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

项目摘要/摘要 艾滋病毒仍然是世界上最具破坏性的疾病之一，有3800万艾滋病毒携带者 (PLWH)和每年额外170万新感染病例。此外，2019年感染疟疾的人数为 据报道，全球病例已达2.29亿例，造成409,000多人死亡。虽然进步了 已经在减少艾滋病毒和疟疾的发病率方面取得了进展，感染这两种疾病的风险是 仍然很棒，特别是在资源有限的国家。重要的是，地方性艾滋病毒和艾滋病的地理重叠 疟疾构成合并感染的高风险，助长了这两种疾病的传播和发病。这个 艾滋病毒和疟疾的负担在孕妇中尤其增加，导致出生不良的风险增加。 结果和孕产妇和婴儿死亡率。值得注意的是，艾滋病毒携带者中的妊娠期疟疾(MIP) 结果会导致更大的不良后果风险，目前可用于MIP的治疗方法仅显示 在世界卫生组织中取得的成功有限。因此，我们的长期目标是确定在MIP免疫发病机制中的关键因素 帮助开发可安全有效地降低孕产妇和胎儿发病率的新疗法 死亡率(WLH值)。这项应用的总体目标是(1)剖析P。 SIV孕期恒河猴(RMS)脆性感染及(2)机制阐明 SIV/P.脆性混合感染期间蜕膜炎症中的中性粒细胞和先天淋巴样细胞(ILCs)。我们的 中心假设是脆性肺炎和SIV合并感染妊娠RMS会导致更大的胎盘 与蜕膜中性粒细胞聚集和ILC水平较高相关的寄生虫血症和功能障碍 与单一感染或健康的RMS相比，激活。提出这项研究的理由是，更好的 了解中性粒细胞和ILCs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，以利用我们的发现来开发新的干预措施来治疗WLH中的MIP。中环 假说将通过追求三个具体目标来检验：1)确定P。 脆性感染与孕期SIV混合感染的影响；2)确定中性粒细胞在 妊娠RMS合并感染时的外周和蜕膜炎症；3)确定ILCs的作用 在调节合并感染的妊娠RMS患者的外周和蜕膜炎症方面。拟议的研究是 创新是因为它专注于使用高度翻译的动物模型来打开新的科学视野 先天免疫功能的关键改变导致SIV和P.脆性共同感染的不良母婴结局 感染，这与艾滋病毒和恶性疟原虫感染的动态密切相关。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。 治疗和预防战略，以减少高度脆弱的世界卫生组织疟疾的发病率和死亡率。

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.