Human nuclear hormone receptor activity contributes to malaria parasite liver stage development

Chemical genetic approaches have had a transformative impact on discovery of drug targets for malaria but have primarily been used for parasite targets. To identify human pathways required for intrahepatic development of parasite, we implemented multiplex cytological profiling of malaria infected hepatocytes treated with liver stage active compounds. Some compounds, including MMV1088447 and MMV1346624, exhibited profiles similar to cells treated with nuclear hormone receptor (NHR) agonist/antagonists. siRNAs targeting human NHRs, or their signaling partners identified eight genes that were critical for Plasmodium berghei infection. Knockdown of NR1D2, a host NHR, significantly impaired parasite growth by downregulation of host lipid metabolism. Importantly, treatment with MMV1088447 and MMV1346624 but not other antimalarials, phenocopied the lipid metabolism defect of NR1D2 knockdown. Our data underlines the use of high-content imaging for host-cellular pathway deconvolution, highlights host lipid metabolism as a drug-able human pathway and provides new chemical biology tools for studying host-parasite interactions. [Display omitted] •High-content imaging can facilitate host-cellular pathway deconvolution•NR1D2 is identified as a novel host NHR regulating intrahepatic parasite growth•Knockdown of NR1D2 impairs host lipid metabolism thereby impacting parasite growth•MMV1044447 and MMV1346624 phenocopy NR1D2 knockdown Mittal et al. highlights the use of morphological profiling for identification of druggable host-cellular pathways. NR1D2 is identified as a novel host NHR regulating intrahepatic growth by regulating host lipid metabolism. Two compounds identified as potential host NHR modulators: MMV1346624 and MMV1088447 phenocopy NR1D2 knockdown.