FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil

Castellucci, Léa; Jamieson, Sarra E.; Miller, E.N.; Almeida, Lana Carneiro; Oliveira, Joyce Moura; Magalhães, Ana Paula Nogueira de; Guimarães, Luiz Henrique; Lessa, Marcus Miranda; Lago, Ednaldo; Jesus, Amélia Ribeiro de; Carvalho, Edgar M.; Blackwell, Jenefer M.

doi:10.1038/gene.2011.37

Cited by 27 publications

(34 citation statements)

References 34 publications

(41 reference statements)

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“…For host genetic association studies, two family-based cohorts were collected during two study periods, 2000–2004 and 2008–2010, as reported previously along with details of epidemiology and clinical phenotypes of disease (Castellucci et al, 2011; Castellucci et al, 2010; Castellucci et al, 2006). Sample collection for the first cohort was based on ascertainment of index cases of ML from medical records of the Corte de Pedra Public Health Post, and active follow-up to identify and collect all other family members, including those with current or past CL disease.…”

Section: Methodsmentioning

confidence: 99%

“…This provided DNA samples (Table 1) from 157 nuclear families that contain 402 CL cases and 39 ML cases. The characteristics of the two cohorts have been described in detail elsewhere (Castellucci et al, 2011), including diagnostic criteria for ML and CL disease.…”

Section: Methodsmentioning

confidence: 99%

“…The infection is associated with a broad spectrum of clinical phenotypes, resulting from both environmental risk factors and a combination of the host’s immune and genetic background. In the last few years we have shown that polymorphisms at genes associated with wound healing and tissue repair are important risk factors for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis (Castellucci et al, 2012; Castellucci et al, 2011). Thus, the FLI1 gene, initially identified and mapped as a gene controlling susceptibility to CL caused by L. major infection in mice (Sakthianandeswaren et al, 2010; Sakthianandeswaren et al, 2005), was also associated with development of CL in humans exposed to L. braziliensis in Brazil.…”

Section: Introductionmentioning

confidence: 99%

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Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil: Role of COL1A1

Almeida

Oliveira

Guimarães

et al. 2015

Infection, Genetics and Evolution

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Previous studies have demonstrated a role for wound healing genes in resolution of cutaneous lesions caused by Leishmania spp. in both mice and humans, including the gene FLI1 encoding Friend leukaemia virus integration 1. Reduction of Fli1 expression in mice has been shown to result in up-regulation of collagen type I alpha 1 (Col1a1) and alpha 2 (Col1a2) genes and, conversely, in down-regulation of the matrix metalloproteinase 1 (Mmp1) gene, suggesting that Fli1 suppression is involved in activation of the profibrotic gene program. Here we examined single nucleotide polymorphisms (SNPs) in these genes as risk factors for cutaneous (CL) and mucosal leishmaniasis (ML), and leishmaniasis per se, caused by L. braziliensis in humans. SNPs were genotyped in 168 nuclear families (250 CL; 87 ML cases) and replicated in 157 families (402 CL; 39 ML cases). Family-based association tests (FBAT) showed the strongest association between SNPs rs1061237 (combined P=0.002) and rs2586488 (combined P=0.027) at COL1A1 and CL disease. This contributes to our further understanding of the role of wound healing in the resolution of CL disease, providing potential for therapies modulating COL1A1 via drugs acting on FLI1.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil: Role of COL1A1

Almeida

Oliveira

Guimarães

et al. 2015

Infection, Genetics and Evolution

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“…Polymorphisms in this factor's gene govern susceptibility to cutaneous leishmaniasis (6,51), and Abl facilitates FLI-1 activation (4). However, decreased FLI-1 activity and subsequent effects on wound healing should not lower parasite burdens (51).…”

Section: Discussionmentioning

confidence: 99%

The Abl and Arg Kinases Mediate Distinct Modes of Phagocytosis and Are Required for Maximal Leishmania Infection

