Integrative Multiomics to Probe Interactions of the Gut Microbiome with Malaria Pathogenesis and Antimalarial Pharmacokinetics in Humans

Johns Hopkins University, Baltimore MD

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Malaria has exerted a selective pressure on the human genome over hundreds of millennia. Evidence suggests that malaria may have also influenced the human microbiome. Animal and human studies previously showed associations between the gut microbiome and malaria severity, the risk of infection, anti-Plasmodium immunity, and antimalarial pharmacokinetics. Conversely, infection with Plasmodium has been shown to acutely alter the gut microbiome, offering for example one explanation for the long-observed association between malaria and non-typhoidal salmonellosis. We propose to investigate various clinical and parasitological relationships between acute P. falciparum infection and the human gut microbiome in the context of a recently completed randomized controlled trial (NCT04009343) and an existing observational cohort, leveraging recent advances in multiomics technology and bioinformatics to pursue mechanistic questions about the malaria-microbiome nexus in a human population. The proposed research is structured according to 3 specific aims that leverage existing fecal specimens and participant data from a recently-completed clinical trial of uncomplicated malaria and forthcoming samples from a Johns Hopkins Malaria Research Institute-funded observational cohort of severe malaria. Aim 1 will deploy metagenomics and metatranscriptomics to characterize the structure and functional potential of the intestinal microbiome and interrogate its relationships to multiple clinical and parasitological outcomes. Aim 2 will leverage existing plasma drug concentration data from a multidose pharmacokinetic design to assess the potential impacts of the microbiome on orally-administered antimalarial drugs. In nonlinear mixed effects models of drug pharmacokinetics, we will test interactions of the primary parameters with structural and derived functional features of the intestinal microbiome. Microbial biochemical pathways of interest that emerge from Aim 1 and 2 results will be tested by integration of metabolomic data generated under Aim 3 with metagenomic and metatranscriptomic data, identifying candidate biomarkers and targets for prognosis, prevention, and adjuvant treatment for future study. The proposed research will generate foundational evidence of clinically and pharmacologically relevant malaria-microbiome interactions in a patient population. More broadly, this work will expand our understanding of the role of the microbiome in disease pathogenesis and drug pharmacokinetics. The investigative team joins malariology and clinical pharmacology expertise with molecular, epidemiological, and computational microbiome-focused expertise to establish a 5-year research project that employs the most up-to-date technology and methods in multiomics to an oft-understudied but globally significant disease. The results would build significantly upon findings from preclinical studies of malaria and the microbiome, which have yet to be translated conclusively to field studies.