Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection

Qi Wu, Lina Zhou, Xin Sun, Zhongfang Yan, Chunxiu Hu, Junping Wu, Long Xu, Xue Li, Huiling Liu, Peiyuan Yin, Kuan Li, Jieyu Zhao, Yanli Li, Xiaolin Wang, Yu Li, Qiuyang Zhang, Guowang Xu, Huaiyong Chen, Qi Wu, Lina Zhou, Xin Sun, Zhongfang Yan, Chunxiu Hu, Junping Wu, Long Xu, Xue Li, Huiling Liu, Peiyuan Yin, Kuan Li, Jieyu Zhao, Yanli Li, Xiaolin Wang, Yu Li, Qiuyang Zhang, Guowang Xu, Huaiyong Chen

Abstract

Severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-like coronavirus are a potential threat to global health. However, reviews of the long-term effects of clinical treatments in SARS patients are lacking. Here a total of 25 recovered SARS patients were recruited 12 years after infection. Clinical questionnaire responses and examination findings indicated that the patients had experienced various diseases, including lung susceptibility to infections, tumors, cardiovascular disorders, and abnormal glucose metabolism. As compared to healthy controls, metabolomic analyses identified significant differences in the serum metabolomes of SARS survivors. The most significant metabolic disruptions were the comprehensive increase of phosphatidylinositol and lysophospha tidylinositol levels in recovered SARS patients, which coincided with the effect of methylprednisolone administration investigated further in the steroid treated non-SARS patients with severe pneumonia. These results suggested that high-dose pulses of methylprednisolone might cause long-term systemic damage associated with serum metabolic alterations. The present study provided information for an improved understanding of coronavirus-associated pathologies, which might permit further optimization of clinical treatments.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
MOS 36-item Short Form Health Survey (SF-36) results for severe recovered respiratory syndrome patients 12 years after recovery.
Figure 2
Figure 2
Differential serum metabolic profiles between recovered SARS and healthy volunteers. (A) OPLS-DA score plot separating the recovered SARS and healthy volunteers (Control). (B) Heat map of significantly altered metabolites detected by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry.
Figure 3
Figure 3
Mapping of differential metabolites related to energy metabolism (A). Relative serum levels of differentially expressed free carnitine, acylcarnitines with long chains, and the ratio of carnitines (C16 + C18) to carnitine (B). Data shown as mean ± SEM. * < 0.05, ** < 0.01.
Figure 4
Figure 4
Mapping of differential metabolites related to arginine and proline metabolism. Data shown as mean ± SEM. * 

Figure 5

Major pathways of phospholipid and…

Figure 5

Major pathways of phospholipid and neutral lipid synthesis. ( A ) Dashed lines…

Figure 5
Major pathways of phospholipid and neutral lipid synthesis. (A) Dashed lines show fatty acid rearrangement through the remodeling process. Correlation analysis of very low-density lipoprotein, phosphatidylinositol, lysophosphatidylinositol, and total triglycerides in (B) recovered SARS and (C) healthy volunteers (Control).

Figure 6

( A ) Cluster analysis…

Figure 6

( A ) Cluster analysis of differentially expressed lipids. ( B ) Fatty…

Figure 6
(A) Cluster analysis of differentially expressed lipids. (B) Fatty acids as a result of phosphatidylinositol remodeling in recovered SARS patients sensitive to phospholipase A2.
Figure 5
Figure 5
Major pathways of phospholipid and neutral lipid synthesis. (A) Dashed lines show fatty acid rearrangement through the remodeling process. Correlation analysis of very low-density lipoprotein, phosphatidylinositol, lysophosphatidylinositol, and total triglycerides in (B) recovered SARS and (C) healthy volunteers (Control).
Figure 6
Figure 6
(A) Cluster analysis of differentially expressed lipids. (B) Fatty acids as a result of phosphatidylinositol remodeling in recovered SARS patients sensitive to phospholipase A2.

