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.

虽然新的儿科艾滋病毒感染人数大幅减少，但这导致了 感染艾滋病毒但未受感染的婴儿人口(IHEU)。国际高浓缩铀已被证明已经改变 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是 很好理解。母乳是传递抗体以保护婴儿免受感染的关键； 尤其是在生命早期，他们的免疫系统还不成熟。艾滋病毒携带者已被证明 与未感染的人相比，有异常的B细胞室，导致多克隆抗体结合。 此外，艾滋病毒感染者的血清中IgG1和IgG3浓度较高，而IgG2水平较低 控制。有趣的是，已经证明IgG2而不是IgG1参与了人类的共生靶向和 已知炎症程度较低，并参与T非依赖性反应。目前还不清楚是否 HIV携带者(WLWHIV)母乳中免疫球蛋白同工型和亚类分布不同。 同样，WLWHIV母乳中免疫球蛋白亚类的分布是否转移到 他们的婴儿尚不清楚。此外，母体抗体已被证明与母体内的共生细菌结合。 并导致小鼠模型中免疫系统的抑制。这些抗体微生物 根据抗体亚类的不同，相互作用也有所不同。例如，虽然IgG2b和IgG3是 能够与共生体结合，它们不与病原菌结合，而只观察到极少量的结合 对于肠道中的IgG1和IgG2c，表明在抗原识别方面的功能差异。无论是类似的 这种现象发生在人类婴儿中，这种结合在艾滋病毒的背景下将如何不同尚不清楚。这个 抗体-微生物结合影响细菌产物从肠道转移到血液中，并减少 抑制小鼠T细胞的激活。类似的相互作用已被证明可以减少系统性 人类免疫球蛋白和免疫球蛋白A缺陷患者的炎症反应。IHEU中抗体与微生物的相互作用 与全身性炎症和免疫激活有关的研究尚不清楚。 我们假设HIV感染改变了乳房中总抗体的数量和亚类分布。 牛奶因此影响抗体-微生物结合谱在婴儿肠道中由于改变转移 抗体。这反过来又塑造了婴儿的肠道微生物区系，从而提高了婴儿的免疫活性。 我们将通过以下具体目标来检验这些假设： 目的1：比较乳汁中免疫球蛋白亚型和亚型的浓度。 产后4周感染HIV(WLWHIV)与未感染的母亲。 目的：比较IHEU和IHEU患者粪便中免疫球蛋白与微生物结合的情况。 伊胡婴儿。 目的：探讨IHEU中抗体-微生物结合与免疫激活的关系。