DYNAMICS OF M. TUBERCULOSIS-SPECIFIC INNATE AND ADAPTIVE IMMUNITY DURING PREGNANCY AND POSTPARTUM IN WOMEN WITH HIV

结核病是低收入人群中艾滋病病毒携带者发病和死亡的最主要原因。 设置。异烟肼预防疗法(IPT)目前被推荐用于结核病高发区的艾滋病毒携带者 在地方性和有证据表明结核病潜伏感染(LTBI+)的非流行地区。以结核病为主 影响年轻人，包括育龄妇女。与其他细胞内病原体感染不同， 妊娠期和产后2周发病率最高的活动性结核病 感染(ATBI)在怀孕期间没有增加，这是令人惊讶的，因为M。 应用干扰素-γ释放试验(IGRA)检测结核分枝杆菌(Mtb)特异性Th1应答 怀孕了。妊娠期间IGRA反应的丧失可能是由于调节的频率增加所致 T细胞(Treg)，这可能也是流感、水痘和疟疾发病率增加的原因 在怀孕期间。我们假设结核分枝杆菌特异的训练性免疫和记忆反应(TMEM) 在妊娠期间保持，而Th1和Th17效应器反应(Tef)减少和Treg 增加。我们将在AIM 1中使用存档于 IMPAACT P1078，将携带艾滋病毒的孕妇随机分为产前或产后两组 (PP)。 目的1.探讨妊娠对结核分枝杆菌训练性免疫、Th1、Th17和Treg反应的影响。 苏巴伊姆1a。比较AP和PP对MTB的Th1、Th17和Treg免疫应答。 假设：Th1和Th17效应器对Mtb的反应较低，Treg较高，TMEM和训练 免疫力不会从AP变为PP。 我们将使用40色光谱流式细胞术和RNAseq对研究开始时和12周时收集的样本进行分析 PP来自在12周PP开始IPT的妇女。 苏巴伊姆1b.目的：探讨结核分枝杆菌感染与妊娠诱导的循环Treg反应的关系。 假设：循环Treg频率增加与对结核分枝杆菌的TJeff反应降低有关 在怀孕期间。将首次检查其他潜在的关联，以产生新的 假设。 我们将测量循环Treg AP的频率，并将它们与TJeff和其他对结核分枝杆菌的反应相关联。 目的2评价IPT对结核分枝杆菌特异性Th1、Th17应答和训练性免疫的影响。TH1触摸屏 已显示在未感染艾滋病毒的人接受ATBI或IPT治疗后有所下降。这可能是由于 由于结核分枝杆菌复制的消除，Th1的抗原刺激减少。这是一个稀缺的 关于治疗对艾滋病毒感染者结核分枝杆菌特异性免疫的影响的信息。然而，这些信息是 这非常重要，因为在艾滋病毒感染的背景下，结核分枝杆菌特异性T细胞的损失增加。使用PBMC 收集在P1078中，我们将测试IPT与结核分枝杆菌特异性下降相关的假设 Th1和Th17细胞，但不影响训练免疫。

Tuberculosis (TB) is the most important cause of morbidity and mortality among people with HIV in low-income settings. Isoniazid prophylactic therapy (IPT) is currently recommended for people with HIV in areas of high TB endemicity and in those with evidence of latent TB infection (LTBI+) in nonendemic areas. TB predominantly affects young adults, including women of reproductive age. Unlike other infections with intracellular pathogens, which carry highest morbidity during pregnancy and first 2 weeks postpartum, the incidence of active TB infections (ATBI) does not increase during pregnancy, which is surprising in view of the significant loss of M. tuberculosis (Mtb)-specific Th1 responses measured by interferon gamma release assays (IGRA) during pregnancy. The loss of IGRA responses during pregnancy is likely due to the increased frequency of regulatory T cells (Treg), which probably also account for the increased morbidity of influenza, varicella and malaria during pregnancy. We hypothesized that Mtb-specific trained immunity and memory responses (Tmem) are maintained during pregnancy, while Th1 and Th17 effector responses (Teff) decrease and Treg increase. We will address this hypothesis in AIM 1 using peripheral blood mononuclear (PBMC) archived in IMPAACT P1078, which randomized pregnant women with HIV to initiate INH antepartum (AP) or postpartum (PP). AIM 1. To evaluate the effect of pregnancy on trained immunity, Th1, Th17 and Treg responses to Mtb. Subaim 1a. To compare trained immunity, Th1, Th17 and Treg responses to Mtb between AP and PP. Hypothesis: Th1 and Th17 effector responses to Mtb are lower, Treg are higher, and Tmem and trained immunity do not change from AP to PP. We will use 40-color spectral flow cytometry and RNAseq on samples collected at study entry and at 12 weeks PP from women who started IPT at 12 weeks PP. Subaim 1b. To evaluate the relationship of responses to Mtb with pregnancy-induced circulating Treg. Hypothesis: Increased frequency of circulating Treg is associated with decreased Teff responses to Mtb during pregnancy. Other potential associations will be examined for the first time to generate new hypotheses. We will measure the frequency of circulating Treg AP and correlate them with Teff and other responses to Mtb. AIM 2 will evaluate the effect of IPT on Mtb-specific Th1 and Th17 responses and trained immunity. Th1 Teff have been shown to decrease after treatment of ATBI or IPT in people without HIV. This is probably due to decreased antigenic stimulation of Th1 Teff due to elimination of Mtb replication. There is a dearth of information on the effect of treatment on Mtb-specific immunity in people with HIV. However, this information is very important due to the increased loss of Mtb-specific T cells in the context of HIV infection. Using PBMC collected in P1078, we will test the hypothesis that IPT is associated with a decrease in Mtb-specific Th1 and Th17 cells, but it does not affect trained immunity.