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率/死亡率的主要原因。这 由猪腹泻病毒（PEDV）引起的新生儿小猪的严重胃肠炎和死亡已导致 在数百万美元的猪行业中。类似于PEDV在猪中的毁灭性影响，轮状病毒（RV）为 全球儿童以及护理和断奶小猪的腹泻和死亡率的主要原因。当前现场 在发达国家有效的口服RV疫苗减弱，在贫困国家缺乏功效 微量营养素缺陷[维生素A缺乏症（VAD）]很常见。因此，增强了母体免疫力和 通过初乳/牛奶被动免疫，是减少病毒影响的理想有效策略 护理新生儿的腹泻。了解怀孕期间肠道免疫的诱导及其作用 从肠道到乳腺（mg）和将IgA分泌到牛奶中的病毒特异性浆液中[通过 缺少肠道内分泌IgA（SIGA）轴。维生素A（VA）对免疫系统具有多效影响 包括诱导粘膜免疫（IGA）和粘膜室中B和T细胞的运输。 但是，VA在诱导和维持乳酸免疫对肠道病毒感染中的作用在很大程度上是 不明确的。具体而言，在三个月，怀孕的母猪和妇女的VA水平下降。还 许多孕妇，特别是在发展中国家，受VAD的影响，但对母亲和 对肠道病毒的乳酸免疫尚不清楚。最近，我们观察到了口服VA的补充 感染了PEDV的怀孕猪可以增强对新生儿哺乳小猪的被动保护。我们还表明 产前VAD会损害仔猪中的吞咽RV特异性IgA抗体分泌（ASC）反应。扩展 了解乳酸免疫，我们将评估VA的影响：i）诱导病毒特异性原发性和 怀孕母猪的次级（记忆）免疫反应； ii）从肠道到病毒特异性IgA ASC的运输 mg; iii）乳酸免疫引起的新生儿保护抗PEDV和RV。我们的具体目标将重点 与维生素相比，阐明了VAD怀孕母猪中Va补充的作用 以下：目标1）通过肠道轴和 未感染的孕妇的肠道/mg免疫反应的调节；目标2）增强乳酸免疫 孕妇母猪的原发性PEDV感染和仔猪被动保护对PEDV挑战（模型流行病毒 感染）;目标3）RV重新启动和重新激活植入RV特异性IgA记忆B细胞反应 暴露的怀孕母猪和仔猪被动保护对RV挑战（模型人畜共患病毒感染）。 我们的双重目的/双重益处研究将增强对肠道轴轴的基本理解， 乳酸免疫和新生儿被动保护，适用于猪和人类。此外，我们会的 验证使用维生素A作为创新，实用且具有成本效益的策略，以增强乳酸 怀孕期间的免疫力和护理新生儿的肠道病毒感染。