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Defining the Gut-Mammary Gland-Secretory Iga Axis in Porcine Epidemic Diarrhea Virus Infected Gilts and Its Impact on Lactogenic

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Defining the Gut-Mammary Gland-Secretory Iga Axis in Porcine Epidemic Diarrhea Virus Infected Gilts and Its Impact on Lactogenic Defining the Gut-Mammary Gland-Secretory IgA Axis in Porcine Epidemic Diarrhea Virus Infected Gilts and its Impact on Lactogenic Immune Protection of Neonatal Suckling Piglets Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Stephanie Langel Graduate Program in Comparative and Veterinary Medicine The Ohio State University 2018 Dissertation Committee Dr. Linda J. Saif, Advisor and Committee Chair Dr. Anastasia N. Vlasova, Committee Member Dr. Qiuhong Wang, Committee Member Dr. Prosper N. Boyaka, Committee Member Copyrighted by Stephanie Mary Neal Langel 2018 2 Abstract Neonates are immune competent but immunologically immature at birth and are highly susceptible to enteric pathogens. For example, porcine epidemic diarrhea virus (PEDV) is a highly virulent re-emerging enteric coronavirus that causes acute diarrhea, dehydration and 80-100% mortality in neonatal piglets. Since its emergence in the United States (US) in 2013, PEDV caused over 8.5 million piglet deaths and $900 million to $1.8 billion in losses to US swine producers in 2014. Lactogenic immunity remains the most promising and effective way to protect neonatal suckling piglets from enteric diseases like PEDV. This is particularly true for domesticated animals like swine and cattle whose epitheliochorial placenta inhibits immunoglobulin (Ig) transfer in utero. Therefore, colostrum [first secretions from the mammary gland (MG)] and milk-derived antibodies (Abs) and other immune factors are the sole source for immune protection after birth. Passive lactogenic immunity is achieved through high titers of IgG Abs in colostrum and a continuous supply of secretory IgA (sIgA) Abs in milk. Specifically, because of their persistence in milk at high titers, sIgA Abs play a major role in conferring passive lactogenic protection against enteric pathogens in suckling neonates. Therefore, our goal was to improve the understanding of maternal and lactogenic immunity induced via the gut-MG-sIgA axis and its role in protection against PEDV in neonatal suckling piglets. iii Our first objective was to study the impact of stage of gestation at time of PEDV infection in pregnant gilts and its implications for generation of lactogenic immunity and protection of PEDV-challenged piglets. To understand how stage of gestation affects maternal immune responses to PEDV, three groups of gilts were orally infected with PEDV in the first, second or third trimester. Control (mock) gilts were inoculated with medium in the third trimester. To determine if lactogenic immunity correlated with protection, all piglets were PEDV-challenged at 3-5 days postpartum. PEDV infection of gilts at different stages of gestation significantly affected multiple maternal systemic immune parameters prepartum, including natural killer (NK) cells, cytokines, B cells and PEDV Abs and antibody secreting cells (ASCs). Second trimester gilts had significantly higher circulating PEDV IgA and IgG Abs and ASCs and PEDV virus neutralizing (VN) Abs post PEDV infection. Coinciding with the significantly higher PEDV Ab responses in second trimester gilts, the survival rate of their PEDV-challenged piglets was 100%, 87.2%, 55.9% and 5.7% for first, third and mock litters, respectively. Additionally, piglet survival positively correlated with PEDV IgA Abs and ASCs and VN Abs in milk and PEDV IgA and IgG Abs in piglet serum. Our findings have implications for gestational timing of oral attenuated PEDV maternal vaccines, whereby PEDV intestinal infection in the second trimester optimally stimulated the gut-MG-sIgA axis resulting in 100% lactogenic immune protection in suckling piglets. Our second objective was to study the impact of vitamin A (VA), an essential micronutrient, on maternal immunity and lactogenic immune protection of neonatal suckling piglets. Gilts received daily oral retinyl acetate (30,000 IU) starting at gestation iv day 76 throughout lactation. At 3-4 weeks prepartum, VA-supplemented (PEDV+VA) and non-supplemented (PEDV) gilts were PEDV or mock inoculated (mock+VA and mock, respectively). PEDV+VA gilts had lower mean PEDV RNA shedding titers and mean diarrhea scores, coinciding with increased frequencies of circulating NK cells post PEDV infection. Nursing piglets were PEDV-challenged at 3-5 days postpartum. The survival rate of PEDV+VA litters was 74.2% compared with 55.9% in PEDV litters. Mock and mock+VA litters had 5.7% and 8.3% survival rates, respectively. PEDV+VA gilts had increased PEDV IgA ASCs and Abs and IgA+β7+ (gut homing) cells in serum prepartum and in milk post-partum at post piglet challenge day (PCD) 5-9. Our findings suggest that oral VA supplementation may act as an adjuvant during pregnancy, enhancing IgA ASC trafficking via the gut-MG-sIgA axis and lactogenic immune protection in nursing piglets. Our third objective was to characterize B lymphocytes and immunoglobulin secreting cells (IgSCs) in colostrum, milk