Influence of parasite encoded inhibitors of serine peptidases in early infection of macrophages with Leishmania major

Eschenlauer, S. C. P., Faria, M. S., Morrison, L. S., Bland, N., Ribeiro-Gomes, F. L., DosReis, G. A., Coombs, G. H. , Lima, A. P. C. A. and Mottram, J. C. (2009) Influence of parasite encoded inhibitors of serine peptidases in early infection of macrophages with Leishmania major. Cellular Microbiology, 11(1), pp. 106-120. (doi:10.1111/j.1462-5822.2008.01243.x)

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Publisher's URL: http://dx.doi.org/10.1111/j.1462-5822.2008.01243.x

Abstract

Ecotin is a potent inhibitor of family S1A serine peptidases, enzymes lacking in the protozoan parasite Leishmania major. Nevertheless, L. major has three ecotin-like genes, termed inhibitor of serine peptidase (ISP). ISP1 is expressed in vector-borne procyclic and metacyclic promastigotes, whereas ISP2 is also expressed in the mammalian amastigote stage. Recombinant ISP2 inhibited neutrophil elastase, trypsin and chymotrypsin with Kis between 7.7 and 83 nM. L. major ISP2–ISP3 double null mutants (Δisp2/3) were created. These grew normally as promastigotes, but were internalized by macrophages more efficiently than wild-type parasites due to the upregulation of phagocytosis by a mechanism dependent on serine peptidase activity. Δisp2/3 promastigotes transformed to amastigotes, but failed to divide for 48 h. Intracellular multiplication of Δisp2/3 was similar to wild-type parasites when serine peptidase inhibitors were present, suggesting that defective intracellular growth results from the lack of serine peptidase inhibition during promastigote uptake. Δisp2/3 mutants were more infective than wild-type parasites to BALB/c mice at the early stages of infection, but became equivalent as the infection progressed. These data support the hypothesis that ISPs of L. major target host serine peptidases and influence the early stages of infection of the mammalian host.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mottram, Professor Jeremy and Coombs, Professor Graham
Authors: Eschenlauer, S. C. P., Faria, M. S., Morrison, L. S., Bland, N., Ribeiro-Gomes, F. L., DosReis, G. A., Coombs, G. H., Lima, A. P. C. A., and Mottram, J. C.
Subjects:Q Science > QR Microbiology
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cellular Microbiology
Publisher:Wiley-Blackwell Publishing
ISSN:1462-5814
ISSN (Online):1462-5822
Published Online:29 October 2008
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
297261Post-genomic analysis of cysteine protease function in Leishmania parasitesJeremy MottramMedical Research Council (MRC)G0000508Infection Immunity and Inflammation Life Sciences