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Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity

OBJECTIVE: Obesity is an established risk factor for higher SARS-CoV-2 viral loads, severe COVID-19 pneumonia requiring hospitalization, and worse outcomes. However, the underlying mechanisms for the increased risk are not well understood. SARS-CoV-2 is a respiratory virus with the primary route of...

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Autores principales: Du, Kang, Sun, Ling, Luo, Zichen, Cao, Yang, Sun, Qiushi, Zhang, Kangzhen, Faizy, Ahmed, Piomelli, Daniele, Lu, Xiang, Shan, Jinjun, Yang, Qin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930181/
https://www.ncbi.nlm.nih.gov/pubmed/35311662
http://dx.doi.org/10.1016/j.metabol.2022.155181
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author Du, Kang
Sun, Ling
Luo, Zichen
Cao, Yang
Sun, Qiushi
Zhang, Kangzhen
Faizy, Ahmed
Piomelli, Daniele
Lu, Xiang
Shan, Jinjun
Yang, Qin
author_facet Du, Kang
Sun, Ling
Luo, Zichen
Cao, Yang
Sun, Qiushi
Zhang, Kangzhen
Faizy, Ahmed
Piomelli, Daniele
Lu, Xiang
Shan, Jinjun
Yang, Qin
author_sort Du, Kang
collection PubMed
description OBJECTIVE: Obesity is an established risk factor for higher SARS-CoV-2 viral loads, severe COVID-19 pneumonia requiring hospitalization, and worse outcomes. However, the underlying mechanisms for the increased risk are not well understood. SARS-CoV-2 is a respiratory virus with the primary route of entry through the lungs, where the Spike protein of SARS-CoV-2 binds to the ACE2 receptor on pneumocytes. Lung surfactant produced by type II pneumocytes plays a major role in respiratory defense against infections. Surfactant predominantly contains lipids, especially phosphatidylcholines (PC), and obesity is characterized by aberrant lipid metabolism. We hypothesized that altered lipid composition in lung surfactant in obesity may promote SARS-CoV-2 infection, leading to severe COVID-19 disease. METHODS: Lipidomic analysis of lung tissue and bronchoalveolar lavage fluid (BALF) was performed using LC-MS/MS. The effects of PCs on SARS-CoV-2 pseudovirus infection were studied in HEK293T cells with ACE2 overexpression and in Vero-E6 cells with endogenous ACE2 expression. For the cell-cell fusion assay, HEK293T-ACE2 and HEK293T expressing SARS-CoV-2 Spike/eGFP were used as the target and effector cells, respectively. RESULTS: Lipidomic analysis revealed that myristic acid-containing dimyristoyl-PC (DMPC) and palmitoylmyristoyl-PC (PMPC) were reduced in lung tissue and BALF from high fat diet-induced obese mice. DMPC and PMPC markedly inhibited wild type and D614G mutant SARS-CoV-2 infection in HEK293T-ACE2 and Vero-E6 cells. Feeding obese mice with trimyristin, the triglycerides of myristic acid, increased DMPC and PMPC levels in lung surfactant. Lipid extract from BALF of trimyristin-treated obese mice mitigated the elevated wild type and D614G mutant SARS-CoV-2 infection. The inhibitory effects of DMPC and PMPC on SARS-CoV-2 infection were reversed by cholesterol. CONCLUSIONS: The reduced DMPC and PMPC in lung surfactant may promote SARS-CoV-2 infection. Increasing DMPC and PMPC in lung surfactant could be an innovative strategy for preventing and treating severe COVID-19 disease in obesity.
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spelling pubmed-89301812022-03-18 Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity Du, Kang Sun, Ling Luo, Zichen Cao, Yang Sun, Qiushi Zhang, Kangzhen Faizy, Ahmed Piomelli, Daniele Lu, Xiang Shan, Jinjun Yang, Qin Metabolism Article OBJECTIVE: Obesity is an established risk factor for higher SARS-CoV-2 viral loads, severe COVID-19 pneumonia requiring hospitalization, and worse outcomes. However, the underlying mechanisms for the increased risk are not well understood. SARS-CoV-2 is a respiratory virus with the primary route of entry through the lungs, where the Spike protein of SARS-CoV-2 binds to the ACE2 receptor on pneumocytes. Lung surfactant produced by type II pneumocytes plays a major role in respiratory defense against infections. Surfactant predominantly contains lipids, especially phosphatidylcholines (PC), and obesity is characterized by aberrant lipid metabolism. We hypothesized that altered lipid composition in lung surfactant in obesity may promote SARS-CoV-2 infection, leading to severe COVID-19 disease. METHODS: Lipidomic analysis of lung tissue and bronchoalveolar lavage fluid (BALF) was performed using LC-MS/MS. The effects of PCs on SARS-CoV-2 pseudovirus infection were studied in HEK293T cells with ACE2 overexpression and in Vero-E6 cells with endogenous ACE2 expression. For the cell-cell fusion assay, HEK293T-ACE2 and HEK293T expressing SARS-CoV-2 Spike/eGFP were used as the target and effector cells, respectively. RESULTS: Lipidomic analysis revealed that myristic acid-containing dimyristoyl-PC (DMPC) and palmitoylmyristoyl-PC (PMPC) were reduced in lung tissue and BALF from high fat diet-induced obese mice. DMPC and PMPC markedly inhibited wild type and D614G mutant SARS-CoV-2 infection in HEK293T-ACE2 and Vero-E6 cells. Feeding obese mice with trimyristin, the triglycerides of myristic acid, increased DMPC and PMPC levels in lung surfactant. Lipid extract from BALF of trimyristin-treated obese mice mitigated the elevated wild type and D614G mutant SARS-CoV-2 infection. The inhibitory effects of DMPC and PMPC on SARS-CoV-2 infection were reversed by cholesterol. CONCLUSIONS: The reduced DMPC and PMPC in lung surfactant may promote SARS-CoV-2 infection. Increasing DMPC and PMPC in lung surfactant could be an innovative strategy for preventing and treating severe COVID-19 disease in obesity. Elsevier Inc. 2022-06 2022-03-18 /pmc/articles/PMC8930181/ /pubmed/35311662 http://dx.doi.org/10.1016/j.metabol.2022.155181 Text en © 2022 Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Du, Kang
Sun, Ling
Luo, Zichen
Cao, Yang
Sun, Qiushi
Zhang, Kangzhen
Faizy, Ahmed
Piomelli, Daniele
Lu, Xiang
Shan, Jinjun
Yang, Qin
Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity
title Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity
title_full Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity
title_fullStr Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity
title_full_unstemmed Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity
title_short Reduced DMPC and PMPC in lung surfactant promote SARS-CoV-2 infection in obesity
title_sort reduced dmpc and pmpc in lung surfactant promote sars-cov-2 infection in obesity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930181/
https://www.ncbi.nlm.nih.gov/pubmed/35311662
http://dx.doi.org/10.1016/j.metabol.2022.155181
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