Host genetic factors in American cutaneous leishmaniasis: a critical appraisal of studies conducted in an endemic area of Brazil

Abstract

American cutaneous leishmaniasis (ACL) is a vector-transmitted infectious disease with an estimated 1.5 million new cases per year. In Brazil, ACL represents a significant public health problem, with approximately 30,000 new reported cases annually, representing an incidence of 18.5 cases per 100,000 inhabitants. Corte de Pedra is in a region endemic for ACL in the state of Bahia (BA), northeastern Brazil, with 500-1,300 patients treated annually. Over the last decade, population and family-based candidate gene studies were conducted in Corte de Pedra, founded on previous knowledge from studies on mice and humans. Notwithstanding limitations related to sample size and power, these studies contribute important genetic biomarkers that identify novel pathways of disease pathogenesis and possible new therapeutic targets. The present paper is a narrative review about ACL immunogenetics in BA, highlighting in particular the interacting roles of the wound healing gene FLI1 with interleukin-6 and genes SMAD2 and SMAD3 of the transforming growth factor beta signalling pathway. This research highlights the need for well-powered genetic and functional studies on Leishmania braziliensis infection as essential to define and validate the role of host genes in determining resistance/susceptibility regarding this disease.

Fig. 1. : the study area and spectrum of clinical disease caused by Leishmania braziliensis infection in Corte de Pedra, state of Bahia, Brazil. A: typical house and farm area; B: typical cutaneous leishmaniasis lesion characterised by granulomatous background and elevated borders; C: disseminated leishmaniasis, a form of disease that is increasing in the study area; D: mucosal leishmaniasis characterised by infiltrated ulcers that can cause extensive destruction of the nasal septum, columella and the upper lip.

Fig. 2. : diagram of genes that have been implicated in susceptibility to cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) disease caused by Leishmania braziliensis in the area of Corte de Pedra, state of Bahia, Brazil, showing involvement of, and interaction with, the transforming growth factor β (TGFβ) pathway. Polymorphisms in genes annotated in red lettering have been associated with CL or ML disease. Turquoise circles indicate the pathway through which interleukin (IL)-6 influences SMAD4 via FLI1. SP1/3 are transcription factors that influence FLI1 expression. CTGF: connective tissue growth factor. Source: Castellucci et al. (2012).