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Infection and Immunity, July 2009, p. 2971-2978, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.00558-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Overexpression of the Natural Inhibitor of Cysteine Peptidases in Leishmania mexicana Leads to Reduced Virulence and a Th1 Response{triangledown}

Karen Bryson,1,{dagger} Sébastien Besteiro,2,{dagger},{ddagger} H. Adrienne McGachy,1 Graham H. Coombs,1 Jeremy C. Mottram,2 and James Alexander1*

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, The John Arbuthnott Building, 27 Taylor St., Glasgow G4 ONR, United Kingdom,1 Wellcome Centre for Molecular Parasitology and Division of Infection and Immunity, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, United Kingdom2

Received 7 May 2008/ Returned for modification 19 June 2008/ Accepted 23 April 2009

Leishmania mexicana cysteine peptidases (CPs) have been identified as important parasite virulence factors. More recently, a natural inhibitor of CPs (ICP) from L. mexicana has been characterized, and ICP mutants have been created. Infection of BALB/c mice with ICP null mutants or ICP reexpressing mutants resulted in nonhealing, progressively growing lesions albeit slightly attenuated compared with the growth of lesions produced by wild-type parasites. In contrast, BALB/c mice infected with mutants overexpressing ICP were able to significantly control lesion growth or heal. While BALB/c mice infected with wild-type parasites, ICP null mutants, or ICP reexpressing mutants produced significant antibody responses, including immunoglobulin E (IgE), no Th1 response, as indicated by antigen-induced splenocyte gamma interferon (IFN-{gamma}) production, could be demonstrated. In contrast, BALB/c mice infected with mutants overexpressing ICP produced significantly less antibody, particularly IgE, as well as significantly reduced splenocyte interleukin-4 and enhanced IFN-{gamma} production. BALB/c mice were able to resolve infection following infection with one ICP overexpressing clone, which was subsequently used for vaccination studies with BALB/c mice. However, no protection was afforded these mice when they were challenged with wild-type parasites. Nevertheless, two other mouse strains susceptible to L. mexicana, C3H and C57BL/6, vaccinated with overexpressing ICP mutants were able to control challenge infection associated with an enhanced Th1 response. This study confirms that L. mexicana CPs are virulence factors and that ICPs have therapeutic potential.

* Corresponding author. Mailing address: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, The John Arbuthnott Building, 27 Taylor St., Glasgow G4 ONR, United Kingdom. Phone: 44 141 548 3925. Fax: 44 141 552 3562. E-mail: j.alexander{at}strath.ac.uk

{triangledown} Published ahead of print on 11 May 2009.

Editor: J. F. Urban, Jr.

{dagger} Both authors contributed equally to the study.

{ddagger} Present address: UMR CNRS 5235, Université de Montpellier 2, Montpellier F-34095, France.

Infection and Immunity, July 2009, p. 2971-2978, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.00558-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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