Overexpression of the natural inhibitor of cysteine peptidases, ICP, in Leishmania mexicana leads to reduced virulence and a Th1 response

Bryson, K., Besteiro, S., McGachy, H. A., Coombs, G. H., Mottram, J. C. and Alexander, J. (2009) Overexpression of the natural inhibitor of cysteine peptidases, ICP, in Leishmania mexicana leads to reduced virulence and a Th1 response. Infection and Immunity, 77(7), pp. 2971-2978. (doi:10.1128/IAI.00558-08) (PMID:19433541) (PMCID:PMC2708542)

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Abstract

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 characterised and ICP mutants have been created. Infection of BALB/c mice with ICP null mutants or ICP re-expressing mutants resulted in non-healing progressively growing lesions albeit slightly attenuated compared with the growth of wild-type parasites. In contrast BALB/c mice infected with mutants over-expressing ICP were able to significantly control lesion growth or heal. While BALB/c mice infected with wild-type parasites, ICP null mutants or ICP re-expressing mutants produced significant antibody responses including IgE, no Th1 response as indicated by antigen-induced splenocyte IFN-{gamma} production could be demonstrated. In contrast, BALB/c mice infected with mutants over-expressing ICP produced significantly less antibody, particularly IgE, as well as significantly reduced splenocyte IL-4, and enhanced IFN-{gamma} production. BALB/c mice were able to resolve infection following infection with one ICP over-expressing clone, which was subsequently used for vaccination studies in BALB/c mice. However, no protection was afforded these mice when they were challenged with wild-type parasites. Nevertheless, 2 other mouse strains susceptible to L. mexicana, C3H and C57BL/6, vaccinated with over-expressing 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

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bryson, Dr Karen and Mottram, Professor Jeremy and Coombs, Professor Graham
Authors: Bryson, K., Besteiro, S., McGachy, H. A., Coombs, G. H., Mottram, J. C., and Alexander, J.
Subjects:Q Science > QR Microbiology > QR180 Immunology
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Infection and Immunity
Journal Abbr.:IAI
Publisher:American Society for Microbiology
ISSN:0019-9567
ISSN (Online):1098-5522
Published Online:11 May 2009

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
454141Analysing the roles of petidases in Leishmania infectivity and pathogenicityJeremy MottramMedical Research Council (MRC)G0700127Infection Immunity and Inflammation Life Sciences