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Chikungunya replication and infection is dependent upon and alters cellular hexosylceramide levels in Vero cells

ABSTRACT: Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes significant global mor-bidity, including fever, rash, and persistent arthralgia. Utilizing untargeted lipidomics, we investi-gated how CHIKV infection alters host cell lipid metabolism in Vero cells. CHIKV infection induced marked catabolism of hexosylceramides, reducing their levels while increasing ceramide byprod-ucts. Functional studies revealed a reliance on fatty acid synthesis, ?-oxidation, and glycosphin-golipid biosynthesis. Notably, inhibition of uridine diphosphate glycosyltransferase 8 (UGT8), es-sential for galactosylceramide production, significantly impaired CHIKV replication and entry. CHIKV was also sensitive to evacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, though the mechanism of inhibition appeared independent of CETP itself, suggesting an off-target effect. These findings highlight specific lipid pathways, particularly glycosphingolipid metabolism, as critical for CHIKV replication and further refine our understanding of how CHIKV exploits host lipid networks. This study provides new insights into CHIKV biology and suggests that targeted investigation of host lipid pathways may inform future therapeutic strategies.

INSTRUMENT(S): ACQUITY UPLC I-Class, Synapt XS

ORGANISM(S): Chikungunya Virus (ncbitaxon:37124)

SUBMITTER: Kelly M. Hines Melinda A. Brindley

PROVIDER: MSV000096887 | MassIVE | Fri Jan 17 14:07:00 GMT 2025

REPOSITORIES: MassIVE

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Project description:Human cytomegalovirus (HCMV) replication requires host metabolism. Infection alters the activity in multiple metabolic pathways, including increasing fatty acid elongation and lipid synthesis. The virus-host interactions regulating the metabolic changes associated with replication are essential to infection. While multiple host factors, including kinases and transcription factors, have been identified to be important to metabolic changes that occurr following HCMV infection, little is known about the viral factors required to alter metabolism. The HCMV UL37x1 protein (pUL37x1) localizes to the mitochondria and ER and controls Ca2+ flux from the ER to the cytosol which may influence metabolism. In this study, we tested the hypothesis that pUL37x1 is important to the metabolic remodeling that is necessary for HCMV replication by using a combination of metabolomics, lipidomics, and metabolic tracers to measure fatty acid elongation. We observed that fibroblast cells infected with wild-type (WT) HCMV had similar levels of metabolites as those infected with a mutant virus lacking the UL37x1 gene, subUL37x1. However, we found that subUL37x1-infected cells had reduced levels of two host proteins that were previously demonstrated to be important for lipid metabolism during HCMV infection—fatty acid elongase 7 (ELOVL7) and ER-stress related kinase PERK—relative to WT-infected cells. Moreover, we observed that HCMV infection results in an increase in phospholipids with very long-chain fatty acid tails (PL-VLCFAs) that contain 26 or more carbons in one of their two tails. The levels of many PL-VLCFAs were lower in subUL37x1-infected cells compared to WT-infected cells. We also show that uninfected cells expressing a high-level of pUL37x1 have a greater amount of lipids relative to control cells. Overall, we conclude that although pUL37x1 is not necessary for network-wide metabolic changes occurring during infection, it is important to the remodeling of lipid metabolic pathways during HCMV infection.

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Chikungunya replication and infection is dependent upon and alters cellular hexosylceramide levels in Vero cells

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