Inhibitor of serine peptidase 2 enhances Leishmania major survival in the skin through control of monocytes and monocyte-derived cells

Goundry, A., Romano, A., Lima, A. P. C.A., Mottram, J. and Myburgh, E. (2018) Inhibitor of serine peptidase 2 enhances Leishmania major survival in the skin through control of monocytes and monocyte-derived cells. FASEB Journal, 32(3), pp. 1315-1327. (doi:10.1096/fj.201700797R) (PMID:29097502) (PMCID:PMC5892728)

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Abstract

Leishmania major is the causative agent of the neglected tropical disease, cutaneous leishmaniasis. In the mouse, protective immunity to Leishmania is associated with inflammatory responses. Here, we assess the dynamics of the inflammatory responses at the lesion site during experimental long-term, low-dose intradermal infection of the ear, employing noninvasive imaging and genetically modified L. major. Significant infiltrates of neutrophils and monocytes occurred at 1–4 d and 2–4 wk, whereas dermal macrophage and dendritic cell (DC) numbers were only slightly elevated in the first days. Quantitative whole-body bioluminescence imaging of myeloperoxidase activity and the quantification of parasite loads indicated that the Leishmania virulence factor, inhibitor of serine peptidase 2 (ISP2), is required to modulate phagocyte activation and is important for parasite survival at the infection site. ISP2 played a role in the control of monocyte, monocyte-derived macrophage, and monocyte-derived DC (moDC) influx, and was required to reduce iNOS expression in monocytes, monocyte-derived cells, and dermal DCs; the expression of CD80 in moDCs; and levels of IFN-γ in situ. Our findings indicate that the increased survival of L. major in the dermis during acute infection is associated with the down-regulation of inflammatory monocytes and monocyte-derived cells via ISP2.—Goundry, A., Romano, A., Lima, A. P. C. A., Mottram, J. C., Myburgh, E. Inhibitor of serine peptidase 2 enhances Leishmania major survival in the skin through control of monocytes and monocyte-derived cells.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lima, Dr Ana and Mottram, Professor Jeremy and Goundry, Miss Amy Louise and Myburgh, Dr Elmarie
Authors: Goundry, A., Romano, A., Lima, A. P. C.A., Mottram, J., and Myburgh, E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:FASEB Journal
Publisher:Federation of American Society of Experimental Biology
ISSN:0892-6638
ISSN (Online):1530-6860
Published Online:02 November 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in FASEB Journal 32(3):1315-1327
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY
611411Proteolysis and life cycle progression in LeishmaniaJeremy MottramMedical Research Council (MRC)MR/K019384/1III - PARASITOLOGY