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

HIV 感染女性妊娠期和产后结核分枝杆菌特异性先天性和适应性免疫的动态

• 批准号: 10674692
• 负责人: ADRIANA WEINBERG
• 金额: $ 19.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674692
• 关键词: Affect; Aftercare; Age; Allogenic; Antigen-Presenting Cells; Archives; Area; Biological Assay; Cells; Chickenpox; Color; Cryopreservation; Fetus; Flow Cytometry; Frequencies; HIV; HIV Infections; Immune; Immune response; Immunity; Immunocompetent; Immunologic Markers; Immunologics; Immunosuppression; In Vitro; Incidence; Infection; Influenza; Interferon Type II; International Maternal Pediatric Adolescent AIDS Clinical Trials; Longevity; Low income; Malaria; Measures; Mediating; Memory; Mononuclear; Morbidity - disease rate; Mycobacterium tuberculosis; Natural Immunity; Participant; Persons; Phase; Population; Postpartum Period; Postpartum Women; Pregnancy; Pregnant Women; Preventive therapy; Probability; Prophylactic treatment; Randomized; Recommendation; Regulatory T-Lymphocyte; Safety; Sampling; Sterility; T-Lymphocyte; Testing; Time; Training; Tuberculosis; Tuberculosis Vaccines; Vaccination; Woman; active method; adaptive immunity; antenatal; arm; cytotoxic; double-blind placebo controlled trial; in vivo; isoniazid; mortality; novel; novel vaccines; pathogen; peripheral blood; prevent; prophylactic; reproductive; response; transcriptome sequencing; treatment effect; tuberculosis treatment; vaccine development; young adult

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.

结核病是低收入人群中艾滋病毒感染者发病和死亡的最重要原因。 设置.异烟肼预防性治疗（IPT）目前被推荐用于结核病高发地区的艾滋病毒感染者 地方病和非地方病地区潜伏性结核感染（LTBI+）的证据。结核病占主导地位 影响年轻人，包括育龄妇女。与其他细胞内病原体感染不同， 在怀孕期间和产后头两周发病率最高的地区， 感染（ATBI）在怀孕期间不增加，这是令人惊讶的，鉴于M. 结核病（Mtb）特异性Th1应答，通过干扰素γ释放试验（IGRA）测定， 怀孕妊娠期间IGRA反应的丧失可能是由于调节性免疫应答的频率增加。 T细胞（Treg），可能也是流感、水痘和疟疾发病率增加的原因 孕期我们假设结核分枝杆菌特异性训练的免疫和记忆反应（TMF） 在妊娠期间维持，而Th1和Th17效应反应（Teff）降低，Treg 增加我们将在AIM 1中使用存档的外周血单核细胞（PBMC）来解决这一假设。 IMPAACT P1078，将感染HIV的孕妇随机分配至产前（AP）或产后开始INH治疗 （PP）. AIM 1.目的探讨妊娠对结核分枝杆菌（Mtb）诱导的训练免疫、Th1、Th17和Treg应答的影响。 Subaim 1a.比较AP和PP对Mtb的训练免疫、Th1、Th17和Treg应答。 假设：Th1和Th17效应器对Mtb的应答较低，Treg较高，TbR和训练的Th1和Th17效应器应答较低， 从AP到PP，免疫力没有变化。 我们将使用40色光谱流式细胞术和RNAseq对研究入组时和第12周时收集的样本进行分析 在12周PP时开始IPT的女性的PP。 Subaim 1b.评价妊娠诱导的循环Treg与抗结核分枝杆菌应答的关系。 假设：循环Treg的频率增加与Teff对Mtb的反应降低相关 孕期其他潜在的关联将首次进行审查，以产生新的 假设 我们将测量循环Treg AP的频率，并将其与Teff和其他对Mtb的反应相关联。 目的2将评估IPT对Mtb特异性Th1和Th17应答和训练免疫的影响。Th1 Teff 在没有HIV的人中，ATBI或IPT治疗后，已经显示出减少。这可能是由于 由于Mtb复制的消除，Th1 Teff的抗原刺激降低。有一个缺乏 关于治疗对艾滋病毒感染者结核分枝杆菌特异性免疫力的影响的信息。然而，这些信息是 这是非常重要的，因为在HIV感染的情况下Mtb特异性T细胞的损失增加。使用PBMC 在P1078中收集的数据，我们将检验IPT与Mtb特异性 Th1和Th17细胞，但它不影响训练的免疫力。