Uncovering the metabolic basis for population differences in the immune response to malaria.

Malaria is a global health epidemic, with an estimated 229 million cases per year resulting in over 400, 000 deaths with the majority of these deaths being in children under the age of 5. The vast majority of cases in sub-Saharan Africa are caused by the Plasmodium falciparum parasite and transmitted via mosquitos. There is currently no approved vaccine for malaria and antimalarial drug resistance is a growing concern. There is hope that a better understanding of the interactions of the parasite and host metabolism could yield better treatment options.

A new study led by Youssef Idaghdour of the Program in Biology at New York University Abu Dhabi has been published in Nature Metabolism aimed to understand the metabolic changes associated with P. falciparum infection (the study was also highlighted in Nature Review Immunology). The scientists integrated Metabolon’s global metabolomics technology with deep phenotypic patient data, including immunophenotyping in two different ethnic groups in Burkina Faso. In this study, samples were collected from children during the dry season, when infection rates are low and continued to collect samples through the wet season when infection rates are high.  Previous studies have determined that while both Gouin and Fulani children live in areas with very high malarial transmission, Fulani children are relatively less susceptible to infection due to an immune response profile that appears to be more adaptive to responding to the parasitic infection. This study design allowed the researchers to profile the serum metabolic changes due to natural infection in Gouin and Fulani children. They identified 195 metabolites that were altered by infection and 92 metabolites altered by parasitemia (the stage of infection when the parasites are in the blood). The altered metabolites included those from lipid biosynthesis, energy pathways and metabolites known to alter the adaptive immune response.

When the researchers compared the alterations in Fulani children to Gouin children they discovered profound differences in the endogenous steroid levels with Gouin children having significantly higher levels of many steroids during infection. Steroids, particularly pregnenolone steroids, were associated with lower levels of cytokines and lymphocytes, which are key to controlling the infection. The metabolomics data were also integrated with transcriptomics to demonstrate the impact of steroids on the expression of key immunoregulatory lymphocyte genes. This finding is important because it may underly the cause of the weakened immune response in Gouin children and their increased susceptibility to malaria.

The approach of integrating metabolomics with immunophenotyping and transcriptomics is key to understanding the immune response to infectious disease. In addition to furthering our understanding of the immune response, these data may lead to improved treatments.