References

    1. van der Hoek L, et al. Identification of a new human coronavirus. Nature medicine. 2004;10:368–373. doi: 10.1038/nm1024.
    1. Woo PC, et al. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. Journal of virology. 2005;79:884–895. doi: 10.1128/JVI.79.2.884-895.2005.
    1. Berry M, Gamieldien J, Fielding BC. Identification of new respiratory viruses in the new millennium. Viruses. 2015;7:996–1019. doi: 10.3390/v7030996.
    1. Menachery VD, et al. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nature medicine. 2015;21:1508–1513. doi: 10.1038/nm.3985.
    1. Menachery VD, et al. SARS-like WIV1-CoV poised for human emergence. Proceedings of the National Academy of Sciences of the United States of America. 2016;113:3048–3053. doi: 10.1073/pnas.1517719113.
    1. Ge XY, et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature. 2013;503:535–538. doi: 10.1038/nature12711.
    1. Tsang KW, et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. The New England journal of medicine. 2003;348:1977–1985. doi: 10.1056/NEJMoa030666.
    1. Chen XP, Cao Y. Consideration of highly active antiretroviral therapy in the prevention and treatment of severe acute respiratory syndrome. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2004;38:1030–1032. doi: 10.1086/386340.
    1. Sainz B, Jr., Mossel EC, Peters CJ, Garry RF. Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) Virology. 2004;329:11–17. doi: 10.1016/j.virol.2004.08.011.
    1. Cheng Y, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. 2005;24:44–46. doi: 10.1007/s10096-004-1271-9.
    1. Jia WD, et al. [Dose of glucocorticosteroids in the treatment of severe acute respiratory syndrome] Nan fang yi ke da xue xue bao=Journal of Southern Medical University. 2009;29:2284–2287.
    1. Yam LY, et al. Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. The Journal of infection. 2007;54:28–39. doi: 10.1016/j.jinf.2006.01.005.
    1. Xu YD, Jiang M, Chen RC, Fang JQ. [Evaluation of the efficacy and safety of corticosteroid in the treatment of severe SARS in Guangdong province with multi-factor regression analysis] Zhongguo wei zhong bing ji jiu yi xue=Chinese critical care medicine=Zhongguo weizhongbing jijiuyixue. 2008;20:84–87.
    1. Lam CW, Chan MH, Wong CK. Severe acute respiratory syndrome: clinical and laboratory manifestations. The Clinical biochemist. Reviews/Australian Association of Clinical Biochemists. 2004;25:121–132.
    1. Chan MH, et al. Steroid-induced osteonecrosis in severe acute respiratory syndrome: a retrospective analysis of biochemical markers of bone metabolism and corticosteroid therapy. Pathology. 2006;38:229–235. doi: 10.1080/00313020600696231.
    1. Griffith JF, et al. Osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids. Radiology. 2005;235:168–175. doi: 10.1148/radiol.2351040100.
    1. Ruiz-Arguello MB, Goni FM, Pereira FB, Nieva JL. Phosphatidylinositol-dependent membrane fusion induced by a putative fusogenic sequence of Ebola virus. Journal of virology. 1998;72:1775–1781.
    1. Johnson KA, Taghon GJ, Scott JL, Stahelin RV. The Ebola Virus matrix protein, VP40, requires phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) for extensive oligomerization at the plasma membrane and viral egress. Scientific reports. 2016;6 doi: 10.1038/srep19125.
    1. Li L, Sun X, Wu Q, Xing Z, Yu H. [The lung function status in patients with severe acute respiratory syndrome after ten years of convalescence in Tianjin] Zhonghua Jie He He Hu Xi Za Zhi. 2015;38:575–578.
    1. Yang N, et al. Phosphatidylinositol 4-kinase IIIbeta is required for severe acute respiratory syndrome coronavirus spike-mediated cell entry. The Journal of biological chemistry. 2012;287:8457–8467. doi: 10.1074/jbc.M111.312561.
    1. Numata M, et al. Phosphatidylinositol inhibits respiratory syncytial virus infection. Journal of lipid research. 2015;56:578–587. doi: 10.1194/jlr.M055723.
    1. Imbernon M, et al. Regulation of GPR55 in rat white adipose tissue and serum LPI by nutritional status, gestation, gender and pituitary factors. Molecular and cellular endocrinology. 2014;383:159–169. doi: 10.1016/j.mce.2013.12.011.
    1. Metz SA. Lysophosphatidylinositol, but not lysophosphatidic acid, stimulates insulin release. A possible role for phospholipase A2 but not de novo synthesis of lysophospholipid in pancreatic islet function. Biochemical and biophysical research communications. 1986;138:720–727. doi: 10.1016/S0006-291X(86)80556-3.
    1. Romero-Zerbo SY, et al. A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans. The Journal of endocrinology. 2011;211:177–185. doi: 10.1530/JOE-11-0166.
    1. Overgaard AJ, et al. Lipidomic and metabolomic characterization of a genetically modified mouse model of the early stages of human type 1 diabetes pathogenesis. Metabolomics: Official journal of the Metabolomic Society. 2016;12 doi: 10.1007/s11306-015-0889-1.
    1. Lauckner JE, et al. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:2699–2704. doi: 10.1073/pnas.0711278105.
    1. Schicho R, Storr M. A potential role for GPR55 in gastrointestinal functions. Current opinion in pharmacology. 2012;12:653–658. doi: 10.1016/j.coph.2012.09.009.
    1. Ford LA, et al. A role for L-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells. British journal of pharmacology. 2010;160:762–771. doi: 10.1111/j.1476-5381.2010.00743.x.
    1. Wu R, et al. Metabolomic analysis reveals that carnitines are key regulatory metabolites in phase transition of the locusts. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:3259–3263. doi: 10.1073/pnas.1119155109.
    1. Rohn H, et al. VANTED v2: a framework for systems biology applications. BMC systems biology. 2012;6 doi: 10.1186/1752-0509-6-139.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다