Clinical observations and experimental animal models implicate the spleen as an important site for host immune responses to blood-borne bacteria. How the spleen's unique tissue structure and the diverse mixture of resident myeloid and lymphoid cells work together in vivo to combat infection remains poorly understood. We expect the native tissue environment to regulate immune cell function in complex and profound ways and therefore in vivo imaging approaches are a crucial complement biochemical and in vitro studies. Using two-photon microscopy and a robust histological analysis, we propose to investigate early phagocyte clearance mechanisms, analyze the trafficking of splenic phagocytes and the role of chemokine signaling in spleen remodeling, and identify the antigen presenting cells (APCs) and tissue microenvironment involved in presenting bacteria-specific antigen to T cells. Our overall goal is to understand how spleen structure impacts immune function. Our hypothesis is that early host-pathogen interactions in the marginal zone induce bactericidal responses in some cells, while in others, those interactions trigger cell migration to the appropriate tissue microcompartments for antigen presentation. Our studies will use the well characterized Listeria model of bacterial infection, in which splenic infection leads to T cell priming and induces long-lasting immunity. The proposed studies will enhance our fundamental understanding of how the spleen responds to blood-borne bacteria and provide a framework for future studies of other more virulent human pathogens.

Public Health Relevance

The spleen is the largest collection of lymphocytes in the human body and plays an important role in immunity to bacteria. However, few details are known regarding how resident immune cells work together to initiate the host immune response to infection. We will use cutting edge single-cell imaging techniques to study the capture of bacteria in the spleen and understand how bacterial antigen is presented to T cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Gondre-Lewis, Timothy A
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Spahn, Jessica H; Li, Wenjun; Bribriesco, Alejandro C et al. (2015) DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation. J Immunol 194:4039-48
Angiari, Stefano; Rossi, Barbara; Piccio, Laura et al. (2013) Regulatory T cells suppress the late phase of the immune response in lymph nodes through P-selectin glycoprotein ligand-1. J Immunol 191:5489-500
Knoop, Kathryn A; Miller, Mark J; Newberry, Rodney D (2013) Transepithelial antigen delivery in the small intestine: different paths, different outcomes. Curr Opin Gastroenterol 29:112-8
Wang, Baomei; Zinselmeyer, Bernd H; Runnels, Herbert A et al. (2012) In vivo imaging implicates CCR2(+) monocytes as regulators of neutrophil recruitment during arthritis. Cell Immunol 278:103-12
Li, Wenjun; Nava, Ruben G; Bribriesco, Alejandro C et al. (2012) Intravital 2-photon imaging of leukocyte trafficking in beating heart. J Clin Invest 122:2499-508
McDole, Jeremiah R; Wheeler, Leroy W; McDonald, Keely G et al. (2012) Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483:345-9
Divekar, Rohit D; Haymaker, Cara L; Cascio, Jason A et al. (2011) T cell dynamics during induction of tolerance and suppression of experimental allergic encephalomyelitis. J Immunol 187:3979-86
Kreisel, Daniel; Sugimoto, Seiichiro; Zhu, Jihong et al. (2011) Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance. Blood 118:6172-82
Mirsky, Henry P; Miller, Mark J; Linderman, Jennifer J et al. (2011) Systems biology approaches for understanding cellular mechanisms of immunity in lymph nodes during infection. J Theor Biol 287:160-70
Edelson, Brian T; Bradstreet, Tara R; Hildner, Kai et al. (2011) CD8α(+) dendritic cells are an obligate cellular entry point for productive infection by Listeria monocytogenes. Immunity 35:236-48

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