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

项目摘要。肠道病毒是导致人类和动物新生儿发病/死亡的主要原因。这个 由猪流行性腹泻病毒(PEDV)引起的新生仔猪严重胃肠炎和死亡 给养猪业造成了数百万美元的损失。与PEDV对猪的破坏性影响相似，轮状病毒(RV)是 这是全球儿童腹泻和死亡的主要原因，也是哺乳和断奶仔猪的主要原因。当前直播 在发达国家有效的减毒口服RV疫苗，在贫穷国家却没有效果 微量营养素缺乏[维生素A缺乏(VAD)]很常见。因此，增强母体免疫力和 通过初乳/牛奶进行被动乳源性免疫，是减少病毒影响的理想和有效的策略 哺乳新生儿的腹泻。对孕期肠道免疫诱导及其作用的认识 从肠道到乳腺(MG)的病毒特异性成浆细胞的运输和乳汁中的IgA分泌[通过 缺乏肠道-MG-分泌型IgA(SIgA)轴。维生素A(VA)对免疫系统有多效性作用 包括诱导粘膜免疫(IgA)和B细胞和T细胞在粘膜间的转运。 然而，VA在诱导和维持对肠道病毒感染的乳源性免疫中的作用很大程度上是 未定义。具体地说，怀孕的母猪和妇女在怀孕的最后三个月经历了维生素A水平的下降。也是 许多孕妇，特别是发展中国家的孕妇，受到VAD的影响，但它对产妇和 针对肠道病毒的乳源性免疫尚不清楚。最近，我们观察到口服维生素A补充剂 感染PEDV的怀孕猪加强了对其新生哺乳仔猪的被动保护。我们还展示了 产前VAD损害仔猪记忆性RV特异性IgA抗体分泌细胞(ASC)反应。要扩大规模 关于乳源性免疫的知识，我们将评估VA在以下方面的影响：i)诱导病毒特异性的原代和 妊娠母猪的二次(记忆)免疫反应；II)病毒特异性IgA ASC从肠道传播到 乳源性免疫诱导的新生儿对PEDV和RV的保护作用。我们的具体目标将集中在 探讨VAD妊娠母猪补充维生素A与补充维生素A对母猪生长发育的影响 目的：1)通过肠道-MG-SIgA轴上调归巢分子和免疫细胞的运输 未感染的妊娠母猪肠道/MG免疫反应的调节；目的2)增强感染后的乳源性免疫 妊娠母猪初次感染PEDV和仔猪对PEDV攻击(模型流行病毒)的被动保护 目的3)在RV Re中维持和重新激活记忆RV特异性的IgA记忆B细胞反应 使怀孕母猪和仔猪对轮状病毒攻击(模拟人畜共患/地方性病毒感染)进行被动保护。 我们的双重目的/双重益处研究将加强对肠道-MG-SIGA轴的基本理解， 乳源性免疫和新生儿被动保护，适用于猪和人。此外，我们还将 验证使用维生素A作为一种创新、实用和成本效益高的策略来启动和促进产乳量 孕期免疫与哺乳期新生儿肠道病毒感染控制。

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.