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

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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.