The Journal of Experimental Medicine
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Published online 14 April 2003 doi:10.1084/jem.20022033
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© Rockefeller University Press, 0022-1007/2003/4/1037 $5.00
The Journal of Experimental Medicine, Volume 197, Number 8, 1037-1043

Brief Definitive Report

CD40 Signaling Is Impaired in L. major–infected Macrophages and Is Rescued by a p38MAPK Activator Establishing a Host-protective Memory T Cell Response

Amit Awasthi1, Ramkumar Mathur1, Aslam Khan1, Bimba N. Joshi1, Nitya Jain1, Sangeeta Sawant2, Ramanamurthy Boppana1, Debashis Mitra1 and Bhaskar Saha1

1 National Centre for Cell Science, Ganeshkhind
2 Bioinformatics Centre, Pune University, Ganeshkhind, Pune 411007, India

Address correspondence to Bhaskar Saha, National Centre for Cell Science, Ganeshkhind, Pune 411007, India. Phone: 0091-20-5690922; Fax: 0091-20-5692259; E-mail: sahab{at}nccs.res.in

Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-{gamma}, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major–infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK)-specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD40-induced p38MAPK phosphorylation, iNOS2 expression and anti-leishmanial function were impaired in Leishmania-infected macrophages but were restored by anisomycin. Anisomycin's effects were reversed by SB203580 emphasizing the role of p38MAPK in CD40-induced iNOS2-dependent leishmanicidal function. Anisomycin administration in L. major–infected BALB/c mice resulted in significant reduction in the parasite load and established a host-protective Th1-type memory response. Also implicated in these findings is a scientific rationale to define novel anti-parasite drug targets and to bypass the problem of drug resistance.

Key Words: Leishmaniasis • immune evasion mechanism • CD40 signaling • p38MAPK • T cell memory


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