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Infection and Immunity, August 2003, p. 4278-4288, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4278-4288.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Impaired Expression of Inflammatory Cytokines and Chemokines at Early Stages of Infection with Leishmania amazonensis

Jiaxiang Ji,1 Jiaren Sun,1 and Lynn Soong1,2*

Departments of Microbiology and Immunology,1 Pathology, WHO Center for Tropical Diseases, Sealy Center for Vaccine Development, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-10702

Received 12 March 2003/ Returned for modification 14 April 2003/ Accepted 28 April 2003

Infection of mice with Leishmania major results in disease progression or resolution, largely depending on the genetic backgrounds of the mouse strains. Infection with Leishmania amazonensis, on the other hand, causes progressive cutaneous lesions in most inbred strains of mice. We hypothesized that deficient activation of early immune responses contributes to the pathogenesis in L. amazonensis-infected mice. To distinguish early molecular events that determine the outcome of Leishmania infections, we examined cytokine gene expression in C57BL/6 mice infected with either L. amazonensis or L. major (a healing model). After 2 to 4 weeks, L. amazonensis-infected mice had significantly delayed and depressed expression of inflammatory cytokines (interleukin-12 [IL-12], gamma interferon, IL-1{alpha}, IL-1ß), CC chemokines (CC chemokine ligand 3 [CCL3]/macrophage inflammatory protein 1{alpha} [MIP-1{alpha}], CCL4/MIP-1ß, CCL5/RANTES, MIP-2), and chemokine receptors (CCR1, CCR2, CCR5) in foot tissues and draining lymph nodes compared to the expression in L. major-infected controls. These findings correlated with defective T-cell responsiveness to parasite stimulation in vivo and in vitro. Adoptive transfer of L. amazonensis-specific Th1 cells prior to infection overcame the immune defects of the animals, leading to complete control of the disease. Studies with gene knockout mice suggested that IL-10, but not IL-4, contributed partially to compromised immunity in L. amazonensis-infected hosts. The data suggest that there is impairment in multiple immune functions at early stages of infection with L. amazonensis parasites and provide a compelling rationale to explore immune augmentation as an intervention in American cutaneous leishmaniasis.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Texas Medical Branch, Medical Research Building 3.132, 301 University Blvd., Galveston, TX 77555-1019. Phone: (409)772-8149. Fax: (409)747-6869. E-mail: lysoong{at}utmb.edu.

Editor: W. A. Petri, Jr.

Infection and Immunity, August 2003, p. 4278-4288, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4278-4288.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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