The impact of vitamin A on the gut-mammary gland-secretory IgA axis during enteric viral infections

肠道病毒感染期间维生素 A 对肠道-乳腺-分泌 IgA 轴的影响

• 批准号: 9759974
• 负责人: Linda J. Saif
• 金额: $ 44.7万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759974
• 关键词: Affect; Animals; Antibodies; Antibody titer measurement; Attenuated; B-Lymphocytes; Blood; Cells; Cessation of life; Chemotaxis; Child; Childhood; Colostrum; Country; Developed Countries; Developing Countries; Development; Diarrhea; Discipline of Nursing; Enteral; Epidemic; Family suidae; Frequencies; Gastroenteritis; Health; Homing; Human; Human Milk; Immune; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin-Secreting Cells; Impairment; Industry; Intestines; Knowledge; Lactation; Lymphocyte; Maintenance; Mammary Gland Parenchyma; Mammary gland; Memory; Memory B-Lymphocyte; Milk; Modeling; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Neonatal; Oral; Plasmablast; Pregnancy; Pregnant Women; Role; Rotavirus; Rotavirus Vaccines; Secretory Immunoglobulin A; Spleen; Supplementation; T-Lymphocyte; Third Pregnancy Trimester; Tissues; Up-Regulation; Viral; Virus; Virus Activation; Virus Diseases; Vitamin A; Vitamin A Deficiency; Weaning; Woman; Zoonoses; acquired immunity; chemokine; cost; cost effective; cytokine; experience; ileum; immune health; innovation; lactogenesis; micronutrient deficiency; mortality; neonatal morbidity; neonate; oral vaccine; pleiotropism; porcine epidemic diarrhea virus; pregnant; prenatal; response; seropositive; suckling; trafficking

Project Summary. Enteric viruses are a major cause of neonatal morbidity/mortality in humans and animals. The severe gastroenteritis and deaths in neonatal piglets caused by porcine epidemic diarrhea virus (PEDV) have resulted in multimillion-dollar losses to the swine industry. Similar to the devastating effects of PEDV in swine, rotavirus (RV) is a leading cause of diarrhea and mortality in children worldwide, as well as in nursing and weaned piglets. Current live attenuated oral RV vaccines that are efficacious in developed countries, lack efficacy in impoverished countries where micronutrient deficiencies [vitamin A deficiency (VAD)] are common. Thus, enhancing both maternal immunity and passive lactogenic immunity via colostrum/milk, are ideal and effective strategies to reduce the impacts of viral diarrheas in nursing neonates. An understanding of the induction of intestinal immunity during pregnancy and its role in trafficking of virus specific plasmablasts from the gut to the mammary gland (MG) and secretion of IgA into milk [via the gut-MG-secretory IgA (sIgA) axis] is lacking. Vitamin A (VA) has pleiotropic effects on the immune system including induction of mucosal immunity (IgA) and trafficking of B and T cells among mucosal compartments. However, the role of VA in induction and maintenance of lactogenic immunity against enteric viral infections is largely undefined. Specifically, pregnant sows and women experience a decline in VA levels during the third trimester. Also many pregnant women, particularly in developing countries, are affected by VAD, but its impact on maternal and lactogenic immunity against enteric viruses is unknown. Recently, we observed that oral VA supplementation of PEDV-infected pregnant swine enhances passive protection of their neonatal suckling piglets. We also showed that prenatal VAD impairs anamnestic RV-specific IgA antibody secreting cell (ASC) responses in piglets. To expand knowledge of lactogenic immunity, we will evaluate the impact of VA on: i) induction of virus-specific primary and secondary (memory) immune responses in pregnant sows; ii) trafficking of virus-specific IgA ASC from intestine to MG; and iii) lactogenic immunity-induced neonatal protection against PEDV and RV. Our Specific Aims will focus on elucidating the effect of VA supplementation in VAD pregnant sows, compared with vitamin A sufficient sows on the following: Aim 1) upregulation of homing molecules and trafficking of immune cells via the gut-MG-sIgA axis and modulation of gut/MG immune responses in uninfected pregnant sows; Aim 2) enhancing lactogenic immunity after primary PEDV infection of pregnant sows and piglet passive protection to PEDV challenge (model epidemic virus infection); and Aim 3) maintenance and reactivation of anamnestic RV-specific IgA memory B cell responses in RV re- exposed pregnant sows and piglet passive protection to RV challenge (model zoonotic/endemic virus infection). Our dual purpose/dual benefit studies will enhance fundamental understanding of the gut-MG-sIgA axis, lactogenic immunity and neonatal passive protection, applicable to swine and humans. Additionally, we will validate use of vitamin A as an innovative, practical and cost-effective strategy to prime and boost lactogenic immunity during pregnancy and control enteric viral infections in nursing neonates.

