The autophagic delivery of intracellular pathogens to the lysosome (where they are destroyed) is emerging as a central mechanism of innate immunity;accordingly, the augmentation of host autophagy represents a potentially powerful new therapeutic approach to combat intracellular pathogens1-3. In our original project, we pursued four specific aims to develop an autophagy-inducing peptide that may be useful as a novel therapeutic in the treatment of diverse intracellular NIAID Class A, B, and C Priority pathogens.
These aims i ncluded: 1. To confirm that the Tat-Beclin 1 peptide is a specific inducer of autophagy in vitro and in vivo. 2. To evaluate the mechanism by which the Tat-Beclin 1 induces autophagy. 3. To evaluate the effects of the Tat-Beclin 1 peptide on the in vitro growth of selected NIAID Category A, B, and C Priority Pathogens. 4. To evaluate the effects of the Tat-Beclin 1 peptide on microbial pathogenesis in mouse models of infection with selected NIAID Category A, B, and C Priority Pathogens. Thus far, we have completed the first aim and made significant progress towards completing Aims 2-4. To accelerate the development of a novel broad-spectrum antimicrobial biological product, the Tat-Beclin 1 autophagy-inducing peptide, we propose to work further on Aims 2-4 in parallel with investigations to determine the optimal dosing, immunogenicity, and preliminary safety profile of the peptide. These studies will help advance the development of a biologically active peptide (or small molecule compound that mimics its action) for the treatment of NIAID priority intracellular pathogens.
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