Alan Sher, Ph.D.

Section Chief

Description of Research Program

The major focus of the Immunobiology Section of the Laboratory of Parasitic Diseases is the study of host resistance and immune regulation in parasitic and other infections of global importance. The ultimate goal of this work is immunologic disease intervention in the form of vaccination or immunotherapy. At the same time, our research on the host response to infection has provided insights into the effector functions and regulatory mechanisms utilized by the vertebrate immune system. Much of the work of the Section is focused on the immunologic analysis in murine models of diseases induced by parasitic and bacterial agents (e.g. Toxoplasma gondii, Mycobacterium spp., Helicobacter spp.). Current activities include functional mapping of host-resistance pathways, studies on IL-10/IL-12 regulation of immunopathology, analysis of Th1 and Th2 differentiation in parasitic infections which induce polarized lymphokine responses, and the investigation of dendritic cell (DC) function and toll-like receptor (TLR) signaling in the initiation of microbial immunity. A separate AIDS program examines mechanisms by which co-infection with intracellular pathogens may promote HIV-1 disease.

Research Group Members: Dragana Jankovic- Staff Scientist; Carl Feng-Staff Scientist, Core; Romina Goldszmid; Tony Rothfuchs; Dan Barber; Lis Antonelli; Katrin Mayer -Fellows and Associates; Kevin Shenderov- Ph.D student, Oxford –NIH program; Sara Hieny, Pat Caspar- Research Technicians; Sandy White-Animal Care Specialist; Gail Taylor-Administrative Assistant

Notable accomplishments in recent years include the demonstration of IL-12 and IL-4 independent pathways for Th1 and Th2 differentiation in parasitic infection, the discovery of TLR and chemokine signaling pathways involved in the activation of DC by Toxoplasma gondii, the identification of a parasite-derived chemokine ligand which stimulates IL-12 production and acts as a co-receptor antagonist for HIV infection, and the assignment of critical functions for two interferon-induced GTPases in host resistance to intracellular protozoan and bacterial infections. In additional studies we have established effector and regulatory functions for bacterial-specific T cells in a model of Helicobacter-induced colitis and evaluated the role of TLR signaling in host resistance to Mycobacterium avium and Mycobacterium tuberculosis.

Awards

Research Career Development Award in Geographic Medicine (The Rockefeller Foundation); Bailey K. Ashford Medal (The American Society of Tropical Medicine and Hygiene).

Memberships

• American Academy of Microbiology
• American Society for Tropical Medicine and Hygiene
• American Association of Immunologists

Editorial Boards

• Microbes and Infection, Parasite Immunology
• Parasitology
• The Journal of Experimental Medicine, Nature Reviews in Immunology

Selected Recent Publications

To view a complete listing, visit PubMed.

Collazo, C. M., G. S. Yap, G. D. Sempowski, K. C. Lusby, L. Tessarollo, G. F. Woude, A. Sher, and G. A. Taylor. 2001. Inactivation of LRG-47 and IRG-47 reveals a family of interferon gamma-inducible genes with essential, pathogen-specific roles in resistance to infection. J. Exp. Med. 194:181.

Aliberti, J., C. Serhan, and A. Sher. 2002. Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. J. Exp. Med. 196:1253.

Jankovic, D., M. C. Kullberg, S. Hieny, P. Caspar, C. M. Collazo, and A. Sher. 2002. In the absence of IL-12, CD4(+) T-cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10(-/-) setting. Immunity 16:429.

Kullberg, M. C., D. Jankovic, P. L. Gorelick, P. Caspar, J. J. Letterio, A. W. Cheever, and A. Sher. 2002. Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis. J. Exp. Med. 196:505.

Aliberti, J., J. G. Valenzuela, V. B. Carruthers, S. Hieny, J. Andersen, H. Charest, C. Reis e Sousa, A. Fairlamb, J. M. Ribeiro, and A. Sher. 2003. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat. Immunol. 4:485.

Bafica, A., C. A. Scanga, M. L. Schito, S. Hieny, and A. Sher. 2003. Cutting edge: in vivo induction of integrated HIV-1 expression by mycobacteria is critically dependent on Toll-like receptor 2. J. Immunol. 171:1123.

Feng, C. G., C. A. Scanga, C. M. Collazo-Custodio, A. W. Cheever, S. Hieny, P. Caspar, and A. Sher. 2003. Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to Mycobacterium avium infection not exhibited by toll-like receptor 2 (TLR2)- and TLR4-deficient animals. J. Immunol. 171:4758.

Golding, H., J. Aliberti, L. R. King, J. Manischewitz, J. Andersen, J. Valenzuela, N. R. Landau, and A. Sher. 2003. Inhibition of HIV-1 infection by a CCR5-binding cyclophilin from Toxoplasma gondii. Blood 102:3280.

Kullberg, M. C., J. F. Andersen, P. L. Gorelick, P. Caspar, S. Suerbaum, J. G. Fox, A. W. Cheever, D. Jankovic, and A. Sher. 2003. Induction of colitis by a CD4+ T-cell clone specific for a bacterial epitope. Proc. Natl. Acad. Sci. U S A 100:15830.

Feng, C. G., C. M. Collazo-Custodio, M. Eckhaus, S. Hieny, Y. Belkaid, K. Elkins, D. Jankovic, G. A. Taylor, and A. Sher. 2004. Mice deficient in LRG-47 display increased susceptibility to mycobacterial infection associated with the induction of lymphopenia. J. Immunol. 172:1163.

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