Although 80% of infectious diseases are initiated at mucosal surfaces, our knowledge of the mechanisms of induction and regulation of mucosal immunity and our ability to exploit the mucosal immune system to prevent infections at or across mucosal surfaces is limited. We have proposed a novel model for regulation of intestinal immunity to enteric viruses by TH1 and TH3, but not TH2 cytokines. We propose that TGF- beta (TH3) regulates the antigen-specific IgA response. Studies proposed in this renewal grant application seek to determine the validity of our model. Rotavirus and VLPs will be used to probe the responses to infection or immunization to define the mechanisms and molecules necessary to induce protective intestinal immune responses. It is hypothesized that VLPs and live rotavirus induce protective immunity by different mechanisms since they induce different IgG subclasses and widely divergent IgA responses. It is further hypothesized that VLPs administered intranasally can overcome the compartmentalized immune responses reported to occur in the common mucosal immune system.
The specific aims are to determine how differences in protective efficacy of virus and VLPs are regulated by differences in (1) inductive or effector cytokine responses, (2) B cell responses, or (3) homing of memory lymphocytes. Quantitative analysis of the B cell responses and cytokine profiles induced following a variety of mucosal immunization protocols and virus challenge will be performed in normal, specifically-- depleted, -upregulated or knockout mice. The results from these basic studies will be relevant to understanding immune regulation and functions at mucosal surfaces and may confirm a novel regulatory mechanism. Further, they will facilitate the design of more effective vaccines for rotavirus and other enteric viruses. The knowledge gained from these basic studies also will be useful in development of new effective vaccine strategies for viral pathogens such as HIV that infect at or invade across mucosal surfaces.
| Miller, Amber D; Blutt, Sarah E; Conner, Margaret E (2014) FoxP3+ regulatory T cells are not important for rotavirus clearance or the early antibody response to rotavirus. Microbes Infect 16:67-72 |
| Preidis, Geoffrey A; Keaton, Mignon A; Campeau, Philippe M et al. (2014) The undernourished neonatal mouse metabolome reveals evidence of liver and biliary dysfunction, inflammation, and oxidative stress. J Nutr 144:273-81 |
| Killoran, Kristin E; Miller, Amber D; Uray, Karen S et al. (2014) Role of innate immunity and altered intestinal motility in LPS- and MnCl2-induced intestinal intussusception in mice. Am J Physiol Gastrointest Liver Physiol 306:G445-53 |
| Lopatin, Uri; Blutt, Sarah E; Conner, Margaret E et al. (2013) Lymphotoxin alpha-deficient mice clear persistent rotavirus infection after local generation of mucosal IgA. J Virol 87:524-30 |
| Preidis, Geoffrey A; Saulnier, Delphine M; Blutt, Sarah E et al. (2012) Host response to probiotics determined by nutritional status of rotavirus-infected neonatal mice. J Pediatr Gastroenterol Nutr 55:299-307 |
| Blutt, S E; Miller, A D; Salmon, S L et al. (2012) IgA is important for clearance and critical for protection from rotavirus infection. Mucosal Immunol 5:712-9 |
| Preidis, Geoffrey A; Saulnier, Delphine M; Blutt, Sarah E et al. (2012) Probiotics stimulate enterocyte migration and microbial diversity in the neonatal mouse intestine. FASEB J 26:1960-9 |
| Williams, Kent; Koyama, Tatsuki; Schulz, Daryl et al. (2011) Use of fluoroscopy to study in vivo motility in mouse pups. J Pediatr Gastroenterol Nutr 52:679-85 |
| Marcelin, Glendie; Miller, Amber D; Blutt, Sarah E et al. (2011) Immune mediators of rotavirus antigenemia clearance in mice. J Virol 85:7937-41 |
| Blutt, Sarah E; Kirkwood, Carl D; Parreno, Viviana et al. (2003) Rotavirus antigenaemia and viraemia: a common event? Lancet 362:1445-9 |
