Characterization of the Lipidomic Profile of Human Coronavirus-Infected Cells: Implications for Lipid Metabolism Remodeling upon Coronavirus Replication

Abstract

Lipids play numerous indispensable cellular functions and are involved in multiple steps in the replication cycle of viruses. Infections by human-pathogenic coronaviruses result in diverse clinical outcomes, ranging from self-limiting flu-like symptoms to severe pneumonia with extrapulmonary manifestations. Understanding how cellular lipids may modulate the pathogenicity of human-pathogenic coronaviruses remains poor. To this end, we utilized the human coronavirus 229E (HCoV-229E) as a model coronavirus to comprehensively characterize the host cell lipid response upon coronavirus infection with an ultra-high performance liquid chromatography-mass spectrometry (UPLC–MS)-based lipidomics approach. Our results revealed that glycerophospholipids and fatty acids (FAs) were significantly elevated in the HCoV-229E-infected cells and the linoleic acid (LA) to arachidonic acid (AA) metabolism axis was markedly perturbed upon HCoV-229E infection. Interestingly, exogenous supplement of LA or AA in HCoV-229E-infected cells significantly suppressed HCoV-229E virus replication. Importantly, the inhibitory effect of LA and AA on virus replication was also conserved for the highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV). Taken together, our study demonstrated that host lipid metabolic remodeling was significantly associated with human-pathogenic coronavirus propagation. Our data further suggested that lipid metabolism regulation would be a common and druggable target for coronavirus infections.

Proteomics of SARS-CoV-2-infected host cells reveals therapy targets

“…Notably, we also observed changes in ER resident proteins reshaping lipid metabolism (Extended Data Fig. 6), consistent with previous reports on other coronaviruses 19 . Together, our quantitative analyses of proteome changes upon SARS-CoV-2 infection revealed host pathways changes upon infection and revealed spliceosome and glycolysis inhibitors as potential therapeutic agents for COVID-19.…”

Unexpected free fatty acid binding pocket in the cryo-EM structure of SARS-CoV-2 spike protein

“…A recent proteomic and metabolomic study of COVID-19 patient sera evidenced continuous decrease of FFAs including LA (26). Lipid metabolome remodeling is a common element of 10 viral infection (27,28), including by the baculovirus (29) used here to express S. For coronaviruses, the LA to arachidonic acid (AA) metabolic pathway was identified as the epicentre of lipid remodeling (9). Interestingly, exogenous supplement of LA or AA suppressed virus replication (9).…”

“…A novel S1/S2 polybasic furin protease cleavage site stimulates entry into host cells and cell-cell 15 fusion (4,7,8). Inside the host cell, human coronaviruses remodel the lipid metabolism to facilitate virus replication (9). Infection by SARS-CoV-2 triggers an unusually impaired and dysregulated immune response (10) and a heightened inflammatory response (11) working in synergy with interferon production in the vicinity of infected cells to drive a feed-forward loop to upregulate ACE2 and further escalate infection (12).…”

COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status

“…Increased PLA2 activity is associated with increased production of bioactive lipids by metabolism of omega-6 PUFAs and lysophosphatidylcholine. Some of the resulting metabolites (e.g., eicosanoids, oxylipins) may help propagate infection and thrombo-inflammatory complications (59), by directly supporting synthesis of viral capsid membranes (24)(25)(26), by targeting All rights reserved. No reuse allowed without permission.…”