Abstract
BackgroundL. braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. Wound healing neutrophil (PMN) and macrophage responses made following the bite of the vector sand fly contribute to disease progression in mice. To look at the interplay between PMN and macrophages in disease progression in humans we asked whether polymorphisms at genes that regulate their infiltration or function are associated with different clinical phenotypes. Specifically, CXCR1 (IL8RA) and CXCR2 (IL8RB) are receptors for chemokines that attract PMN to inflammatory sites. They lie 30-260 kb upstream of SLC11A1, a gene known primarily for its role in regulating macrophage activation, resistance to leishmaniasis, and wound healing responses in mice, but also known to be expressed in PMN, macrophages and dendritic cells.MethodsPolymorphic variants at CXCR1, CXCR2 and SLC11A1 were analysed using Taqman or ABI fragment separation technologies in cases (60 CL; 60 ML), unrelated controls (n = 120), and multicase families (104 nuclear families; 88 ML, 250 CL cases) from Brazil. Logistic regression analysis, family-based association testing (FBAT) and haplotype analysis (TRANSMIT) were performed.ResultsCase-control analysis showed association between the common C allele (OR 2.38; 95% CI 1.23-4.57; P = 0.009) of CXCR1_rs2854386 and CL, supported by family-based (FBAT; Z score 2.002; P = 0.045) analysis (104 nuclear families; 88 ML, 250 CL cases). ML associated with the rarer G allele (Z score 1.999; P = 0.046). CL associated with a 3' insertion/deletion polymorphism at SLC11A1 (Z score 2.549; P = 0.011).ConclusionsThe study supports roles for CXCR1 and SLC11A1 in the outcome of L. braziliensis infection in humans. Slc11a1 does not influence cutaneous lesion development following needle injection of Leishmania in mice, suggesting that its role here might relate to the action of PMN, macrophage and/or dendritic cells in the wound healing response to the sand fly bite. Together with the CXCR1 association, the data are consistent with hypotheses relating to the possible role of PMN in initiation of a lesion following the delivery of parasites via the sand fly bite. Association of ML with the rare derived G allele suggests that PMN also have an important positive role to play in preventing this form of the disease.
Highlights
L. braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis
Pro-inflammatory cytokines, including tumor necrosis factor (TNF) and interferon-g (IFN-g), and macrophage activation are important in eventual self-healing, but an exaggerated response is associated with mucosal leishmaniasis (ML) [4,5]
Analysis for susceptibility to L. braziliensis per se (i.e. cutaneous leishmaniasis (CL)+ML compared to NC+delayed-type hypersensitivity test (DTH)+) did not improve the significance (Table 2) suggesting that, CL disease usually precedes ML disease, there was something different about the ML patient group which meant that they did not contribute to this association
Summary
L. braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. Wound healing neutrophil (PMN) and macrophage responses made following the bite of the vector sand fly contribute to disease progression in mice. CXCR1 (IL8RA) and CXCR2 (IL8RB) are receptors for chemokines that attract PMN to inflammatory sites They lie 30-260 kb upstream of SLC11A1, a gene known primarily for its role in regulating macrophage activation, resistance to leishmaniasis, and wound healing responses in mice, and known to be expressed in PMN, macrophages and dendritic cells. Pro-inflammatory responses elicited by polymorphonuclear neutrophils (PMN) as part of the wound healing response to the bite of the sand fly vector are important in initiation of lesion development in mice [6] It has been hypothesized [7] that differences in the ability of macrophages and dendritic cells from different inbred mouse strains to respond to apoptotic versus necrotic PMN arising during the wound healing response to an infected sand fly bite determines disease progression. Expression patterns for chemokines have been associated with the evolution of large and small lesions in mice following L. braziliensis infection, influenced by both the strain of parasite [10] and the mouse genetic background [8]
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