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ROTAVIRUS PATHOGENESIS, INNATE IMMUNITY AND THEIR IMMUNE MODULATION BY PROBIOTICS IN A PIGLET MODEL AND IN VITRO

Shao, Lulu
http://orcid.org/0000-0002-1441-4744
http://rave.ohiolink.edu/etdc/view?acc_num=osu1449150624

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Rotavirus (RV) is a major pathogen causing acute gastroenteritis in children under 5 and in young animals. Because no specific antiviral therapy is available, effective RV vaccines are crucial to prevent morbidity and mortality. However, licensed RV vaccines for humans have low efficacy in developing countries, and emerging RV strains (including G9) may decrease vaccine efficacy. Our goal was to improve understanding of RV pathogenesis, cross-protection and correlates of protection and probiotics/commensals, age and tissue-specific effects on innate immunity in a pig model. Our first objective was to assess the pathogenesis of porcine RV (PRV) G9P[13] and evaluate short-term cross-protection between G9P[13] and human RV (HRV) G1P[8] in a gnotobiotic (Gn) pig model. Gn pigs were inoculated with G9P[13] and challenged with G1P[8], or vice versa. G9P[13] induced longer fecal virus shedding than G1P[8] and generated complete short-term cross-protection in pigs challenged with G1P[8] or G9P[13], whereas G1P[8] induced only partial protection against G9P[13] challenge. G9P[13] replicated more extensively in porcine monocyte-derived dendritic cells (DCs) than G1P[8]. Our results suggest that heterologous protection by the current monovalent G1P[8] vaccine against emerging G9 strains should be evaluated in further studies to prevent wider dissemination of G9 strains. Our second objective was to compare the influence of age, diet, microbiota and tissue origin on TLR expression in mononuclear cells (MNCs) and DCs isolated from spleen, ileum and mesenteric lymph nodes (MLNs) of germfree (GF) and conventional pigs. TLR mRNA expression profiles were distinct between GF and conventional pigs, and were generally lower in ileal MNCs/DCs which may be due to microbiota-driven immunoregulatory/immunosuppressive mechanisms to avoid overstimulation by dampening TLR expression levels. Comparison of TLR expression profiles in GF and conventional pigs demonstrated that exposure to commensal microbiota may be of more importance than age in TLR expression, further highlighting the critical role of commensal microbiota in the development of systemic and mucosal immune systems of neonates. Our third objective was to examine the differential effects of live probiotic bacteria on splenic, ileal and MLN MNCs from Gn pigs. MNCs were analyzed after treatment with probiotics and/or inactivated HRV (inactHRV) in vitro to determine DC frequencies and cytokine levels. We found that the Gram-positive probiotics Lactobacilus rhamnosus GG (LGG) and Bifidobacterium lactis Bb12 (Bb12) decreased the frequencies of conventional DC (cDC) and activated (MHCII+) cDC in ileal and MLN of inactHRV-exposed or untreated MNCs. In contrast, the Gram-negative probiotic Escherichia coli Nissle 1917 (EcN) increased plasmacytoid DC (pDC) and (MHCII+) pDC frequencies in MLN MNCs. In inactHRV-exposed groups, EcN, LGG and Bb12 reduced cytokine levels of IL-6 (pro-inflammatory), IFN-alpha (innate/anti-viral), IL-12 (Th1), and IL-4 (Th2) in splenic MNCs; whereas, EcN increased IL-10 (T-regulatory) levels. These results demonstrate that Gram-positive and Gram-negative probiotic bacteria differentially modulate DC frequencies, surface phenotypes and functions in vitro. Collectively, these findings improve our understanding of RV pathogenesis, correlates of protection, and the development of porcine innate immunity. This knowledge should help to improve RV vaccine efficacy and aid in design of new vaccines. V
Linda Saif, J (Advisor)
Anastasia Vlasova, N (Other)
Prosper Boyaka, N (Committee Member)
Renukaradhya Gourapura, J (Committee Member)
Gireesh Rajashekara (Committee Member)
248 p.
Immunology; Virology

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Citations

  • Shao, L. (2015). ROTAVIRUS PATHOGENESIS, INNATE IMMUNITY AND THEIR IMMUNE MODULATION BY PROBIOTICS IN A PIGLET MODEL AND IN VITRO [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449150624

    APA Style (7th edition)

  • Shao, Lulu. ROTAVIRUS PATHOGENESIS, INNATE IMMUNITY AND THEIR IMMUNE MODULATION BY PROBIOTICS IN A PIGLET MODEL AND IN VITRO. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1449150624.

    MLA Style (8th edition)

  • Shao, Lulu. "ROTAVIRUS PATHOGENESIS, INNATE IMMUNITY AND THEIR IMMUNE MODULATION BY PROBIOTICS IN A PIGLET MODEL AND IN VITRO." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449150624

    Chicago Manual of Style (17th edition)

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