Laboratory of Parasitic Diseases

Alan Sher, Ph.D.

Chief, Laboratory of Parasitic Diseases
Chief, Immunobiology Section

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 used 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.) although the group is also engaged in several clinical collaborations. Current activities include the identification of pattern recognition receptors and their ligands in toxoplasma and mycobacterial infections, studies on the roles of IL-1, Type-1 and Type-2 IFN, and IL-12 in the regulation of host resistance to M. tuberculosis; analysis of Th1 and Th2 differentiation in parasitic infections that induce polarized lymphokine responses; and the role of dendritic cells (DC) in this process. The lab also has a major interest in the regulation of Th1-dependent immunopathology in both T. gondii and mycobacterial infections and in Immune Reconstitution Inflammatory Syndrome (IRIS), an acute illness seen in HIV-1+ individuals co-infected with mycobacteria and other pathogens following antiretroviral therapy.

Research Group Members: Dragana Jankovic, associate scientist; Carl Feng, staff scientist (core); Dan Barber, fellow; Katrin Mayer-Barber, fellow; Bruno Andrade, fellow; Alena Srinivasin, fellow; Kevin Shenderov, Ph.D. student, Oxford–NIH program; Dave Kugler, Ph.D. student, Johns Hopkins GPP; Alexsey Novikov, HHMI Scholar; Sara Hieny, research technician; Pat Caspar, research technician; Sandy White, animal procedure specialist; Gail Taylor, lab operations coordinator

Notable accomplishments in recent years include the following:

• Demonstration of the role of TLR 11-recognition of parasite profilin in the induction of IL-12 during T. gondii infection
• Identification of the T2 ribonuclease Omega-1 as the schistosome egg component responsible for conditioning DC to trigger Th2 responses
• Elucidation of endoplasmic reticulum fusion with parasitophorous vacuoles as a mechanism of cross-presentation in T. gondii-infected DC
• Studies identifying the respective role of TLR, IL-1R signaling, and the inflammasome in host resistance to M. tuberculosis and in the adjuvant activity of the mycobacterial component in Complete Freunds Adjuvant
• Identification of IL-10-producing Th1 cells as major regulators of immunopathology in T. gondii infection
• Discovery of major roles for the GTPase Irgm1(LRG47) in the regulation of hematopoietic stem development and in IFN-dependent autophagic cell death in T lymphocytes
• First description of in situ cellular dynamics with mycobacterial granulomas in a mammalian host
• Discovery of major role for IL-23 in bacterial-induced colitis
• Discovery of role of lipoxins in suppressing cellular response to M. tuberculosis, thereby promoting infection
• Development of a murine model for studying the pathogenesis of Immune Reconstitution Inflammatory Syndrome (IRIS)

Awards

Research Career Development Award in Geographic Medicine (The Rockefeller Foundation); Bailey K. Ashford Medal (The American Society of Tropical Medicine and Hygiene), U.S. PHS Superior Service Award, NIH Director’s Mentoring Award.

Memberships

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

Editorial Boards

• Faculty of 1000 (Section Head Immunity to Infections)
• The Journal of Experimental Medicine (Senior Editor)
• Nature Reviews in Immunology

Selected Recent Publications

To view a complete listing, visit PubMed.

Mayer-Barber KD, Barber DL, Shenderov K, White SD, Wilson MS, Cheever A, Kugler D, Hieny S, Caspar P, Nunez G, Schlueter D, Flavell RA, Sutterwala FS, Sher A. Caspase-1 independent IL-1β production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol. 2010 Apr 1;184(7):3326-30.

Steinfelder S, Andersen JF, Cannons JL, Feng CG, Joshi M, Dwyer D, Caspar P, Schwartzberg PL, Sher A, Jankovic D. The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1). J Exp Med. 2009 Aug 3;206(8):1681-90.

Goldszmid RS, Coppens I, Lev A, Caspar P, Mellman I, Sher A. Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells. J Exp Med. 2009 Feb 16;206(2):399-410.

Feng CG, Zhen L, Jankovic D, Bafica A, Cannons JL, Watford WT, Chaussabel D, Hieny S, Caspar P, Schwartzberg PL, Lenardo MJ, Sher A. The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T-cell populations by preventing interferon-γ-induced cell death. Nat Immunol. 2008 Nov 9;(11):1279-87.

Jankovic D, Kullberg MC, Feng CG, Goldszmid RS, Collazo CM, Wilson M, Wynn TA, Kamanaka M, Flavell RA, Sher A. Conventional T-bet+Foxp3-Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med. 2007 Feb 19;204(2):273-283.

Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science. 2005 Jun 10;308(5728):1626-9.

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