An Autophagy^lnducing Peptide as a Novel Therapeutic for Intracellular NIAID Cla

细胞内病原体的自噬递送到溶酶体(在那里它们被摧毁)正在出现 先天免疫的核心机制；因此，宿主自噬的增强代表着一种 潜在强大的新治疗方法，以对抗细胞内病原体1-3。在我们最初的项目中，我们 追求四个特定目标以开发一种自噬诱导多肽，该多肽可能用作一种新的治疗方法 在治疗不同的细胞内NIAID A、B和C类优先病原体。这些目标包括： 1.证实Tat-Beclin 1肽是体内外自噬的特异性诱导剂。 2.探讨Tat-Beclin 1诱导自噬的机制。 3.评价TAT-Beclin 1肽对选定的NIAID A类细胞体外生长的影响， B和C优先病原菌。 4.评价TAT-Beclin 1肽对小鼠实验性肺炎微生物发病机制的影响。 感染选定的NIAID A、B和C类优先病原体。 到目前为止，我们已经完成了第一个目标，并在实现目标2-4方面取得了重大进展。至 加快新型广谱抗菌生物制品TAT-Beclin 1的开发 自噬诱导肽，我们建议在研究的同时进一步研究目标2-4，以确定 多肽的最佳剂量、免疫原性和初步安全性。这些研究将会有所帮助 促进生物活性多肽(或模拟其作用的小分子化合物)的开发 用于治疗NIAID优先的细胞内病原体。

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 included: 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.