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May 2nd, 2020
May 2nd, 2020
BST* Executive summary prepared by Marina T. Botana1 and Raymond C. Valentine2
1 São Paulo, SP, 04116-240, Brazil; m.botana23@gmail.com ; +55-11-97283-7799
2 Professor Emeritus, University of California, Davis, CA 95616, USA; ray@ecowizards.com ; +1-802-275-2980
The current global pandemic of infections by SARS-CoV-2 has rekindled interest in benefits and risks of the lipid-based membrane of this deadly virus. The lipid membrane of SARS-CoV-2 is both its strength and its weakness. Infectious RNA extracted from RNA viruses is shielded from degradation by two different biological polymers - either protein or lipid coatings. Each of the virus coating polymers offers both benefits and risks1,2. Protein coatings of RNA virus particles (e.g. poliovirus) are generally more stable against specific classes of virucides such as lipophilic solvents. In contrast, lethal lipid viruses such as SARS-CoV-2 are more sensitive to various lipid solvents3 (e.g. alcohol-based sanitizer and soap).
Almost every day global scientific efforts reveal something new about this lipid virus. The latest “omics” methodologies, including genomics, have become major tools for research on this virus4,5, but lipidomics and bioenergetics data are still underrepresented in this field. The purpose of this blog is to highlight data from lipidomic and bioenergetic analyses showing a close linkage between lipids in virus membranes and the molecular pathology of SARS-CoV-2. We propose that SARS-CoV-2 can rapidly switch its membrane lipid structure-function. This membrane adaption might maximize the viral replication cycle6,7 and enhance protection against distinct environmental stresses.
Figure 1: Structure and lipid composition of synaptic vesicles (SV). a) Illustration of synaptic signaling mediating neuronal communication and SVs; b) 3D electron micrograph reconstruction of a presynapse highlighting distinct protein particles at membrane surface (adapted from Maidorn et al., 2016); c) membrane lipids compositions of SV; d) fatty acid diversity in membrane lipids of synaptic vesicles (data from c and d were adapted from Takamori et al., 2006).
Coronavirus surrogates of SARS-CoV-2 hijack the lipidome of host cells7,8. For example, DHA (docosahexaenoic acid C22:6) and other highly unsaturated membrane fatty acids are upregulated8,9. This spectrum of virus-induced membrane fatty acids synthesized by the infected host cell resembles, but does not completely overlap, with the lipid composition of specialized lipid trafficking vesicles such as synaptic vesicles (SV) (Figure 1). Because of the similarity of SARS-CoV-2 and SV (compare a and b in Figures 1 and 2) particles, we suggest that the virus might hijack the pathway for synthesis of highly unsaturated lipid trafficking vesicles such as SV. The take-home lesson is the dramatically different fatty acid profile induced in virus-infected cells versus the fatty acid composition of virus particles entering the environment (Figure 2 and 3). One of the simplest mechanisms to explain such lipidome alterations is a quick exchange of membranes at the point of exocytosis. This comprehensive remodeling might create a more robust viral membrane for withstanding environmental stresses. A later report on this general topic will link the above membrane structural changes with the remarkable electrochemical properties of SARS-CoV-2 particles.
The take-home lesson is the dramatically different fatty acid profile induced in virus-infected cells versus the fatty acid composition of virus particles entering the environment (Figure 2 and 3). One of the simplest mechanisms to explain such lipidome alterations is a quick exchange of membranes at the point of exocytosis. This comprehensive remodeling might create a more robust viral membrane for withstanding environmental stresses. A later report on this general topic will link the above membrane structural changes with the remarkable electrochemical properties of SARS-CoV-2 particles.
Figure 2: Structure and lipid composition of SARS-CoV-2. a) cryo-microscopy of SARS-CoV-2 particle; b) scanning electron microscopy showing particles of SARS-CoV-2 (in gold) emerging from surface of cells cultured in the lab (NIAID Rocky Mountains Laboratory); c) lipid composition of cells infected with HCoV-229E (alpha coronavirus) against control (adapted from Yan et al., 2020).
Figure 3: Dysregulated metabolites in plasma from COVID-19 patients. Heatmap shows 82 regulated metabolites belonging to six major classes: fatty acids, steroids, glycerophospholipid, sphingolipid, choline and serotonins. Upregulated metabolites are in red and downregulated metabolites are in blue (adapted from Shen et al., 2020).
It is not a surprise that membranes of SV (for a review see Takamori et al., 2006) are extremely specialized for rapid and efficient transmission of electrical signals to and from even the most rapid-firing muscles10,11. In contrast, we believe that the membrane is responsible for conserving the electrical power of a SARS-CoV-2 particle. Finally, we propose that SARS-CoV-2 adaptation of quickly changing its membrane structure is essential for stress tolerance against 1) different environmental stressors and 2) efficient and fast replication inside the host cells. We hypothesize that the size of SARS-CoV-2 virions, as well as particles of other coronaviruses and lipid SV is variable. Each individual vesicle/particle might differ in its exact membrane lipid composition.
References:
1 - VALENTINE, Raymond C.; VALENTINE, David L. Omega-3 fatty acids in cellular membranes: a unified concept. Progress in lipid research, v. 43, n. 5, p. 383-402, 2004.
2 - VALENTINE, Raymond C.; VALENTINE, David L. Omega-3 fatty acids and the DHA principle. Boca Raton: Taylor and Francis Group, 2009.
3 – RABENAU, H. F. et al. Efficacy of various disinfectants against SARS coronavirus. Journal of Hospital Infection, v. 61, n. 2, p. 107-111, 2005.
4 – GUO, Yan-Rong et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak–an update on the status. Military Medical Research, v. 7, n. 1, p. 1-10, 2020.
5 - ZHOU, Peng et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, v. 579, n. 7798, p. 270-273, 2020.
6 - SNIJDER, Eric J. et al. Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex. Journal of virology, v. 80, n. 12, p. 5927-5940, 2006.
7 – VAN DER SCHAAR, Hilde M. et al. Fat (al) attraction: picornaviruses usurp lipid transfer at membrane contact sites to create replication organelles. Trends in microbiology, v. 24, n. 7, p. 535-546, 2016.
8 - YAN, Bingpeng et al. Characterization of the lipidomic profile of human coronavirus-infected cells: Implications for lipid metabolism remodeling upon coronavirus replication. Viruses, v. 11, n. 1, p. 73, 2019.
9 - SHEN, Bo et al. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. medRxiv, 2020.
10 - VALENTINE, Raymond C.; VALENTINE, David L. Neurons and the DHA principle, Boca Raton: Taylor and Francis Group, 2013.
11 - VALENTINE, Raymond C.; VALENTINE, David L. Human longevity: Omega-3 fatty acids, bioenergetics, molecular biology, and evolution. Boca Raton: Taylor and Francis Group, 2015.
12 - MAIDORN, Manuel; RIZZOLI, Silvio O.; OPAZO, Felipe. Tools and limitations to study the molecular composition of synapses by fluorescence microscopy. Biochemical Journal, v. 473, n. 20, p. 3385-3399, 2016.
13 - TAKAMORI, Shigeo et al. Molecular anatomy of a trafficking organelle. Cell, v. 127, n. 4, p. 831-846, 2006.
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