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GNPS - Dengue virus reduces AGPAT1 expression to alter phospholipids and enhance infection in Aedes aegypti

ABSTRACT: We characterized how DENV hijacks the mosquito lipidome to identify targets for novel transmission-blocking interventions. To describe metabolic changes throughout the mosquito DENV cycle, we deployed a Liquid chromatography–high resolution mass spectrometry (LC-HRMS) workflow including spectral similarity annotation in cells, midguts and whole mosquitoes at different times post infection. We revealed a major aminophospholipid reconfiguration with an overall early increase, followed by a reduction later in the cycle. We phylogenetically characterized acylglycerolphosphate acyltransferase (AGPAT) enzyme isoforms to identify those that catalyze a rate-limiting step in phospholipid biogenesis, the acylation of lysophosphatidate to phosphatidate. We showed that DENV infection decreased AGPAT1, but did not alter AGPAT2 expression in cells, midguts and mosquitoes. Depletion of either AGPAT1 or AGPAT2 increased aminophospholipids and partially recapitulated DENV-induced reconfiguration before infection in vitro. However, only AGPAT1 depletion promoted infection by maintaining high aminophospholipid concentrations. In mosquitoes, AGPAT1 depletion also partially recapitulated DENV-induced aminophospholipid increase before infection and enhanced infection by maintaining high aminophospholipid concentrations. These results indicate that DENV inhibition of AGPAT1 expression promotes infection by increasing aminophospholipids, as observed in the mosquito’s early DENV cycle. Furthermore, in AGPAT1-depleted mosquitoes, we showed that enhanced infection was associated with increased consumption/redirection of aminophospholipids. Our study suggests that DENV regulates aminophospholipids, especially phosphatidylcholine and phosphatidylethanolamine, by inhibiting AGPAT1 expression to increase aminophospholipid availability for virus multiplication.

INSTRUMENT(S): Xevo G2 Q-Tof, LTQ Orbitrap XL

ORGANISM(S): Aedes Aegypti (ncbitaxon:7159)

SUBMITTER: Guillaume Marti Julien Pompon

PROVIDER: MSV000083868 | GNPS | Mon May 27 23:46:00 BST 2019

REPOSITORIES: GNPS

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Project description:The obligate intracellular, gram-negative bacterium, Chlamydophila pneumoniae (Cpn), has impact as an acute and chronic disease-causing pathogen. Little is known about changes in the Cpn transcriptome during its biphasic developmental cycle (the acute infection) and persistence stages that are linked to chronic diseases. To analyze Cpn CWL029 gene expression, we designed a pathogen-specific oligo microarray and optimized the extraction method for pathogen RNA. Throughout the acute infection, ratio expression profiles for each gene were generated using 48 hours post infection as a reference. Based on these profiles, significantly expressed genes were separated into 12 expression clusters using SOM clustering and manually into the ‘early’, ‘mid’, ‘late’ and ‘tardy’ cluster classes. The latter two were differentiated because the ‘tardy’ class showed steadily increasing expression at the end of the cycle. The transcriptome of the Cpn elementary body (EB) and published EB proteomics data were compared to the cluster profile of the acute infection. We found an intriguing association between ‘late’ genes and genes coding for EB proteins, whereas ‘tardy’ genes were mainly associated with genes coding for EB mRNA. It has been published that iron depletion leads to Cpn persistence. We compared the gene expression profiles during iron depletion-mediated persistence with the expression clusters of the acute infection. This led to the finding that establishment of iron depletion-mediated persistence is more likely a mid-cycle arrest in development rather than a completely distinct gene expression pattern. Taken together, here we describe the Cpn transcriptome during the acute infection with ‘late’ genes correlating to EB proteins and ‘tardy’ genes to EB mRNA. Expression profiles during iron mediated-persistence led us to propose the hypothesis that the transcriptomic ‘clock’ is arrested during acute mid-cycle. Keywords: time course, iron, persistence, Chlamydia, Chlamydophila, pneumoniae, recovery, pathogen, life cycle, developmental cycle

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GNPS - Dengue virus reduces AGPAT1 expression to alter phospholipids and enhance infection in Aedes aegypti

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