项目摘要。肠道病毒是人类和动物新生儿发病/死亡的主要原因。这 猪流行性腹泻病毒（PEDV）引起新生仔猪严重胃肠炎和死亡 给养猪业造成数百万美元的损失。与 PEDV 对猪的破坏性影响类似，轮状病毒 (RV) 它是全世界儿童以及哺乳仔猪和断奶仔猪腹泻和死亡的主要原因。当前直播 减毒口服 RV 疫苗在发达国家有效，但在贫困国家缺乏效力 微量营养素缺乏[维生素 A 缺乏 (VAD)] 很常见。因此，增强母体免疫力 通过初乳/牛奶进行的被动泌乳免疫是减少病毒影响的理想且有效的策略 哺乳期新生儿腹泻。了解妊娠期肠道免疫的诱导及其作用 病毒特异性浆母细胞从肠道运输到乳腺 (MG) 以及 IgA 分泌到乳汁中 [通过 缺乏肠道-MG-分泌型 IgA (sIgA) 轴]。维生素 A (VA) 对免疫系统具有多效性作用 包括诱导粘膜免疫 (IgA) 以及粘膜区室中 B 细胞和 T 细胞的运输。 然而，VA 在诱导和维持针对肠道病毒感染的泌乳免疫中的作用很大程度上是 不明确的。具体来说，怀孕母猪和女性在妊娠晚期的 VA 水平会下降。还 许多孕妇，特别是发展中国家的孕妇，都受到 VAD 的影响，但它对孕产妇和孕妇的影响 针对肠道病毒的泌乳免疫尚不清楚。最近，我们观察到口服 VA 补充剂 感染 PEDV 的孕猪增强了对其新生乳猪的被动保护。我们还表明 产前 VAD 会损害仔猪记忆性 RV 特异性 IgA 抗体分泌细胞 (ASC) 反应。扩大 了解泌乳免疫后，我们将评估 VA 对以下方面的影响： i) 诱导病毒特异性初级和 怀孕母猪的次级（记忆）免疫反应； ii) 将病毒特异性 IgA ASC 从肠道转运至 MG； iii) 泌乳免疫诱导的新生儿针对 PEDV 和 RV 的保护。我们的具体目标将集中于 阐明与维生素 A 充足的母猪相比，补充 VA 对 VAD 怀孕母猪的影响 目标 1) 通过肠道-MG-sIgA 轴上调归巢分子和免疫细胞运输，以及 调节未感染怀孕母猪的肠道/MG 免疫反应；目标2）增强产后泌乳免疫力 妊娠母猪和仔猪原发性 PEDV 感染对 PEDV 攻击（模型流行病毒）的被动保护 感染）;目标 3) 在 RV 重新激活中维持和重新激活记忆性 RV 特异性 IgA 记忆 B 细胞反应 暴露怀孕母猪和仔猪对 RV 攻击的被动保护（人畜共患/地方性病毒感染模型）。 我们的双重目的/双重益处研究将增强对肠道-MG-sIgA 轴的基本了解， 泌乳免疫和新生儿被动保护，适用于猪和人。此外，我们将 验证使用维生素 A 作为一种创新、实用且具有成本效益的策略来启动和促进泌乳 怀孕期间的免疫力和控制哺乳期新生儿的肠道病毒感染。