Mechanisms of innate immune dysfunction in SIV/malaria co-infection in pregnancy

项目概要/摘要 艾滋病毒仍然是世界上最具破坏性的疾病之一，有3800多万人感染艾滋病毒 （PLWH），每年新增170万例感染。此外，在2019年， 据报道，全世界已有2.29亿例病例，造成40.9万多人死亡。虽然进步 在减少艾滋病毒和疟疾的发病率方面取得的进展， 特别是在资源有限的国家。重要的是，艾滋病毒流行的地理重叠， 疟疾构成了合并感染的高风险，助长了这两种疾病的传播和发病。的 艾滋病毒和疟疾的负担在孕妇中尤其严重，导致不良生育的风险增加 结果和母婴死亡率。值得注意的是，感染艾滋病毒妇女的妊娠期疟疾（MIP） 导致更大的不良后果风险，目前可用于MIP的治疗仅显示 在WLH中的有限成功。因此，我们的长期目标是确定MIP免疫发病机制中的关键因素， 帮助开发新的治疗方法，可以安全有效地降低孕产妇和胎儿的发病率， WLH中的死亡率。本申请的总体目标是（1）剖析P的致病结果。 SIV+妊娠恒河猴（RM）的脆性感染和（2）机械阐明的作用， 中性粒细胞和先天性淋巴样细胞（ILC）在SIV/P.脆性共同感染过程中的蜕膜炎症。我们 中心假设是，妊娠RM的脆性P.和SIV共感染将导致更大的胎盘 与较高水平的蜕膜中性粒细胞蓄积和ILC相关的寄生虫血症和功能障碍 活化，与单一感染或健康RM相比。拟议研究的基本原理是， 了解中性粒细胞和ILC在胎盘功能障碍中的复杂相互作用将促进随后的， 有针对性的研究，利用我们的研究结果，开发新的干预措施，以治疗MIP在WLH。中央 本研究将通过以下三个具体目标来检验这一假说：1）确定P. 脆性感染和SIV合并感染在妊娠期间的影响; 2）确定中性粒细胞在 妊娠RM合并感染期间的外周和蜕膜炎症;以及3）确定ILC的作用 调节合并感染的妊娠RM的外周和蜕膜炎症。拟议的研究是 创新，因为它专注于使用高度转化的动物模型来打开新的科学视野， 先天性免疫功能的关键改变导致SIV和P.脆性共 感染，这密切平行的艾滋病毒和恶性疟原虫感染的动态。拟议的研究是 意义重大，因为它有望为未来的临床前研究提供强有力的循证基础 MIP在WLH中的生物学机制。最终，这些研究将提供新的发展机会， 在高度脆弱的妇女和生殖健康地区，减少疟疾发病率和死亡率的治疗和预防战略。

PROJECT SUMMARY/ABSTRACT HIV remains one of the world’s most devastating diseases, with more than 38 million people living with HIV (PLWH) and an additional 1.7 million new infections per year. Moreover, in 2019, infection with malaria was reported to have reached 229 million cases worldwide and caused over 409,000 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, the geographical overlap in endemic HIV and malaria constitutes a high risk for co-infection, fueling transmission and pathogenesis of both diseases. The burdens of HIV and malaria are particularly elevated in pregnant women, leading to increased risk of poor birth outcomes and maternal and infant mortality. Notably, malaria in pregnancy (MIP) in women living with HIV (WLH) results in even greater risk of adverse outcomes and the treatments currently available for MIP have only shown limited success in WLH. Therefore, our long-term goal is to identify key factors in MIP immunopathogenesis to aid in development of new therapeutics that can safely and effectively reduce maternal and fetal morbidity and mortality in WLH. The overall objectives for this application are to (1) dissect the pathogenic outcomes of P. fragile infection in SIV+ pregnant rhesus macaques (RMs) and (2) mechanistically elucidate the role of neutrophils and innate lymphoid cells (ILCs) in decidual inflammation during SIV/P. fragile co-infection. Our central hypothesis is that P. fragile and SIV co-infection of pregnant RMs will result in greater placental parasitemia and dysfunction that associates with higher levels of decidual neutrophil accumulation and ILC activation, as compared to mono-infected or healthy RMs. The rationale for the proposed research is that a better understanding of the complex interplay of neutrophils and ILCs in placental dysfunction will promote subsequent, targeted studies to leverage our findings to develop novel interventions to treat MIP in WLH. The central hypothesis will be tested by pursuing three specific aims: 1) To identify key pathogenic consequences of P. fragile infection and the impact of SIV co-infection during pregnancy; 2) To define the role of neutrophils in peripheral and decidual inflammation during co-infection of pregnant RMs; and 3) To determine the role of ILCs in regulating peripheral and decidual inflammation in co-infected pregnant RMs. The proposed research is innovative because it focuses on using a highly translational animal model to open new scientific horizons on key alterations in innate immune function that drive poor maternal and fetal outcomes in SIV and P. fragile co- infection, which closely parallels the dynamics of HIV and P. falciparum infection. The proposed research is significant because it is expected to provide a strong, evidence-based foundation for future pre-clinical studies of the biological mechanisms of MIP in WLH. Ultimately, these studies will provide new opportunities to develop therapies and prevention strategies to reduce morbidity and mortality due to malaria in highly vulnerable WLH.