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Phosphatidic acid phosphatase 1 impairs SARS-CoV-2 replication by affecting the glycerophospholipid metabolism pathway
Authors:Bingpeng Yan  Shuofeng Yuan  Jianli Cao  Kingchun Fung  Pok-Man Lai  Feifei Yin  Kong-Hung Sze  Zhenzhi Qin  Yubin Xie  Zi-Wei Ye  Terrence Tsz-Tai Yuen  Kenn Ka-Heng Chik  Jessica Oi-Ling Tsang  Zijiao Zou  Chris Chun-Yiu Chan  Cuiting Luo  Jian-Piao Cai  Kwok-Hung Chan  Tom Wai-Hing Chung  Anthony Raymond Tam  Hin Chu  Dong-Yan Jin  Ivan Fan-Ngai Hung  Kwok-Yung Yuen  Richard Yi-Tsun Kao  Jasper Fuk-Woo Chan
Abstract:Viruses exploit the host lipid metabolism machinery to achieve efficient replication. We herein characterize the lipids profile reprogramming in vitro and in vivo using liquid chromatography-mass spectrometry-based untargeted lipidomics. The lipidome of SARS-CoV-2-infected Caco-2 cells was markedly different from that of mock-infected samples, with most of the changes involving downregulation of ceramides. In COVID-19 patients'' plasma samples, a total of 54 lipids belonging to 12 lipid classes that were significantly perturbed compared to non-infected control subjects'' plasma samples were identified. Among these 12 lipid classes, ether-linked phosphatidylcholines, ether-linked phosphatidylethanolamines, phosphatidylcholines, and ceramides were the four most perturbed. Pathway analysis revealed that the glycerophospholipid, sphingolipid, and ether lipid metabolisms pathway were the most significantly perturbed host pathways. Phosphatidic acid phosphatases (PAP) were involved in all three pathways and PAP-1 deficiency significantly suppressed SARS-CoV-2 replication. siRNA knockdown of LPIN2 and LPIN3 resulted in significant reduction of SARS-CoV-2 load. In summary, these findings characterized the host lipidomic changes upon SARS-CoV-2 infection and identified PAP-1 as a potential target for intervention for COVID-19.
Keywords:COVID-19   lipidomics   phosphatidic acid phosphatases   SARS-CoV-2
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