causes visceral leishmaniasis (VL) in Brazil. We previously observed that VL is more common in males than females living in endemic neighborhoods, despite similar exposure. Using a larger sample, we document that VL is more common in males than females, but only after puberty. BALB/c and C57BL/6 mouse models confirmed that there is a biological basis for male susceptibility to symptomatic VL, showing higher parasite burdens in males than females. Female C57BL/6 mice generated more antigen-induced cytokines associated with curative responses (interferon-γ, interleukin [IL]-1β). Males expressed higher levels of IL-10 and tumor necrosis factor, which are linked to exacerbated disease. Different parasite lines entered or survived at a higher rate in macrophages of male- than female-origin. These results suggest that males are inherently more susceptible to than females and that mice are a valid model to study this sex-dependent difference.

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Summary Genetic risk factors contribute to asymptomatic versus symptomatic visceral leishmaniasis (VL) outcomes following infection with Leishmania infantum. We therefore carried out a family-based (N=918 post-quality control fully genotyped and phenotyped individuals) candidate gene study for symptomatic VL or asymptomatic delayed type hypersensitivity (DTH) skin test phenotypes in highly endemic neighborhoods of northeast Brazil. A total of 248 SNPs were genotyped in 42 genes selected as candidates on the basis of prior genetic, immunological and transcriptional profiling studies. The most significant association with the VL phenotype was with SNP rs6785358 (p=5.7e-04; pcorrected= 0.026) 3.8 kb upstream of TGFBR2, the gene encoding the type 2 receptor for transforming growth factor beta (TGF-β). A second inhibitory member of the TGB-β superfamily signaling pathway, SMAD7, was associated with the DTH phenotype (SNP rs7238442: p=0.001; pcorrected=0.051). The most significant association for the DTH phenotype was with SNP rs10800309 (p=−8.4e-06; pcorrected= 3.9e-04) situated 3.1 kb upstream of FCGR2A, the gene encoding the low affinity IIa receptor for the Fc fragment of IgG. Overall, our results imply a role for IgG-mediated inflammation in determining DTH associated with asymptomatic infection, and contribute to growing evidence that the TGFβ pathway is important in the immunopathogenesis of VL. (196 words; 200 words allowed)

Visceral leishmaniasis [VL] represents a major public health problem in many areas of the world. This review focuses on the impact of periurbanization on the epidemiology and treatment of VL, using Brazil as an example. VL continues to be mostly a disease of poverty with impact on families. However, the disease has expanded in Latin America, with foci reported as far south as Argentina. There is an increasing overlap of Leishmania infantum chagasi and HIV infections and other immunosuppressive conditions, resulting in VL emerging as an opportunistic infection. This new setting poses new challenges for VL disease control and patient management.

Infection with the protozoan Leishmania infantum can lead to asymptomatic infection and protective immunity, or to the progressive and potentially fatal disease visceral leishmaniasis (VL). Published studies show host genetic background determines in part whether infected individuals will develop a symptomatic or asymptomatic outcome. The purpose of the current study was to fine map chromosome regions previously linked with risk for symptomatic (chromosome 9) or asymptomatic (chromosomes 15 and 19) manifestations of L. infantum infection. We conducted a family-based genetic study of VL and asymptomatic infection (detected by a DTH skin test) with a final post quality control sample of 961 individuals with full genotype and phenotype information from highly endemic neighborhoods of northeast Brazil. A total of 5485 SNPs under the linkage peaks on chromosomes 9, 15 and 19 were genotyped. No strong SNP associations were observed for the DTH phenotype. The most significant associations with the VL phenotype were with SNP rs1470217 (p = 5.9e−05; pcorrected = 0.057) on chromosome 9, and with SNP rs8107014 (p = 1.4e−05; pcorrected = 0.013) on chromosome 19. SNP rs1470217 is situated in a 180 kb intergenic region between TMEM215 (Transmembrane protein 215) and APTX (Aprataxin). SNP rs8107014 lies in the intron between exons 26 and 27 of a 34 exon transcript (ENST00000204005) of LTBP4, (Latent transforming growth factor-beta-binding protein 4a). The latter supports growing evidence that the transforming growth factor-beta pathway is important in the immunopathogenesis of VL.