Browsing by Author "Tin, Christine"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Modeling human enteric dysbiosis and rotavirus immunity in gnotobiotic pigs
    Twitchell, Erica; Tin, Christine; Wen, Ke; Zhang, Husen; Becker-Dreps, Sylvia; Azcarate-Peril, M. Andrea; Vilchez, Samuel; Li, Guohua; Ramesh, Ashwin; Weiss, Mariah; Lei, Shaohua; Bui, Tammy; Yang, Xingdong; Schultz-Cherry, Stacey L.; Yuan, Lijuan (2016)
    BACKGROUND: Rotavirus vaccines have poor efficacy in infants from low- and middle-income countries. Gut microbiota is thought to influence the immune response to oral vaccines. Thus, we developed a gnotobiotic (Gn) pig model of enteric dysbiosis to study the effects of human gut microbiota (HGM) on immune responses to rotavirus vaccination, and the effects of rotavirus challenge on the HGM by colonizing Gn pigs with healthy HGM (HHGM) or unhealthy HGM (UHGM). The UHGM was from a Nicaraguan infant with a high enteropathy score (ES) and no seroconversion following administration of oral rotavirus vaccine, while the converse was characteristic of the HHGM. Pigs were vaccinated, a subset was challenged, and immune responses and gut microbiota were evaluated. RESULTS: Significantly more rotavirus-specific IFN-γ producing T cells were in the ileum, spleen, and blood of HHGM than those in UHGM pigs after three vaccine doses, suggesting HHGM induces stronger cell-mediated immunity than UHGM. There were significant correlations between multiple Operational Taxonomic Units (OTUs) and frequencies of IFN-γ producing T cells at the time of challenge. There were significant positive correlations between Collinsella and CD8+ T cells in blood and ileum, as well as CD4+ T cells in blood, whereas significant negative correlations between Clostridium and Anaerococcus, and ileal CD8+ and CD4+ T cells. Differences in alpha diversity and relative abundances of OTUs were detected between the groups both before and after rotavirus challenge. CONCLUSION: Alterations in microbiome diversity and composition along with correlations between certain microbial taxa and T cell responses warrant further investigation into the role of the gut microbiota and certain microbial species on enteric immunity. Our results support the use of HGM transplanted Gn pigs as a model of human dysbiosis during enteric infection, and oral vaccine responses.
  • Thumbnail Image
    Modeling human enteric dysbiosis and rotavirus immunity in gnotobiotic pigs. [poster]
    Twitchell, Erica; Tin, Christine; Wen, Ke; Zhang, Husen; Becker-Dreps, Sylvia; Azcarate-Peril, M. Andrea; Vilchez, Samuel; Li, Guohua; Ramesh, Ashwin; Weiss, Mariah; Lei, Shaohua; Bui, Tammy; Yang, Xingdong; Schultz-Cherry, Stacey L.; Yuan, Lijuan (2016-12)
    Background Oral vaccines, such as those for rotavirus are less efficacious in children from underdeveloped regions, where most severe disease occurs, than in children from more affluent areas. This disparity may be due to altered gut microbiota composition (dysbiosis), environmental enteropathy (EE), high maternal antibody titers, malnutrition, or influence of concurrent enteropathogens. Composition of gut microbiota in children is influenced by method of delivery, environmental hygiene and nutritional status. Studies have shown composition of gut microbiota to be significantly different between African and northern European infants and between malnourished and well-nourished children. A recent study has shown that EE was associated with failure of the oral rotavirus vaccine Rotarix, and underperformance of the oral polio vaccine. An animal model to study the effects of enteric dysbiosis on oral vaccine immunity is needed to evaluate potential treatments to reverse the dysbiosis and/or improve vaccine efficacy. Pigs and humans have similar immune systems, high genomic and protein sequence homology, omnivorous diet, and colonic fermentation, making pigs valuable models in biomedical research. The neonatal gnotobiotic (Gn) pig is a well-established model of human rotavirus disease and immunity.
  • Thumbnail Image
    Probiotic Lactobacillus rhamnosus GG Enhanced Th1 Cellular Immunity but Did Not Affect Antibody Responses in a Human Gut Microbiota Transplanted Neonatal Gnotobiotic Pig Model
    Wen, Ke; Tin, Christine; Wang, Haifeng; Yang, Xingdong; Li, Guohua; Giri-Rachman, Ernawati; Kocher, Jacob; Bui, Tammy; Clark-Deener, Sherrie; Yuan, Lijuan (PLOS, 2014-04-10)
    This study aims to establish a human gut microbiota (HGM) transplanted gnotobiotic (Gn) pig model of human rotavirus (HRV) infection and diarrhea, and to verify the dose-effects of probiotics on HRV vaccine-induced immune responses. Our previous studies using the Gn pig model found that probiotics dose-dependently regulated both T cell and B cell immune responses induced by rotavirus vaccines. We generated the HGM transplanted neonatal Gn pigs through daily feeding of neonatal human fecal suspension to germ-free pigs for 3 days starting at 12 hours after birth. We found that attenuated HRV (AttHRV) vaccination conferred similar overall protection against rotavirus diarrhea and virus shedding in Gn pigs and HGM transplanted Gn pigs. HGM promoted the development of the neonatal immune system, as evidenced by the significantly enhanced IFN-c producing T cell responses and reduction of regulatory T cells and their cytokine production in the AttHRV-vaccinated pigs. The higher dose Lactobacillus rhamnosus GG (LGG) feeding (14 doses, up to 109 colonyforming-unit [CFU]/dose) effectively increased the LGG counts in the HGM Gn pig intestinal contents and significantly enhanced HRV-specific IFN-c producing T cell responses to the AttHRV vaccine. Lower dose LGG (9 doses, up to 106 CFU/dose) was ineffective. Neither doses of LGG significantly improved the protection rate, HRV-specific IgA and IgG antibody titers in serum, or IgA antibody titers in intestinal contents compared to the AttHRV vaccine alone, suggesting that an even higher dose of LGG is needed to overcome the influence of the microbiota to achieve the immunostimulatory effect in the HGM pigs. This study demonstrated that HGM Gn pig is an applicable animal model for studying immune responses to rotavirus vaccines and can be used for studying interventions (i.e., probiotics and prebiotics) that may enhance the immunogenicity and protective efficacy of vaccines through improving the gut microbiota