Malaria Parasite Genomics, Development, Drug Resistance, Pathogenesis, and Host-parasite Interaction

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Between 2024 and 2025, we continued to investigate the molecular mechanisms of malaria pathogenesis and signaling pathways using the Plasmodium yoelii and Plasmodium berghei parasites. We also tested compounds on the human malaria parasite Plasmodium falciparum to develop potential treatments and study drug resistance. We revised and published several manuscripts, worked on several ongoing projects, and initiated new research projects. We have made good progress in these projects: 1. We have finished sequencing and assembling the genome of another P. yoelii strain (N67C), an isogenic parasite of N67. We also sequenced the mRNA from the N67 and N67C parasites to improve genome annotation. A paper entitled “Comparative genomics of Plasmodium yoelii nigeriensis N67 and N67C: Genome-wide polymorphisms, differential gene expression, and drug resistance” was published in BMC Genomics. (2024) 25:1035. https://doi.org/10.1186/s12864-024-10961-4. 2. We continued to work on the project by studying metabolite changes in mice after infection with four P. yoelii strains and Plasmodium berghei ANKA (PbA). Deficiencies of metabolites such as amino acids and nucleotides were found in infected mice, some of which are strain-specific. A manuscript describing the results has been submitted for publication. 3. We have made good progress mapping parasite genes stimulating differential immune responses. We have performed genetic crosses of P. yoelii 17XNL and N67C, cloned 80 parasite progenies, infected mice with the progenies (28 progenies so far), and extracted RNAs from infected mice for RNA sequencing. Several genetic loci have been identified through the analysis of host gene expression, genotyping of parasite genome-wide polymorphisms, and trans-species expression quantitative trait locus (ts-eQTL) analysis. We have identified many candidate genes from the Plasmodium yoelii parasite, including one that can affect the host's type I interferon response in vitro. We are performing allelic exchange experiments to further confirm the gene function. A manuscript is being developed, awaiting the functional data before submission. 4. We made some progress on the project to study the forces exerted by PbA during ookinete and sporozoite movement through the 3-D matrix. We are measuring sporozoite motility in the 3-D matrix and studying potential factors that can influence parasite motility. Additionally, we are studying factors that can stimulate parasite movement and potential receptors mediating the signaling. 5. We are also characterizing some MARCH1 (a host E3 ubiquitin ligase known to degrade CD86 and MHC II to downgrade host immunity) inhibitors identified from our high-throughput chemical screening. We are studying the molecular mechanisms of inhibition and the optimal treatment schemes for diseases, including malaria and cancer. 6. We have tested several compounds on the human malaria parasite Plasmodium falciparum, including in combination with known antimalarial drugs such as chloroquine. Several compounds that can reverse drug resistance are being tested.