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Infection and Immunity, June 2009, p. 2330-2342, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00057-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Designing Therapies against Experimental Visceral Leishmaniasis by Modulating the Membrane Fluidity of Antigen-Presenting Cells{triangledown}

Subha Banerjee,1 June Ghosh,1 Subha Sen,1 Rajan Guha,1 Ranjan Dhar,1 Moumita Ghosh,1 Sanchita Datta,1 Bikramjit Raychaudhury,1 Kshudiram Naskar,1 Arun Kumar Haldar,1 C. S. Lal,2 K. Pandey,2 V. N. R. Das,2 Pradeep Das,2 and Syamal Roy1*

Indian Institute of Chemical Biology, Council of Scientific & Industrial Research, 4 Raja S.C. Mullick Road, Kolkata 700032, India,1 Rajendra Memorial Research Institute of Medical Sciences, Indian Council of Medical Research, Patna 800007, India2

Received 16 January 2009/ Returned for modification 2 March 2009/ Accepted 6 March 2009

The membrane fluidity of antigen-presenting cells (APCs) has a significant bearing on T-cell-stimulating ability and is dependent on the cholesterol content of the membrane. The relationship, if any, between membrane fluidity and defective cell-mediated immunity in visceral leishmaniasis has been investigated. Systemic administration of cholesterol by liposome delivery (cholesterol liposomes) in Leishmania donovani-infected hamsters was found to cure the infection. Splenic macrophages as a prototype of APCs in infected hamsters had decreased membrane cholesterol and an inability to drive T cells, which was corrected by cholesterol liposome treatment. The effect was cholesterol specific because liposomes made up of the analogue 4-cholesten-3-one provided almost no protection. Infection led to increases in interleukin-10 (IL-10), transforming growth factor beta, and IL-4 signals and concomitant decreases in gamma interferon (IFN-{gamma}), tumor necrosis factor alpha, and inducible NO synthase signals, which reverted upon cholesterol liposome treatment. The antileishmanial T-cell repertoire, whose expansion appeared to be associated with protection, was presumably type Th1, as shown by enhanced IFN-{gamma} signals and the predominance of the immunoglobulin G2 isotype. The protected group produced significantly more reactive oxygen species and NO than the infected groups, which culminated in killing of L. donovani parasites. Therefore, cholesterol liposome treatment may be yet another simple strategy to enhance the cell-mediated immune response to L. donovani infection. To our knowledge, this is the first report on the therapeutic effect of cholesterol liposomes in any form of the disease.

* Corresponding author. Mailing address: Indian Institute of Chemical Biology, Council of Scientific & Industrial Research, Kolkata 700032, India. Phone: 091-033-2473-3491. Fax: 091-033-2473-0284. E-mail: sroy{at}iicb.res.in

{triangledown} Published ahead of print on 16 March 2009.

Editor: W. A. Petri, Jr.

Infection and Immunity, June 2009, p. 2330-2342, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00057-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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