Impact of HIV exposure, feeding status, and microbiome on immune ontogeny and vaccine responses in infants

HIV 暴露、喂养状况和微生物组对婴儿免疫个体发育和疫苗反应的影响

• 批准号: 10116253
• 负责人: Catherine A Blish
• 金额: $ 42.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-11 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116253
• 关键词: Accounting; Acellular Vaccines; Address; Adult; Affect; Age; Antibiotic Prophylaxis; Antigens; Antiviral Agents; Area; Automobile Driving; BCG Live; Birth; Blood; Cell model; Cells; Cellular Immunity; Cessation of life; Characteristics; Child; Cohort Studies; Communicable Diseases; Cytotoxic T-Lymphocytes; Data; Development; Diarrhea; Environment; Exclusive Breastfeeding; Exposure to; Failure; Feces; Foundations; Genetic; Growth; HIV; HIV Infections; HIV-exposed uninfected infant; Human Milk; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunological Models; In Vitro; Infant; Infant Development; Infection; Lead; Life; Locales; Location; Mothers; Mucous Membrane; Natural Increases; Natural Killer Cells; Neonatal; Newborn Infant; Pertussis; Pertussis Vaccine; Phenotype; Predisposition; Pregnant Women; Prevalence; Process; Resources; Respiratory Tract Infections; Risk; Role; Rotavirus; Rotavirus Vaccines; Saliva; Sampling; Shapes; South Africa; Specimen; T cell receptor repertoire sequencing; T-Lymphocyte; T-Lymphocyte Subsets; T-cell diversity; Vaccination; Vaccines; Viral; Vulnerable Populations; Work; breast milk microbiome; cohort; cytokine; diarrheal disease; fecal microbiome; feeding; fighting; gut microbiome; high risk; in utero; infant infection; infection rate; infection risk; maternal microbiome; microbial; microbiome; mortality; mucosal vaccine; neonatal immunity; neonatal infection; neonatal period; neonate; predictive modeling; respiratory; response; saliva sample; stool sample; success; tool; vaccination outcome; vaccine response; vaccine-induced immunity

PROJECT SUMMARY Each year, approximately 8 million children under the age of five die, and approximately 3.3 million of those deaths occur in the neonatal period. Infections are the single largest contributor to these deaths, accounting for an estimated 36% of the mortality. However, our understanding of how the neonatal and infant immune system influence this susceptibility to infectious diseases is limited. Thus, to elucidate mechanisms that regulate the development of infant immunity, we propose evaluating immune development in a setting of high risk of neonatal and infant infection. In particular, infants who are exposed to HIV, yet remain uninfected, suffer increased rates of respiratory and diarrheal illnesses. Feeding status is also associated with altered risk of infection, with exclusively breastfed children less likely to suffer diarrheal illness and death. Our preliminary data suggest that both HIV exposure and feeding status influence the infant microbiome, which is increasingly recognized for its important role in driving immune development. Thus, to better understand the unique characteristics of immune development in neonates and infants, we propose evaluating the impact of HIV exposure and feeding status on the interplay between the microbiome, innate and adaptive cellular immune ontogeny, and vaccination outcomes. Our preliminary data also suggests that HIV exposure leads to oligoclonality in the T cell repertoire, potentially narrowing the spectrum of antigens to which infant T cells can respond. We have also found that HIV infection increases natural killer (NK) cell diversity while decreasing NK cell cytotoxic function. Using longitudinal samples collected from HIV-exposed uninfected (HEU) and HIV- unexposed (HU) babies in an area of extremely high HIV prevalence in South Africa, we will: 1) compare the T and NK cell repertoires and function between HEU and HU babies, 2) determine the impact of maternal HIV, feeding status, gut and breastmilk microbiome on the infant mucosal microbiome, and 3) build a predictive model of effective pertussis and rotavirus vaccines to identify the major factors that associate with vaccine success or failure. This study will provide a comprehensive understanding of how cellular immune responses and the microbiome evolve in the first year of life and influence the ability to generate an effective cellular and humoral immune responses.

项目总结 每年约有800万五岁以下儿童死亡，其中约330万 死亡发生在新生儿期。感染是造成这些死亡的最大单一因素，占 估计有36%的死亡率。然而，我们对新生儿和婴儿免疫系统如何 这种对传染病易感性的影响是有限的。因此，为了阐明调控 婴儿免疫的发展，我们建议在高风险的情况下评估免疫发展。 新生儿和婴儿感染。特别是，接触艾滋病毒但仍未感染的婴儿遭受 呼吸道和腹泻疾病的发病率增加。喂养状态也与改变的风险有关。 感染，纯母乳喂养的儿童患腹泻病和死亡的可能性较小。我们的预赛 数据表明，艾滋病毒暴露和喂养状况都会影响婴儿的微生物群，这种微生物群正日益增多。 因其在推动免疫发展方面的重要作用而得到认可。因此，为了更好地理解独特的 新生儿和婴儿免疫发育的特点，我们建议评估艾滋病毒的影响 微生物群、先天免疫和获得性细胞免疫相互作用的暴露和饲养状况 个体发育和疫苗接种结果。我们的初步数据还表明，接触艾滋病毒会导致 T细胞谱系中的寡克隆性，潜在地缩小了婴儿T细胞可以针对的抗原谱 请回答。我们还发现，艾滋病毒感染增加了自然杀伤(NK)细胞的多样性，而减少了NK细胞 细胞细胞毒作用。使用从暴露于艾滋病毒的非感染者(HEU)和艾滋病毒- 在南非艾滋病毒感染率极高的地区，未暴露(HU)婴儿，我们将：1)比较T 以及HEU和HU婴儿之间的NK细胞谱系和功能，2)决定母亲HIV的影响， 喂养状态、肠道和母乳微生物群对婴儿粘膜微生物群的影响，以及3)建立预测性 有效百日咳和轮状病毒疫苗的模型，以确定与疫苗相关的主要因素 成功或失败。这项研究将提供对细胞免疫反应的全面了解 微生物组在生命的第一年进化，影响产生有效细胞和 体液免疫反应。

项目成果

Stereotypic Expansion of T Regulatory and Th17 Cells during Infancy Is Disrupted by HIV Exposure and Gut Epithelial Damage.

• DOI: 10.4049/jimmunol.2100503
• 发表时间: 2022-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Dzanibe S;Lennard K;Kiravu A;Seabrook MSS;Alinde B;Holmes SP;Blish CA;Jaspan HB;Gray CM
• 通讯作者: Gray CM

Disrupted memory T cell expansion in HIV-exposed uninfected infants is preceded by premature skewing of T cell receptor clonality.

在暴露于 HIV 的未感染婴儿中，记忆性 T 细胞增殖受到破坏，随后 T 细胞受体克隆性就会过早发生偏差。

• DOI: 10.1101/2023.05.19.540713
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Dzanibe,Sonwabile;Wilk,AaronJ;Canny,Susan;Ranganath,Thanmayi;Alinde,Berenice;Rubelt,Florian;Huang,Huang;Davis,MarkM;Holmes,Susan;Jaspan,HeatherB;Blish,CatherineA;Gray,CliveM
• 通讯作者: Gray,CliveM