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To identify susceptibility loci for visceral leishmaniasis we undertook genome-wide association studies in two populations; 989 cases and 1089 controls from India, and 357 cases in 308 Brazilian families (1970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, resulting in Pcombined=2.76×10−17 and OR(95%CI)=1.41(1.30-1.52) across the three cohorts at rs9271858. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.

The protozoan Leishmania chagasi can cause disseminated, fatal visceral leishmaniasis (VL) or asymptomatic infection in humans. We hypothesized that host genetic factors contribute to this variable response to infection. A family study was performed in neighborhoods of endemicity for L. chagasi near Natal in northeastern Brazil. Study subjects were assessed for the presence of VL or asymptomatic infection, which was defined by a positive delayed-type hypersensitivity (DTH) skin test response to Leishmania antigen without disease symptoms. A genomewide panel of 385 autosomal microsatellite markers in 1254 subjects from 191 families was analyzed to identify regions of linkage. Regions with potential linkage to the DTH response on chromosomes 15 and 19, as well as a novel region on chromosome 9 with potential linkage to VL, were identified. Understanding the genetic factors that determine whether an individual will develop symptomatic or asymptomatic infection with L. chagasi may identify proteins essential for immune protection against this parasitic disease and reveal strategies for immunotherapy or prevention.

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Outcomes of infection with Leishmania chagasi range from self-resolving infection to visceral leishmaniasis (VL). Risk factors determining development of disease are not totally understood, but probably include environmental influences and host genetics. We assessed whether nutrition influenced the outcome of Leishmania infection by comparing relatives of children with VL with either self-resolving Leishmania spp. infection or apparently uninfected households. We observed a decrease in body mass index (P < 0.0005) and mid-upper arm circumference for age (P = 0.022) z-scores for children with VL. Levels of vitamin A were lower in active children with VL as measured by serum retinol (P = 0.035) and the modified-relative-dose-response test (P = 0.009). Higher birth weight (P = 0.047) and albumin concentrations (P = 0.040) protected against disease. Increased breastfeeding time (P = 0.036) was associated with asymptomatic infection. The results indicate that modifiable nutritional aspects are associated with the outcome of Leishmania spp. infection in humans.

Abstract. Visceral leishmaniasis (VL) is fatal if untreated, and there are no vaccines for this disease. High levels of CD4-derived interferon-γ (IFN-γ) in the presence of low levels of interleukin-10 (IL-10) predicts vaccine success. Tumor necrosis factor-α (TNF-α) is also important in this process. We characterized human immune responses in three groups exposed to Leishmania infantum chagasi in Brazil: 1) drug-cured VL patients (recovered VL); 2) asymptomatic persons with positive Leishmania-specific delayed-type hypersensitivity skin reactions (DTH+); and 3) DTH-negative household contacts. Magnitude of DTH correlated with crude Leishmania antigen-driven IFN-γ, TNF-α, and IL-5, but not IL-10. DTH+ persons showed equivalent levels of IFN-γ, but higher levels of IL-10, to tryparedoxin peroxidase and Leishmania homolog of receptor for activated C kinase compared with recovered VL patients. The IFN-γ:IL-10 and TNF-α:IL-10 ratios were higher in recovered VL patients than in DTH+ persons. Seven of 11 novel candidates (R71, L37, N52, L302.06, M18, J41, and M22) elicited cytokine responses (36-71% of responders) in recovered VL patients and DTH+ persons. This result confirmed their putative status as cross-species vaccine/immunotherapeutic candidates.

Abstract. Visceral leishmaniasis (VL), caused by Leishmania infantum chagasi (L.i. chagasi syn. infantum) in northeastern Brazil, was responsible for 51,000 new VL cases from 1980 to 2003. Household presence of L. infantum-infected dogs is a major risk factor for human infection. Despite culling of dogs based on seropositivity, canine L. infantum seroprevalence remains near 20%, suggesting that dog culling is ineffective for preventing VL spread. We administered a cross-sectional survey to 224 households within 300 m of the homes of VL human patients diagnosed within the last year. The goal was to develop a model for voluntary preventative use based on characteristics and motivations of dog owners. We identified that owner knowledge deficiencies regarding canine transmission of L. infantum associated with increased risk of dog infection (odds ratio [OR] = 3.681, confidence interval [CI] = 1.223, 11.08). Higher owner education was associated with decreased levels of dog seropositivity (OR = 0.40, CI = 0.20, 0.81). Pet attachment (P = 0.036) and perception of risk/disease knowledge (P = 0.040) were significantly associated with willingness to voluntarily purchase canine VL prevention. These results highlight the importance of owner attachment to their pet in implementing reservoirtargeted zoonotic VL prevention.

Vitamin A contributes to preservation of airway function during and in recovery after upper respiratory infection in children.