. FTY720 (Fingolimod) is an approved drug in humans for treatment of relapsing-remitting multiple sclerosis, and other S1P receptor- targeting drugs have gone through phase III clinical trials, demonstrating the translational potential of this approach. This work may therefore identify a drug that can be repurposed for treatment of pertussis. To test the hypothesis that administration of FTY720 to experimentally infected baboons will significantly reduce pertussis disease, we will compare the effectiveness of aerosol administration versus oral delivery of the drug (the latter is used in humans) to 6-9-month-old baboons, which manifest typical pertussis symptoms, as well as compare the effectiveness of drug administration versus antibiotic treatment. In addition, by analyzing lung inflammation in these animals, we will be able to test the hypothesis that lung inflammatory pathology (as also seen in infected mice) is associated with the severe cough symptomology of pertussis.