Distinct amino acid and lipid perturbations characterize acute versus chronic malaria
Up to three quarters of all malaria cases are chronic, which presents a major hurdle for combatting the disease. These chronic cases are often asymptomatic, but can have long term negative health effects for the infected, while serving as source for mosquito-borne transmission. While malaria worldwide still presents a major health concern, the biological mechanisms behind chronic malaria are not well understood.
In a new study by Cordy et al, metabolomics and transcriptomics techniques were used to observe alterations in metabolism between chronic and acute cases of malaria. The goal was to identify metabolites and parasite transcriptional features that could help distinguish the two cases to better understand the biology behind disease progression. To determine the relevance of animal models, the authors monitored macaques infected with Plasmodium coatneyi longitudinally, and compared with human samples infected with Plasmodium falciparum. Throughout the study, the authors observed clinical parameters, plasma metabolomes, and parasite transcriptional profiles.
Untargeted high-resolution mass spectrometry analysis was used to measure and annotate metabolic profiles. Targeted metabolomics was then used to further characterize and quantify clinically relevant metabolites for each type of infection. Metabolomics results showed global changes between both infection types in amino acid, biogenic amine, carnitine, and lipid metabolism, while transcriptomics in macaques revealed alterations in amine, fatty acid, lipid, and energy metabolism.
Targeted, tandem mass spectrometry data also revealed significant perturbations in clinically related metabolic ratios in human samples. The Fischer ratio (liver dysfunction), kynurenine to tryptophan (immunosuppression/tolerance), mono-unsaturated to saturated phosphatidylcholines (fatty acid desaturases activity), and total lyso-phosphatidylcholines to total phosphatidylcholines (phospholipases activity) were all found to be significantly altered, peaking in the acute case where the disease was most active. The metabolic ratio indicators correlated well with the pathway analysis from the untargeted data and demonstrated that both fatty acid metabolism and lipid degradation were elevated during the acute cases.
When looked at together, the authors discovered a large set of metabolites and indicators are differentially and significantly expressed in chronic malaria compared to acute cases. These observed alterations in metabolites may be key to better understanding the biology of host-parasite interactions in malarial disease progression. Further, it was demonstrated that metabolite alterations in the macaques were comparable to those from humans, providing a robust animal model for future studies. The study demonstrates a first attempt at integrating various data types and animal models to provide a wholistic picture for better understanding the dynamics between acute and chronic malaria.
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Cordy RJ, Patrapuvich R, Lili LN, Cabrera-Mora M, Chien J, Tharp GK, Khadka M, Meyer EVS, Lapp SA, Joyner CJ, Garcia A, Banton S, Tran V, Luvira V, Rungin S, Saeseu T, Rachaphaew N, Pakala SB, DeBarry JD, MaHPIC Consortium, Kissinger JC, Ortlund EA, Bosinger SE, Barnwell JW, Jones DP, Uppal K, Li S, Sattabongkot J, Moreno A, Galinski MR: Distinct amino acid and lipid perturbations characterize acute versus chronic malaria (2019) JCI Insight | https://doi.org/10.1172/jci.insight.125156