Examining childhood immunity to Leishmania parasites as a path to smarter therapies
Marcela Moncada-Velez, PhD
BACKGROUND: Visceral Leishmaniasis (VL), also commonly called kala-azar, is a neglected tropical infectious disease caused by Leishmania parasites, with an incidence of 500,000 new cases per year (50,000 of which will be fatal, even if the best currently-available treatment is given). Approximately 350 Million people in 88 countries live in Leishmania-endemic areas and are therefore at risk of infection. Although exposure to Leishmania parasites occurs in up to 30% of individuals in these regions, the development of severe and disseminated infection (VL) occurs in a minority of infected individuals, most of them children. VL is therefore a major childhood medical problem.
GAP: Most previous studies have focused on the environmental and socioeconomic factors that increase the risk of developing VL. However, the biological basis of VL susceptibility is still unknown. This proposal aims to discover the human genetic and immunological determinants of Leishmania infection outcomes, to understand why some children, but not others, develop VL after exposure to Leishmania parasites.
HYPOTHESIS: VL results from both exposure to Leishmania parasites and genetically-determined ‘gaps’ in human immune function.
METHODS: We propose a thorough, unbiased and rigorous genetic dissection of VL in affected children using whole-exome sequencing (WES) technology. Patients and their parents (“trios”) will undergo approved informed consent procedures, provide blood and saliva samples, and undergo WES. Then, using several bioinformatic tools we will sift through thousands of mutations to choose the best candidates for functional validation and therefore, to establish causal relationships between genotype and infectious phenotype. The targeted enrolment is 50 VL patients and their parents, over 2 years.
IMPACT: All currently-available therapies for VL target the microbe, not the human immune response, and are also highly toxic to the child. This study will, for the first time, probe the human genetic determinants of Leishmania immunity, which will lead us to understand the mechanisms of Leishmania susceptibility. This line of research will ultimately lead to meaningful improvements in child health, as once armed with this knowledge, we may design smarter therapies which exploit the human immune system to eradicate this deadly disease.
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