and MG tissue and cytokines in colostrum and milk of lactating swine. B lymphocytes were mainly CD2+/-CD21- (Ig-producing and/or memory) with few CD2+CD21+ (naïve) cells. We observed large numbers of IgSCs in colostrum and milk with significantly higher IgG IgSCs in colostrum and IgA and IgM IgSCs in late lactation milk. Additionally, milk contained α4+β7+ (gut homing receptor) B lymphocytes and enteric virus-specific IgG and IgA ASCs. TGF-β was the dominant cytokine in MG secretions and the concentration of IL-17 and IL-22 increased in mid and late lactation milk. Our results demonstrate that porcine milk contains Ig-producing B cells, many of which originate from the intestine, and pro/anti-inflammatory cytokines. v Our findings demonstrate that second trimester gilts have the greatest capacity to generate a robust PEDV humoral immune response prior to parturition, resulting in the highest amount of lactogenic immune protection against PEDV challenge in neonatal suckling piglets. Additionally, it suggests pregnancy should not be evaluated as a single event and development of a successful attenuated PEDV vaccine requires consideration of stage of gestation at the time of vaccination. Additionally, our results show that oral VA supplementation can be used as a cost-effective strategy to stimulate and enhance the gut-MG-sIgA axis to increase lactogenic immune protection of neonatal suckling piglets. Lastly, our results provide a better understanding of swine colostrum, milk and MG tissue B lymphocytes and colostrum and milk cytokines that may facilitate future studies investigating their role in neonatal immune development and protection. Understanding the gut-MG-sIgA axis and lactogenic immunity is critical to advance animal health and welfare within the swine industry. Additionally, the similarities between the human and swine immune systems make the pig a viable translational animal model, particularly for the study of infectious disease and vaccine development during pregnancy. Our pregnant swine model is applicable to endemic and emerging enteric viral diseases in humans and animals, as similar maternal vaccination strategies may be needed to enhance the gut-MG-sIgA axis and neonatal protection. vi Dedication This dissertation is dedicated to my wonderful family John Langel and Steve, Kathy and Stevie Neal. Love, Stephanie Mary vii Acknowledgments “You win with people.” –Coach Woody Hayes. It is the people who surround us that lead us to success. I am infinitely grateful to everyone over the past five years who contributed to my PhD and this dissertation. There are few professors who are as passionate about their work and the success of their students as Dr. Linda Saif. It is certain that I would not be the scientist and scholar I am today if it wasn’t for her continuous support and guidance. I am thankful for her feedback and effort to improve my scientific acumen over the last five years and am forever grateful for the opportunity to complete my PhD in her laboratory. I would like to extend my heartfelt gratitude to my scientific mentor and committee member, Dr. Anastasia Vlasova, for her support, mentorship, patience, and friendship throughout my doctoral program. Her guidance influenced all areas of my life and I aspire to become the mentor that she has been for me. I have the most sincere respect and gratitude for my committee members, Drs. Qiuhong Wang and Prosper Boyaka. Thank you both for your willingness and time to serve on my committee. I greatly benefited from Dr. Wang’s expertise in the field of virology and her experience working with PEDV. I am thankful for our positive interactions in the hallways of FAHRP and time spent together at scientific meetings. Additionally, I am thankful to have such a highly-skilled, well-regarded mucosal viii immunologist as Dr. Boyaka on my committee. His committed passion and expertise in the field of mucosal immunology positively shaped my program and this dissertation. The past and present members of the Saif laboratory kept me engaged and motivated during my doctoral program. An enormous thank you to Francine Chimelo Paim, Marcia Lee, Rosario Candelero, Juliet Chepngeno, Moyasar Alhamo, Sayaka Takanashi, Michael Husheem, Kwonil Jung, Yusheng Guo, Sukumar Kandasamy, David Fischer, Ayako Nakamura, Abdul Rauf, Kattie McGrath, Alexandra Magyar, Katie Anderson, Rebecca Mikalaki, Paige McAtee, Kaci Way and Kaci Agar. I am so grateful for their knowledge, helpful assistance and friendship. It was an honor to have worked with such intelligent, dynamic people. I sincerely thank the FAHRP veterinary staff, Dr. Juliette Hanson, Dennis Hartzler, Sara Tallmadge, Megan Strothers, Ronna Wood, Jeff Ogg, Kaitlyn Starr and Alden Sewell. Without their hard work and assistance, it is certain that this dissertation would have not been possible. Thank you to the FAHRP office administration, Hannah Gehman, Robin Weimer and Jen Shrock for their tireless efforts in making FAHRP a great place to work. Thank you to the FAHRP custodians, Sharon Chapman and Warren DuBois for keeping our building clean and safe. To all of my FAHRP and OARDC colleagues, it was an honor to get to know you and your families over the last five years.
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