Our laboratory investigates innate and adaptive immune responses to infection by pathogenic organisms. We have established several model systems to characterize innate immunity and antigen specific T cell responses. We use the intracellular bacterium Listeria monocytogenes to investigate early defense against bacterial infection.
Mice infected with L. monocytogenes develop a rapid inflammatory response that is followed by a robust and highly protective T cell mediated immune response. The early inflammatory response is essential for survival and inflammatory monocyte recruitment to sites of infection is central to this process (Figure 1). Our laboratory is characterizing the recruitment of inflammatory monocytes from the bone marrow into the bloodstream and infected tissues following systemic infection with L. monocytogenes. We have found that the CCR2 chemokine receptor is essential for monocyte emigration from the bone marrow and that cellular infection with L. monocytogenes induces the production of MCP-1, the ligand for CCR2. We have generated novel mouse strains that enable us to detect in vivo chemokine expression and inflammatory monocyte trafficking within infected tissues.
Inflammatory monocytes (in green) are recruited to foci of Listeria infection in the spleen. Focal induction of ICAM-1 expression in the liver (in red) targets monocytes to sites of bacterial infection.
Phase contrast image of two Clostridium difficile strains that differ in virulence undergoing sporulation.
A second focus of our laboratory concerns mucosal immune defense against intestinal pathogens such as Clostridium difficile and Vancomycin-resistant Enterococcus (VRE). These pathogens inhabit the intestine and are important causes of infection in hospitalized patients. Infection by these organisms generally occurs following antibiotic treatment and antibiotic-mediated disturbance of the normal intestinal microbiota enhances susceptibility to these pathogens (Figure 2). We are using these models to dissect the mechanisms by which commensal bacteria enhance resistance to microbial pathogens. We have demonstrated that antibiotic-mediated depletion of commensal bacteria decreases the expression of antimicrobial factors by the intestinal mucosa, enabling organisms like VRE to thrive and invade the bloodstream. Our laboratory is developing new approaches to enhance mucosal resistance in a variety of clinical circumstances where the intestinal microbiota is disturbed (e.g. following allogeneic hematopoietic stem cell transplantation).
Our laboratory also investigates the impact of antibiotics on the composition of the intestinal microbiota, using the Roche-454 multiparallel pyrosequencing platform (Figure 3). Our laboratory has demonstrated that antibiotics induce dramatic and long-term shifts of the intestinal microbiota that markedly enhance susceptibility to colonization and infection with VRE and Clostridium difficile.
Our laboratory collaborates with the laboratory of Michael Glickman to investigate CD4 T cell responses to Mycobacterium tuberculosis. We have generated a T cell receptor transgenic mouse strain specific for the immunodominant ESAT-6 epitope. T cells from this mouse provide resistance to M. tuberculosis infection, enabling us to perform experiments to optimize CD4 T cell-mediated protection and to discover and enhance mechanisms of protective immunity to tuberculosis.
van Heijst JW, Ceberio I, Lipuma LB, Samilo DW, Wasilewski GD, Gonzales AM, Nieves JL, van den Brink MR, Perales MA, Pamer EG. Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation. Nat Med. 2013 Mar;19(3):372-7. doi: 10.1038/nm.3100. Epub 2013 Feb 24.
Ubeda C, Bucci V, Caballero S, Djukovic A, Toussaint NC, Equinda M, Lipuma L, Ling L, Gobourne A, No D, Taur Y, Jenq RR, van den Brink MR, Xavier JB, Pamer EG. Intestinal microbiota containing Barnesiella species cures vancomycin-resistant Enterococcus faecium colonization. Infect Immun. 2013 Mar;81(3):965-73. doi: 10.1128/IAI.01197-12. Epub 2013 Jan 14.
Ubeda C, Lipuma L, Gobourne A, Viale A, Leiner I, Equinda M, Khanin R, Pamer EG. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J Exp Med. 2012 Jul 30;209(8):1445-56. doi: 10.1084/jem.20120504. Epub 2012 Jul 23.
Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, Lee YJ, Dubin KA, Socci ND, Viale A, Perales MA, Jenq RR, van den Brink MR, Pamer EG.Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012 Oct;55(7):905-14. doi: 10.1093/cid/cis580. Epub 2012 Jun 20.
Kinnebrew MA, Buffie CG, Diehl GE, Zenewicz LA, Leiner I, Hohl TM, Flavell RA, Littman DR, Pamer EG. Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity. 2012 Feb 24;36(2):276-87. doi: 10.1016/j.immuni.2011.12.011. Epub 2012 Feb 2.
Member, Association of American Physicians (2011)
Fellow, Infectious Diseases Society of America (2010)
Member, American Society for Clinical Investigation (1998)
Pew Scholar in the Biomedical Sciences, Pew Charitable Trust (1994)
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