Influence of breast milk immunoglobulins on gut microbiota and immune development in infants exposed to HIV

母乳免疫球蛋白对 HIV 感染婴儿肠道微生物群和免疫发育的影响

• 批准号: 10313728
• 负责人: Donald Nyangahu
• 金额: $ 32.99万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313728
• 关键词: Address; Antibodies; Antigens; Automobile Driving; B-Lymphocytes; Bacteria; Bacterial Translocation; Binding; Blood; Cell Compartmentation; Cells; Cohort Studies; Communicable Diseases; Development; Enzyme-Linked Immunosorbent Assay; Exposure to; Feces; Fluorochrome; Functional disorder; HIV; HIV Infections; HIV-1; HIV-exposed uninfected infant; Human; Human Milk; IL8 gene; IgA Deficiency; IgG Deficiency; IgG1; IgG2; IgG3; Immune; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulins; Immunologic Factors; Immunologic Markers; Immunologics; Infant; Infant Health; Infection; Inflammation; Inflammatory; Inherited; Interferons; Interleukin-6; Intervention; Knowledge; Lead; Life; Maternal antibody; Measures; Mediating; Microbe; Morbidity - disease rate; Mothers; Mucous Membrane; Mus; Newborn Infant; Patients; Persons; Phenotype; Plasma; Population; Postpartum Period; Pregnant Women; Probiotics; Proteins; Recommendation; Research; Role; Sampling; Secretory Immunoglobulin A; Serum; Shapes; Shotguns; South Africa; Stains; T cell response; T-Cell Activation; TNF gene; Taxonomy; Testing; Transfer Factor; Vertical Disease Transmission; Woman; Work; antibody transfer; antiretroviral therapy; bacterial community; commensal bacteria; gut bacteria; gut colonization; gut microbiota; immune activation; improved; metagenomic sequencing; microbial; microbiota; mortality; mouse model; offspring; pathogenic bacteria; pediatric human immunodeficiency virus infection; polyclonal antibody; prenatal exposure; pup; response; systemic inflammatory response; therapy development

While the number of new pediatric HIV infections has been drastically reduced, this has led to an increasing population of infants who are HIV-exposed but uninfected (iHEU). iHEU have been shown to have altered immunity and gut bacterial communities. However, the mechanisms behind these phenotypes in iHEU are not well understood. Human breast milk is key in transferring antibodies to protect the baby against infections; especially early in life when their immune system is still immature. Persons living with HIV have been shown to have an abnormal B cell compartment which leads to polyclonal antibody binding compared to uninfected people. Also, HIV infected people have higher concentrations of IgG1 and IgG3 and reduced IgG2 in their serum versus controls. Interestingly, IgG2 and not IgG1 has been shown to be involved in commensal targeting in humans and is known to be less inflammatory and involved in T-independent responses. It is not clear whether the immunoglobulin isotypes and subclass distribution differs in the breast milk of women living with HIV (WLWHIV). Similarly, whether the distribution of immunoglobulin subclasses in breast milk of WLWHIV are transferred to their infants is unknown. Moreover, maternal antibodies have been shown to bind to commensal bacteria in the newborn gut and lead to dampening of the immune system in mouse models. These antibody-microbe interactions were shown to differ depending on the antibody subclass. For example, while IgG2b and IgG3 were able to bind to commensals, they did not bind to pathogenic bacteria while only minimal binding was observed for IgG1 and IgG2c in the gut, suggesting functional differences in terms of antigen recognition. Whether a similar phenomenon occurs in human infants and how the binding will differ in the context of HIV is unknown. The antibody-microbe binding impacted translocation of bacterial products from the gut into the blood and reduced dampened T cell activation in murine pups. Similar interactions have been shown to reduce systemic inflammation in human patients with IgG and IgA deficiencies. Whether antibody-microbe interaction in iHEU associate with systemic inflammation and immune activation is unexplored. We hypothesize that HIV infection alters the quantity and subclass distribution of total antibody in breast milk thereby impacting the antibody-microbe binding profile in the infant gut due to altered transfer of antibody. This in turn shapes infant gut microbiota resulting in increased immune activation in infants. We will test these hypotheses with the following specific aims: Aim 1: Compare concentrations of immunoglobulin isotypes and subclasses in breast milk of women living with HIV (WLWHIV) versus uninfected mothers at 4 weeks postpartum. Aim 2: Compare the immunoglobulin-microbe binding profile of IgG and IgA subclasses in stool of iHEU versus iHU infants. Aim 3: Assess the relationship between antibody-microbe binding and immune activation in iHEU.

虽然新的小儿艾滋病毒感染的数量已大大减少，但这导致了增加 艾滋病毒暴露但未感染的婴儿人群（IHEU）。 IHEU已显示已更改 免疫和肠道细菌群落。但是，IHEU中这些表型背后的机制不是 理解。人类母乳是转移抗体以保护婴儿免受感染的关键。 尤其是在其免疫系统仍然不成熟的生命早期。与艾滋病毒同住的人已被证明 与未感染的人相比，具有异常的B细胞室，导致多克隆抗体结合。 此外，艾滋病毒感染的人具有较高浓度的IgG1和IgG3，而血清中的IgG2降低了 控件。有趣的是，IgG2而不是IgG1已被证明参与了人类和 已知炎症性较小，参与T非依赖性反应。尚不清楚是否 艾滋病毒（WLWHIV）的妇女的母乳中，免疫球蛋白同种型和亚类分布不同。 同样，WLWHIV母乳中免疫球蛋白亚类的分布是否转移到 他们的婴儿是未知的。此外，孕产妇抗体已显示与共生细菌结合 新生儿肠道并导致小鼠模型中免疫系统的衰减。这些抗体 - 微生物 相互作用显示取决于抗体亚类。例如，IgG2B和IgG3是 能够与共生结合，它们不与致病细菌结合，而仅观察到最小结合 对于肠道中的IgG1和IgG2C，表明在抗原识别方面存在功能差异。是否类似 现象发生在人类婴儿中以及在艾滋病毒背景下的结合将如何不同。这 抗体 - 微生物结合影响了细菌产物从肠道中的易位，并减少了 鼠幼犬中的T细胞激活抑制。已经显示出类似的相互作用以减少全身性 IgG和IgA缺乏症患者的炎症。 IHEU中的抗体 - 微生物相互作用是否 与全身性炎症和免疫激活结合在一起。 我们假设HIV感染改变了乳腺中总抗体的数量和亚类分布 牛奶因此会影响婴儿肠道抗体微粒结合曲线，这是由于改变的转移 抗体。反过来，这形成了婴儿肠道菌群，导致婴儿的免疫激活增加。 我们将以以下特定目的测试这些假设： 目标1：比较妇女的母乳中免疫球蛋白同种型和子类的浓度 产后4周的艾滋病毒（WLWHIV）与未感染的母亲。 AIM 2：比较IHEU粪便中IgG和IgA子类的免疫球蛋白 - 微生物结合曲线 婴儿。 AIM 3：评估IHEU中抗体微粒结合与免疫激活之间的关系。