Engineering topics

Weinstein, Jules B.

Publications and source records attributed to Weinstein, Jules B..

3 records

DOE OSTI2022

A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants

A comprehensive understanding of host dependency factors for SARS-CoV-2 remains elusive. Here, we map alterations in host lipids following SARS-CoV-2 infection using nontargeted lipidomics. We find that SARS-CoV-2 rewires host lipid metabolism, significantly altering hundreds of lipid species to effectively establish infection. We correlate these changes with viral protein activity by transfecting human cells with each viral protein and performing lipidomics. We find that lipid droplet plasticity is a key feature of infection and that viral propagation can be blocked by small-molecule glycerolipid biosynthesis inhibitors. We find that this inhibition was effective against the main variants of concern (alpha, beta, gamma, and delta), indicating that glycerolipid biosynthesis is a conserved host dependency factor that supports this evolving virus.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

A global lipid map defines a network essential for Zika virus replication

Zika virus (ZIKV), an emerging mosquito-borne pathogen of global concern, remodels intra-cellular lipid membranes to form replication factories. How ZIKV regulates lipid networks to allow infection, and consequences for disease is poorly understood. Here, we performed comprehensive lipidomics to create a lipid network map during ZIKV infection. We found that ZIKV significantly alters host lipid composition with striking changes seen within sub-classes of sphingolipids. We also demonstrated that ectopic expression of NS4B, one of the non-structural proteins of ZIKV with known roles in ZIKV replication resulted in similar changes on cellular lipidome. Ceramide, a key bioactive molecule with functions in signaling and apoptosis, redistributes to ZIKV replication factories. Increase of ceramide through knockout of sphingomyelin synthase or via sphingomyelinase-catalyzed degradation of sphingomyelin to ceramide sensitizes cells to ZIKV infection. Remarkably, we observed an enrichment of pro-apoptotic ceramide sub-species in infected cells, providing a link between ZIKV biogenesis and apoptosis. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

A global lipid map defines a network essential for Zika virus replication

>Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we performed comprehensive lipidomics to create a lipid network map during ZIKV infection. We found that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein resulted in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocked ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.

59 BASIC BIOLOGICAL SCIENCES↗