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: 10459554
• 负责人: Donald Nyangahu
• 金额: $ 18.85万
• 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/10459554
• 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.

虽然新的儿童艾滋病毒感染人数大幅减少，但这导致了儿童艾滋病毒感染人数的增加。 暴露于艾滋病毒但未感染的婴儿群体。iHEU已被证明改变了 免疫力和肠道细菌群落。然而，iHEU中这些表型背后的机制并不明确。 很好理解。母乳是传递抗体以保护婴儿免受感染的关键; 特别是在免疫系统还不成熟的生命早期。艾滋病毒感染者已被证明 与未感染的人相比，具有导致多克隆抗体结合的异常B细胞区室。 此外，与HIV感染者相比，HIV感染者血清中的IgG 1和IgG 3浓度更高，而IgG 2浓度降低 对照有趣的是，已经显示IgG 2而不是IgG 1参与人的靶向免疫， 已知其炎症性较小，并参与T细胞非依赖性反应。不清楚是否 免疫球蛋白同种型和亚类分布在艾滋病毒感染妇女的母乳中存在差异（WLWHIV）。 同样，WLWHIV母乳中免疫球蛋白亚类的分布是否转移到 他们的孩子是未知的。此外，母体抗体已被证明可以与哺乳动物中的肠道细菌结合。 新生儿肠道，并导致小鼠模型中免疫系统的抑制。这些抗体微生物 显示相互作用根据抗体亚类而不同。例如，虽然IgG 2b和IgG 3是 它们能够与细菌结合，但不与致病菌结合，而仅观察到最小的结合 对于肠道中的IgG 1和IgG 2c，表明在抗原识别方面的功能差异。是否类似 这种现象发生在人类婴儿中，并且在HIV的背景下结合将如何不同是未知的。的 抗体-微生物结合影响细菌产物从肠道到血液的移位， 抑制了幼鼠体内的T细胞活化。类似的相互作用已被证明可以减少系统性 在IgG和伊加缺乏的人类患者中的炎症。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相关的研究尚未探索。 我们推测HIV感染改变了乳腺组织中总抗体的数量和亚类分布 牛奶，从而影响婴儿肠道中的抗体-微生物结合谱， 抗体的这反过来又塑造了婴儿肠道微生物群，导致婴儿免疫激活增加。 我们将检验这些假设，具体目标如下： 目的1：比较患有乳腺癌的妇女母乳中免疫球蛋白同种型和亚类的浓度 艾滋病毒（WLWHIV）与未感染的母亲在产后4周。 目的2：比较iHEU粪便中IgG和伊加亚类的免疫球蛋白-微生物结合谱， iHU婴儿。 目的3：评价iHEU中抗体-微生物结合与免疫激活的关系。