article · The Journal of Infectious Diseases
Visceral leishmaniasis is a severe parasitic disease characterized by fever, weight loss, and organ enlargement. Following an outbreak in Sudan where over five per cent of treated patients suffered relapses, often clustering within families, genetic analysis was carried out to understand the cause. Whole-exome sequencing of affected individuals and family controls identified rare nonsense and missense variants in the alkylglycerol monooxygenase gene associated with recurrence. These mutations followed an autosomal dominant pattern with incomplete penetrance. The gene is heavily expressed in the liver and in blood-forming cells, and it influences platelet-activating factor production in macrophages, a mechanism connected to anti-parasitic immune activity. These findings provide evidence that relapses in this condition can stem from host genetic susceptibility rather than alterations in parasite virulence.
Patients cured of visceral leishmaniasis can experience dangerous relapses. Identifying that these recurrences are influenced by inherited host genetics rather than changes in the parasite clarifies why certain individuals are vulnerable. This biological insight helps explain the familial clustering of relapses and highlights specific immune pathways involved in long-term clearance of the infection.
The discovery points towards potential diagnostic applications, such as genetic screening to identify cured patients at high risk of relapse. It may also provide targets for therapies supporting host immune pathways. However, this is early-stage fundamental research based on a small family cohort, and the abstract indicates no immediate commercial development or clinical tools ready for deployment.
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Background: Visceral leishmaniasis (kala-azar, KA) is the most severe form of leishmaniasis, characterized by fever, weight loss, hepatosplenomegaly, and lymphadenopathy. During an outbreak of KA in Babar El Fugara (Sudan), 5.7% of cured patients displayed relapses, with familial clustering in half the cases. Methods: We performed whole-exome sequencing on 10 relapsing individuals and 11 controls from 5 nuclear families. Results: Rare homozygous and compound-heterozygous nonsense (c.1213C > T, rs139309795, p.Arg405*) and missense (c.701A > G, rs143439626, p.Lys234Arg) mutations of the alkylglycerol monooxygenase (AGMO) gene were associated with KA relapse in 3 families. Sequencing in additional family members confirmed the segregation of these mutations with relapse and revealed an autosomal dominant mode of transmission. These mutations were detected heterozygous in 2 subjects among 100 unrelated individuals with KA who never relapsed after cure, suggesting incomplete penetrance of AGMO deficiency. AGMO is expressed in hematopoietic cells, and is strongly expressed in the liver. AGMO modulates PAF production by mouse macrophages, suggesting that it may act through the PAF/PAF receptor pathway previously shown to have anti-Leishmania activity. Conclusions: This is the first demonstration that relapses after a first episode of KA are due to differences in human genetic susceptibility and not to modifications of parasite pathogenicity.
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DOI: 10.1093/infdis/jix277
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