Research Project
10129726
PROJECT SUMMARY/ABSTRACT Pulmonary bacterial infections account for a staggering amount of morbidity and mortality worldwide, particularly from Mycobacterium tuberculosis (Mtb). Furthermore, drug resistant strains of Mtb are emerging at an alarming rate, making antibiotic-based control of these epidemics less productive. Alternative intervention strategies that prevent infection or synergize with antibiotic treatments would have a major impact on the global disease burden by interrupting transmission. In particular, healthcare workers, household contacts of individuals with active disease and immunocompromised individuals are disproportionally at higher risk of infection due to elevated pathogen exposures and weakened immune systems, respectively. We hypothesize that a focused pre- or post-exposure prophylaxis strategy using aerosol delivery of lytic mycobacteriophage may provide sterilizing protection in these high-risk populations and offer a more immediate solution while efficacious anti-mycobacterial vaccines are being developed. Bacteriophage (phage) have been minimally used in emergency clinical applications for skin and soft tissue infections and disseminated bacterial infections, but not to-date as an aerosol strategy against pulmonary mycobacteria. One limitation in the field preventing these advancements is the availability of a reproducible preclinical model of aerosol phage delivery that can be leveraged for efficacy testing. Importantly, our preliminary proof-of-concept results suggest that aerosol delivery of phage to mice can significantly reduce bacterial burden after challenge with Mtb. In order to advance aerosol phage delivery, in Aim 1 we will refine our preclinical model to alleviate this limitation by leveraging commercially available technology to reproducibly deliver phage as an aerosol. In Aim 1 we will leverage spray drying technologies generate dry powder phage, with an emphasis on compositions that afford thermostability, and evaluate the efficacy-limiting anti-phage or tolerogenic host immune responses generated after repeated phage delivery. Aim 2 will be devoted to determining if high titer aerosol delivery of phage cocktails can effectively prevent infection after pulmonary challenge with drug sensitive and drug resistant Mtb in a preclinical mouse model and evaluating drug and phage synergy in vitro and in vivo. Completion of the Aims in this proposal will lead to 1) the establishment of a novel reproducible system for aerosol delivery of phage, 2) lay the foundation for dry powder product delivery (e.g. inhalers) that can reach more remote and resource limited areas of the world, 3) provide translational scientific knowledge about host responses to mucosal phage delivery and lastly, 4) establishing preclinical efficacy against Mtb that will help advance aerosol phage delivery as a viable and translational stop-gap for pulmonary bacterial transmission.
