Host Defense Against HIV-related Pulmonary Infections

在本次更新/重新提交中，本计划项目将继续开发新型候选疫苗， 接种艾滋病毒相关肺部病原体疫苗。先前提交的一项关切是缺乏协同作用 在以肺囊虫（小鼠中的鼠肺囊虫）和结核分枝杆菌为重点的项目之间， 控制这些HIV相关病原体所需的免疫机制是非常不同的。疫苗 针对PCP的诱导保护主要依赖于抗体应答，而TB需要T细胞应答。 为了实现对一种重要的、持续存在的肺部病原体的更大关注和协同作用，我们选择 将重新提交申请的重点仅放在真菌病原体耶氏肺孢子虫（小鼠中的鼠肺孢子虫）上。 虽然肺含有对微生物病原体具有一定活性的常驻吞噬细胞，但有效的宿主 防御需要迅速扩大肺中免疫效应细胞的数量和功能的能力 组织对感染性挑战的反应。肺部对这种挑战的细胞反应主要是 通过将新细胞从其他细胞区室（骨髓、淋巴组织）递送到肺组织， 血管系统该计划项目的总体主题是开发疫苗接种方法， 将免疫效应细胞递送到肺组织中以防止定植或增加肺组织的清除。 肺孢子虫我们认为，有效的呼吸道病原体疫苗必须刺激细胞和 在宿主暴露于病原体的部位-肺组织的粘膜表面-的抗体反应。 此外，为了充分解决与艾滋病毒感染有关的呼吸道感染这一全球性问题， 候选疫苗应在正常宿主和数量减少或 T淋巴细胞的功能

In this renewal/resubmission, this Program Project will continue to develop novel vaccine candidates and vaccination for HIV-related pulmonary pathogens. A concern of the prior submission was a lack of synergy between projects focused on Pneumocystis jirovecii (P. murina in mice) and Mycobacterium tuberculosis as the immunological mechanism needed to control these HIV-associated pathogens are very disparate. Vaccine induced protection against PCP relies largely on antibody responses whereas TB requires T-cells responses. To achieve greater focus and synergy on a significant, persistent pulmonary pathogen, we have chosen to focus this resubmission application solely on the fungal pathogen, Pneumocystis jirovecii (P. murina in mice). Although the lungs contain resident phagocytes with some activity against microbial pathogens, efficient host defense requires the capacity to rapidly expand the numbers and functions of immune effector cells in lung tissue in response to an infectious challenge. The lungs mount a cellular response to such a challenge mainly by delivering new cells to lung tissue from other cellular compartments (bone marrow, lymphoid tissue) through the vasculature. The overall theme of this Program Proiect is to develop vaccination approaches to enhance the delivery of immune effector cells into lung tissue in order to prevent colonization or augment clearance of Pneumocystis. We believe that efficient vaccines for respiratory pathogens must stimulate both cellular and antibody responses at the site of host exposure to the pathogen- at mucosal surfaces in lung tissue. Furthermore, to adequately address the global problem of respiratory infection associated with HIV infection, candidate vaccines should have efficacy both in normal hosts and in persons with diminished numbers or function of T-lymphocytes.