Stuart M Levitz, M.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Infectious Diseases and Immunology
   Medicine

Joint Faculty In:
   Molecular Genetics and Microbiology

Other Affiliation(s):
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Interplay between a host immune system and opportunistic fungal pathogens

We are focused upon the study of the interplay between the host immune system and opportunistic fungal pathogens, particularly Cryptococcus neoformans. C. neoformans frequently infects persons with impaired T cell function, especially those with AIDS. A major ongoing project in the laboratory is the molecular characterization of cryptococcal antigens that stimulate T cells to proliferate. In this regard, we have explored the mechanisms by which mannosylation of fungal proteins contributes to antigenicity. Essential to antigenicity is efficient uptake of the fungal antigens by dendritic cell mannose receptors. The eventual goal of this project is twofold. First, to better understand how the immunocompetent host protects itself against C. neoformans. Second, to develop a recombinant vaccine that would protect individuals at risk. Using the model antigen, ovalbumin, we are also developing model recombinant vaccines that exploit the ability of fungal mannosylation to target dendritic cells. Finally, the laboratory is studying how the major virulence factor of C. neoformans, polysaccharide capsule, modifies the immunological response and
enhances the pathogenicity of the fungus.

Representative Publications:

Shoham S, Huang C, Chen JM, Golenbock DT, Levitz SM. Toll-Like Receptor 4 mediates intracellular signaling without TNFarelease in response to Cryptococcus neoformans polysaccharide capsule. J Immunol. 166:4620-4626, 2001.

Levitz SM, Nong SH, Mansour MK, Huang C, Specht CA.Molecular Characterization of a Mannoprotein with Homology to Chitin Deacetylases that Stimulates T Cell Responses to Cryptococcus neoformans. Proc Natl Acad Sci (USA ). 98:10422-10427, 2001.

Mansour MK, Schlesinger L, Levitz SM. Optimal T-cell responses to Cryptococcus neoformans mannoprotein are dependent on recognition of conjugated carbohydrates by mannose receptors. J Immunol. 168:2872-2879, 2002.

Weber SM, Chen JM, Levitz SM. Inhibition of mitogen activated protein kinase signaling by chloroquine. J Immunol. 168:5303-9, 2002

Huang C, Nong SH, Mansour MK, Specht CA, Levitz SM. Purification and characterization of a second immunoreactive mannoprotein from Cryptococcus neoformans that stimulates T cell responses. Infect Immun. 70: 5485-93, 2002.

Mambula SS, Sau K, Henneke P, Golenbock DT, Levitz SM. Toll-Like Receptor (TLR) Signaling in response to Aspergillus fumigatus. J Biol Chem. 277:39320-6, 2002.

Sau K, Mambula SS, Latz E, Henneke P, Golenbock DT, Levitz SM. The antifungal drug amphotericin B promotes inflammatory cytokine release by a TLR- and CD14–dependent mechanism: A molecular basis for the infusion-related toxicity of amphotericin B. J Biol Chem. 278:37561-8, 2003.

Mansour MK, Yauch LE, Rottman JB, Levitz SM. Protective efficacy of antigenic fractions in mouse models of cryptococcosis. Infect Immun. 72:1746-54, 2004.

Bellocchio S, Montagnoli C, Bozza S, Gaziano R., Rossi G, Mambula SS, Vecchi A, Mantovani A, Levitz SM, Romani L. The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol. 172:3059-69, 2004.

Yauch LE, Mansour MK, Shoham S, Rottman JB, Levitz SM. Involvement of CD14, Toll-like Receptor (TLR) 2, TLR4, and MyD88 in the host response to the fungal pathogen Cryptococcus neoformans in vivo. Infect Immun. 72: 5373-5382, 2004.

Kelly RM, Chen J, Yauch LE, Levitz SM. Opsonic requirements for dendritic cell-mediated responses to Cryptococcus neoformans. Infect Immun. 73:592-8, 2005.

Yauch LE, Mansour MK, Levitz SM. Receptor-mediated clearance of Cryptococcus neoformans capsular polysaccharide in vivo. Infect Immun. 73:8429-32, 2005.

Lam JS, Specht CA , Mansour MK, Levitz SM. A model vaccine exploiting fungal mannosylation to increase antigen immunogenicity. J Immunol. 175:7496-503, 2005.

Mansour MK, Latz E, Levitz SM. Cryptococcus neoformans glycoantigens are captured by multiple lectin receptors and presented by dendritic cells. J Immunol. 176:3053-61, 2006.

Levitz SM, Specht CA. The molecular basis for the immunogenicity of Cryptococcus neoformans mannoproteins. FEMS Yeast Research. 6:513-24. 2006.

Wozniak K, Vyas JM, Levitz SM. In vivo role of dendritic cells in a murine model of pulmonary cryptococcosis. Infect Immun. 74:3817-24, 2006.

Yauch LE, Lam JS, Levitz SM.Direct inhibition of T cell responses by the Cryptococcus capsular polysaccharide glucuronoxylomannan. PLoS Pathogens, 2:e120. 2006.  

Possible rotation projects in the lab include:

1.      Exploring the immunological effects of conjugating β-glucan to antigens (and thereby targeting the beta-glucan receptor, dectin-1).

2.      Examining the cytokine profile of dendritic cells and T cells responding to differentially mannosylated antigens.

3.      Comparing adjuvants vis-à-vis their capacity to stimulate and bias dendritic cell responses.

Biography:

B.A. New York University, 1975

M.D. New York University School of Medicine, 1979

Keywords: Pathogenesis, Vaccine

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