Wetzel

McMahon-Pratt

Koleske

2012

Molecular and Cellular Biology

104

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Leishmania, an obligate intracellular parasite, binds several receptors to trigger engulfment by phagocytes, leading to cutaneous or visceral disease. These receptors include complement receptor 3 (CR3), used by promastigotes, and the Fc receptor (FcR), used by amastigotes. The mechanisms mediating uptake are not well understood. Here we show that Abl family kinases mediate both phagocytosis and the uptake of Leishmania amazonensis by macrophages (Ms). Imatinib, an Abl/Arg kinase inhibitor, decreases opsonized polystyrene bead phagocytosis and Leishmania uptake. Interestingly, phagocytosis of IgG-coated beads is decreased in Arg-deficient Ms, while that of C3bi-coated beads is unaffected. Conversely, uptake of C3bi-coated beads is decreased in Abl-deficient Ms, but that of IgG-coated beads is unaffected. Consistent with these results, Abl-deficient Ms are inefficient at C3bi-opsonized promastigote uptake, and Arg-deficient Ms are defective in IgG1-opsonized amastigote uptake. Finally, genetic loss of Abl or Arg reduces infection severity in murine cutaneous leishmaniasis, and imatinib treatment results in smaller lesions with fewer parasites than in controls. Our studies are the first to demonstrate that efficient phagocytosis and maximal Leishmania infection require Abl family kinases. These results highlight Abl family kinase-mediated signaling pathways as potential therapeutic targets for leishmaniasis. L eishmania parasites cause cutaneous or visceral disease in 1 to 2 million people a year in the developing world (17). Leishmania undergoes two life cycle stages: (i) the promastigote, found in the sand fly, and (ii) the amastigote, found in mammalian hosts. When an infected sand fly bites a host, the injected promastigotes must be engulfed by phagocytes to establish infection. The promastigotes then differentiate into amastigotes within the phagolysosome. If the amastigote finds itself outside a cell, it must be reengulfed for continued infection (23).Several M surface proteins permit Leishmania uptake. Promastigote internalization is mediated by the fibronectin receptor (integrin ␣5␤1) (2), the mannose-fucose receptor (63, 64), and complement receptors CR1 (10) and CR3 (38). Promastigotes may interact directly with CR3 (49), but binding is facilitated by opsonization with C3bi, a complement component (22,37,40,45). Both CR3 and the Fc receptor (FcR) mediate amastigote uptake (16); interactions with the latter are facilitated by IgG opsonization (35). The FcR subclass Fc␥R, which mediates IgG-mediated phagocytosis (33), is most likely responsible for amastigote uptake by Ms. Indeed, internalization of IgG-opsonized amastigotes via FcR␥I and -III sustains infection in murine cutaneous leishmaniasis (8,24,65). Adhesion of Leishmania to any of these receptors causes an actin-rich phagocytic cup to form and engulf the parasite (30). Our study explores the requirement for actin regulatory proteins in efficient Leishmania internalization.The Abl family kinases Abl and Arg translate signals from adhesion and growth...

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“…Linkage studies of MCL in mice have shown that resistance to Leishmania major and wound healing are controlled by FL1 [9]. In humans, associations of opposite alleles of FL1 with CL and MCL have been demonstrated [42,43]. FL1 is a transcription factor that represses CTGF (encoding connective tissue growth factor) expression via transforming growth factor-b signalling, thereby affecting collagen synthesis.…”

Section: Leishmaniasismentioning

confidence: 97%

Host genetics and parasitic infections

Mangano

Modiano

2014

Clinical Microbiology and Infection

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Parasites still impose a high death and disability burden on human populations, and are therefore likely to act as selective factors for genetic adaptations. Genetic epidemiological investigation of parasitic diseases is aimed at disentangling the mechanisms underlying immunity and pathogenesis by looking for associations or linkages between loci and susceptibility phenotypes. Until recently, most studies used a candidate gene approach and were relatively underpowered, with few attempts at replicating findings in different populations. However, in the last 5 years, genome-wide and/or multicentre studies have been conducted for severe malaria, visceral leishmaniasis, and cardiac Chagas disease, providing some novel important insights. Furthermore, studies of helminth infections have repeatedly shown the involvement of common loci in regulating susceptibility to distinct diseases such as schistosomiasis, ascariasis, trichuriasis, and onchocherciasis. As more studies are conducted, evidence is increasing that at least some of the identified susceptibility loci are shared not only among parasitic diseases but also with immunological disorders such as allergy or autoimmune disease, suggesting that parasites may have played a role in driving the evolution of the immune system.

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FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil

Cited by 27 publications

References 34 publications

Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil: Role of COL1A1

Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil: Role of COL1A1

The Abl and Arg Kinases Mediate Distinct Modes of Phagocytosis and Are Required for Maximal Leishmania Infection

Host genetics and parasitic infections

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