Scott B. Snapper
Boston Children's Hospital, Laboratory for Mucosal Immunology
Division of Gastroenterology and Nutrition
300 Longwood Ave., Enders 676
Boston, MA 02115
Topics and Potential Rotation Projects:
1) Leukocyte and Epithelial Cell Signaling and Trafficking; 2) Host-Microbial Interactions; 3) Innate and Adaptive Immune Mechanisms for Regulating Inflammation; 4) Regulation of the Actin-Cytoskeleton
Leukocyte and Epithelial Cell Signaling and Trafficking
Our laboratory is broadly interested in cell signaling pathways that regulate blood cells and epithelial cells in health and disease. We have focused on the Wiskott-Aldrich syndrome protein (WASP) family of signaling molecules that act as molecular scaffolds integrating incoming cell surface signals to the actin cytoskeleton. The Wiskott-Aldrich syndrome (WAS) is an immunodeficiency characterized by leukocyte dysfunction, cancer, and thrombocytopenia. The hematopoietic specific protein WASP, defective in these patients, and the ubiquitously expressed N-WASP are cytoplasmic proteins that when activated by Rho-family GTPases binds to the Arp2/3 complex and drives actin assembly. These proteins regulate such diverse activities as cell movement and proliferation, vesicular trafficking, immune synapse formation and host:pathogen interactions. We have employed gene-targeting approaches to generate mice and cell lines deficient for several WASP family members. Using various approaches, we are defining hematopoietic and epithelial signaling pathways regulated by WASP-proteins to characterize broadly the role of the actin-cytoskeleton in cellular function.
Many intracellular pathogens utilize the host's actin-based machinery to invade cells and to move within and between cells. These pathogens have surface proteins that interact and stimulate host proteins resulting in the activation of a complicated signaling cascade resulting in directed actin polymerization. Shigella, Salmonella, Listeria, EPEC, and Vaccinia are examples of pathogens that depend on the host-actin cytoskeletal machinery for their pathogenicity. Utilizing live imaging technologies and molecular and cellular techniques, we are continuing to investigate mechanistically the relationship between microbial and host proteins in the process by which pathogens invade and survive within cells.
Innate and Adaptive Immune Mechanisms for Regulating Inflammation
Inflammatory disorders of the gastrointestinal tract are associated with dysregulation of the innate or adaptive immune system. Various genetic models have demonstrated: a central role for dysregulated T-cells, the requirement of bacteria or bacterial products, an exaggerated Th1 response, and the role of disrupted mucosal integrity in the development of intestinal inflammation. We are characterizing the mechanism of colitis in WASP-KO mice and other mouse models. We have determined that unlike most models of IBD, the colitis in WASP-deficiency is associated with a Th2 cytokine profile. Utilizing knock-out, transgenic and transfer technologies, we are addressing the role of specific subsets of lymphocytes (e.g., regulatory T-cells) and the role of microbial infection in the development of inflammation.
Snapper SB, Takeshima F, Anton I, Liu CH, Thomas S, Nguyen D, Dudley D, Fraser H, Purich D, Klein C, Bronson R, Mulligan R, Southwick F, Geha R, Goldberg M, Rosen FS, Hartwig J, Alt FW. N-WASP-Deficiency Reveals Distinct Pathways for Cell Surface Projections and Microbial Actin-Based Motility. Nature Cell Biology 2001;3:897-904.
Shibata T, Takeshima F, Chen F, Alt FW, Snapper SB. Cdc42 Facilitates Invasion but Not the Actin-Based Motility of Shigella. Current Biology 2002;12:341-5.
Maillard M., Cotta-de-Almeida V, Takeshima F, Nguyen D, Michetti P, Nagler C, Bhan AK, and Snapper SB. 2006. The Wiskott Aldrich Syndrome Protein Is Required For The Function of CD4+CD25+Foxp3+ Regulatory T cells. J Exp. Med. 2007 Feb; 204: 381-391.
Cotta-de-Almeida V, Westerberg L., Maillard M., Onaldi D., Wachtel H, Chung U, Xavier R, Alt, FW, and Snapper, S.B. 2007. WASP and N-WASP are Critical for T cell Development. PNAS.
Nguyen D, Almeida V, Takeshima F, Mizoguchi A, Bhan AK, Snapper SB. Th2 Cytokine Skewing in Colitis Associated with WASP-Deficiency. Gastroenterology. 2007. In Press.
Last Update: 1/6/2014