Neutrophil-driven mucosal dysfunction in SIV/malaria co-infection

项目摘要/摘要 随着3700万艾滋病毒携带者(PLWH)的感染和每年新增170万人感染， 艾滋病毒仍然是世界上最具破坏性的疾病之一。此外，2018年，疟疾感染人数为 据报道，全球病例已达2.28亿例，造成40.5万多人死亡。虽然 在减少艾滋病毒和疟疾的发病率、感染这两种疾病之一的风险方面取得了进展 疾病仍然很严重，特别是在资源有限的国家。重要的是，由于艾滋病毒和疟疾是地方病 相似地区，地理重叠构成合并感染的极大风险，助长了传播和 两种疾病的发病机制。艾滋病毒和疟疾都被证明会引起胃肠道疾病(GI)。 病理，包括上皮屏障的破坏和微生物移位的增加。这些疾病 特征与发病率和死亡率高度相关；然而，潜在的生物学特征 它们发生的机制仍不清楚。先前的研究表明，炎性中性粒细胞 在SIV/HIV感染期间，SIV/HIV感染期间，SIV/HIV在胃肠道积聚、过度激活并具有延长生存能力的能力。 此外，先前的研究表明，中性粒细胞功能的改变与疟疾有关。 发病机制。然而，中性粒细胞在黏膜功能障碍和发病和死亡风险中的作用 尚未确定艾滋病毒/疟疾合并感染的背景。我们的全球假设是疟疾合并感染 感染SIV的恒河猴的死亡将导致胃肠道中性粒细胞聚集和过度活跃 这将导致免疫活性升高、上皮屏障功能障碍和微生物移位。在……里面 这项拟议的项目，我们的目标是纵向评估中性粒细胞在整个疟疾感染过程中的动力学和功能 感染了SIV的恒河猴。此外，我们还将描述中性粒细胞在急性加重中的作用。 SIV/疟疾混合感染猕猴的粘膜免疫激活、屏障完整性和微生物易位。 最后，我们将利用体外共培养系统来研究使用中性粒细胞靶向策略来限制 炎症反应和恢复屏障的完整性。总而言之，这些研究将产生关于 疟疾合并感染对SIV相关免疫功能障碍的影响。此外，这些实验将为 为未来针对中性粒细胞以减少肠道炎症的临床前和临床研究奠定基础 并恢复粘膜的动态平衡。最终，这一项目的成功完成将推动 开发更有效的治疗方法，用于资源有限的情况，在那里艾滋病毒和疟疾的负担 都是最棒的。

PROJECT SUMMARY/ABSTRACT With more than 37 million people living with HIV (PLWH) and an additional 1.7 million new infections per year, HIV remains one of the world’s most devastating diseases. Moreover, in 2018, infection with malaria was reported to have reached 228 million cases worldwide and to have caused over 405,000 deaths. Although advances have been made in reducing the incidence of both HIV and malaria, the risk of infection with either disease is still great, especially in resource-limited countries. Importantly, as HIV and malaria are endemic to similar areas, the geographical overlap constitutes a great risk for co-infection, fueling the transmission and pathogenesis of both diseases. HIV and malaria have each been shown to cause gastrointestinal (GI) pathologies, including disruption of the epithelial barrier and elevated microbial translocation. These disease characteristics are highly associated with risk of morbidity and mortality; however, the underlying biological mechanisms by which they occur remain unclear. Previous work suggested that inflammatory neutrophils accumulate, are hyperactivated, and have prolonged survival capabilities in the GI tract during SIV/HIV infection. Additionally, prior studies demonstrated that alterations in neutrophil function associates with malaria pathogenesis. However, the role of neutrophils in mucosal dysfunction and risk for morbidity and mortality in the context of HIV/malaria co-infection has not been established. Our global hypothesis is that malaria co-infection of SIV-infected rhesus macaques will result in increased neutrophil accumulation and hyperactivity in the GI tract, which will lead to elevated immune activation, epithelial barrier dysfunction and microbial translocation. In the proposed project, we aim to longitudinally assess neutrophil kinetics and function throughout malaria infection of SIV-infected rhesus macaques. Additionally, we will characterize the role of neutrophils in exacerbated mucosal immune activation, barrier integrity, and microbial translocation in SIV/malaria co-infected macaques. Finally, we will utilize in vitro co-culture systems to investigate the use of neutrophil targeting strategies to limit inflammatory responses and restore barrier integrity. In sum, these studies will generate critical knowledge of the impact of malaria co-infection on SIV-associated immune dysfunction. Moreover, these experiments will lay the groundwork for future pre-clinical and clinical studies targeting neutrophils to reduce intestinal inflammation and restore mucosal homeostasis. Ultimately, the successful completion of this project will propel the development of more effective therapies for use in resource-limited settings, where the burden of HIV and malaria are greatest.