Dr. Shi's research interests are focused regulation of mucosal immunity in the gastrointestinal tract.
Research of Hai Ning Shi, DVM, PhD
Hai Ning Shi, DVM, PhD
Mucosal Immunology Laboratory, Pediatric GI Unit, MGHfC, Assistant Professor of Pediatrics, Harvard Medical School
My research interests are focused regulation of mucosal immunity in the gastrointestinal tract. We use both in vivo and in vitro approaches to elucidate the mechanisms by which an intestinal helminth infection modulates intestinal inflammation induced by pathogenic and non-pathogenic enteric bacteria. Helminths infect 2 billion people world-wide. The distribution of several pathogenic helminth infections coincides geographically with many devastating microbial diseases, such as HIV, malaria and tuberculosis. The major importance of helminth infections includes not only the direct pathogenic effect of the worms, but also the modulation of the host immune system, which may alter the response to other antigens and cause additional immunopathology (1). Helminths induce Th2 polarization of helper T cells, which may alter the response to other pathogens or antigens. Using our recently established helminth- bacterial co-infection mouse model, we demonstrated that infection with the intestinal helminth parasite, Heligmosomoides polygyrus, results in the development of exacerbated intestinal inflammation in mice infected with the Gram-negative bacterial enteropathogen Citrobacter rodentium, a mouse pathogen similar to human EPEC (2, 3). The results from our subsequent study indicate that one of the mechanisms by which helminths exert their effects may involve their activation of alternatively activated macrophages (4), as evidenced by the markedly up-regulated expression of Ym1, Fizz1 and Arg 1 in macrophages from H. polygyrus-infected mice (Figure 1 A). Ex vivo functional analysis of macrophages from helminth-infected mice demonstrated that their ability to kill phagocytosed bacteria was significantly impaired (Figure 1B and C).
Currently, as outlined in Figure 2, we explore the mechanism(s) by which helminths alter the T cell response to enteric bacteria and determine how the helminth-induced response alters intestinal epithelial barrier function and the phenotype and function of macrophages, compromising their ability to control bacteria and contributing to impaired host defense and increased tissue injury. This project is supported by a recently awarded NIH R01 grant (DK082427).
Another area of study in our lab is directed at clarifying the role of maternal factors during gestation in the development of immunity and the induction of allergic diseases in the early life of the offspring (5). The immune system in the gastrointestinal tract is unique. It prevents the invasion of disease-causing microorganisms in the gut lumen and at the same time it induces non-responsiveness to normal constituents of the gut (normal microbiota and food proteins). The intestinal immunity of a child, in particular, can be influenced by the mother's immune status during both prenatal and/or postnatal stages. We are currently examining the immunologic effects on the fetal and newborn offspring of "atopic" mother mice and mothers whose immune system is dysregulated compared to normal immuno-competent mothers. We also investigate how this maternal influence may be modified to be potentially protective. We ultimately seek to elicit information that may help protect children from developing food allergy and enhance their immune capacity to react to antigenic challenges (infections). We anticipate that this project will be funded by a research grant from Nestle Research Institute. We are currently working on an agreement with Nestle for the proposed research.
The third area of our research focuses on how intestinal colonization of probiotics and/or treatment with prebiotics early in life influences the development and regulation of host innate and adaptive immune responses. Recently we have shown that preinoculation of murine gut with Lactobacillus acidophilus early in life enhances host defense against enteric bacterial infection and attenuates bacteria-mediated colitis (6, 7). We study the effects of early inoculation of probiotics and/or prebiotics on intestinal adaptive immunity and cell signaling molecules. Our research will help provide greater insight into how intestinal microorganisms may alter the regulatory mechanisms of mucosal immunity, which may be instrumental in the establishment of more effective and safer preventive and therapeutic approaches for the treatment of immune-mediated disorders and for the design of effective mucosal vaccines.