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

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。的 猪流行性腹泻病毒（PEDV）引起仔猪严重的胃肠炎和死亡 给养猪业造成了数百万美元的损失与猪中PEDV的破坏性作用相似，轮状病毒（RV）是一种 是全世界儿童腹泻和死亡的主要原因，也是哺乳期和断奶仔猪腹泻和死亡的主要原因。当前直播 在发达国家有效的减毒口服RV疫苗，在贫困国家缺乏效力， 微量营养素缺乏症[维生素A缺乏症（VAD）]很常见。因此，增强母体免疫力和 通过初乳/牛奶的被动催乳免疫，是减少病毒感染的理想和有效的策略。 新生儿护理中的痔疮。妊娠期肠道免疫的诱导及其作用 在将病毒特异性浆母细胞从肠道运输到乳腺（MG）和将伊加分泌到乳汁中[通过 肠-MG-分泌型伊加（sIgA）轴]缺乏。维生素A（VA）对免疫系统有多效性作用 包括粘膜免疫（伊加）的诱导和B和T细胞在粘膜区室之间的运输。 然而，VA在诱导和维持针对肠道病毒感染的催乳免疫中的作用在很大程度上是不确定的。 未定义。具体而言，怀孕母猪和妇女在妊娠晚期经历VA水平下降。也 许多孕妇，特别是发展中国家的孕妇，受到VAD的影响，但其对孕产妇和 针对肠道病毒的催乳免疫是未知的。最近，我们观察到口服VA补充剂 PEDV感染的妊娠猪增强了其新生哺乳仔猪的被动保护。我们还发现， 产前VAD损害仔猪的回忆性RV特异性伊加抗体分泌细胞（ASC）应答。扩大 我们将评估VA对以下方面的影响：i）诱导病毒特异性原发性和 妊娠母猪的次级（记忆）免疫应答; ii）病毒特异性伊加ASC从肠道运输至 MG;和iii）催乳免疫诱导的针对PEDV和RV的新生儿保护。我们的具体目标将侧重于 阐明了与维生素A充足的母猪相比，在VAD妊娠母猪中补充VA对 目的1）通过肠-MG-sIgA轴上调归巢分子和运输免疫细胞， 调节未感染妊娠母猪的肠道/MG免疫应答;目的2）在 妊娠母猪和仔猪对PEDV攻击（模式流行病毒）的被动保护 感染）;和目的3）RV再感染中回忆RV特异性伊加记忆B细胞应答的维持和再激活。 暴露妊娠母猪和仔猪对RV攻毒的被动保护（模型人畜共患/地方性病毒感染）。 我们的双重目的/双重益处研究将增强对肠-MG-sIgA轴的基本理解， 催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，实用和具有成本效益的策略，以启动和促进催乳 妊娠期免疫和控制新生儿肠道病毒感染。

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.