{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T11:18:16Z","timestamp":1770895096831,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Enterprise Europe Network Niedersachsen (EEN) of the NBank","award":["ZW7-85152684"],"award-info":[{"award-number":["ZW7-85152684"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Intracellular lipid droplets (LDs) can accumulate in response to inflammation, metabolic stresses, and other physiological\/pathological processes. Herein, we investigated whether spike proteins of SARS-CoV-2 induce LDs in human peripheral blood mononuclear cells (PBMCs) and in pulmonary microvascular endothelial cells (HPMECs). PBMCs or HPMECs were incubated alone or with endotoxin-free recombinant variants of trimeric spike glycoproteins (Alpha, Beta, Delta, and Omicron, 12 \u00b5g\/mL). Afterward, cells were stained with Oil Red O for LDs, cytokine release was determined through ELISA, and the gene expression was analyzed through real-time PCR using TaqMan assays. Our data show that spikes induce LDs in PBMCs but not in HPMECs. In line with this, in PBMCs, spike proteins lower the expression of genes involving lipid metabolism and LD formation, such as SREBF1, HMGCS1, LDLR, and CD36. On the other hand, PBMCs exposed to spikes for 6 or 18 h did not increase in IL-1\u03b2, IL-6, IL-8, MCP-1, and TNF\u03b1 release or expression as compared to non-treated controls. Thus, spike-induced LD formation in PBMCs seems to not be related to cell inflammatory activation. Further detailed studies are warranted to investigate in which specific immune cells spikes induce LDs, and what are the pathophysiological mechanisms and consequences of this induction in vivo.<\/jats:p>","DOI":"10.3390\/microorganisms11112683","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T07:24:04Z","timestamp":1698823444000},"page":"2683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Human PBMCs Form Lipid Droplets in Response to Spike Proteins"],"prefix":"10.3390","volume":"11","author":[{"given":"Kokilavani","family":"Sivaraman","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9705-1389","authenticated-orcid":false,"given":"Paco","family":"Pino","sequence":"additional","affiliation":[{"name":"ExcellGene SA, 1970 Monthey, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillaume","family":"Raussin","sequence":"additional","affiliation":[{"name":"ExcellGene SA, 1970 Monthey, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Anchisi","sequence":"additional","affiliation":[{"name":"ExcellGene SA, 1970 Monthey, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Metayer","sequence":"additional","affiliation":[{"name":"ExcellGene SA, 1970 Monthey, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Dagany","sequence":"additional","affiliation":[{"name":"ExcellGene SA, 1970 Monthey, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Held","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9733-6162","authenticated-orcid":false,"given":"Sabine","family":"Wrenger","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Welte","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria J.","family":"Wurm","sequence":"additional","affiliation":[{"name":"ExcellGene SA, 1970 Monthey, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1114-4520","authenticated-orcid":false,"given":"Florian M.","family":"Wurm","sequence":"additional","affiliation":[{"name":"ExcellGene SA, 1970 Monthey, Switzerland"},{"name":"Faculty of Life Sciences, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne, 1015 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4343-6851","authenticated-orcid":false,"given":"Beata","family":"Olejnicka","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabina","family":"Janciauskiene","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s00709-011-0329-7","article-title":"The dynamic roles of intracellular lipid droplets: From archaea to mammals","volume":"249","author":"Murphy","year":"2012","journal-title":"Protoplasma"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/s41419-020-2297-3","article-title":"Lipid droplets: Platforms with multiple functions in cancer hallmarks","volume":"11","author":"Cruz","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.tcb.2007.06.004","article-title":"Proteins under new management: Lipid droplets deliver","volume":"17","author":"Welte","year":"2007","journal-title":"Trends Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bosch, M., Sweet, M.J., Parton, R.G., and Pol, A. (2021). Lipid droplets and the host-pathogen dynamic: FATal attraction?. J. Cell Biol., 220.","DOI":"10.1083\/jcb.202104005"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2114739119","DOI":"10.1073\/pnas.2114739119","article-title":"Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages","volume":"119","author":"Vrieling","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Czamara, K., Stojak, M., Pacia, M.Z., Zieba, A., Baranska, M., Chlopicki, S., and Kaczor, A. (2021). Lipid Droplets Formation Represents an Integral Component of Endothelial Inflammation Induced by LPS. Cells, 10.","DOI":"10.3390\/cells10061403"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4303","DOI":"10.1038\/s41467-021-24632-5","article-title":"Intracellular lipid droplet accumulation occurs early following viral infection and is required for an efficient interferon response","volume":"12","author":"Monson","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41419-021-03527-9","article-title":"Evidences for lipid involvement in SARS-CoV-2 cytopathogenesis","volume":"12","author":"Nardacci","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dias, S.S.G., Soares, V.C., Ferreira, A.C., Sacramento, C.Q., Fintelman-Rodrigues, N., Temerozo, J.R., Teixeira, L., Nunes da Silva, M.A., Barreto, E., and Mattos, M. (2020). Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1009127"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e28630","DOI":"10.1002\/jmv.28630","article-title":"Genetic variety of ORF3a shapes SARS-CoV-2 fitness through modulation of lipid droplet","volume":"95","author":"Wang","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8801","DOI":"10.1128\/JVI.77.16.8801-8811.2003","article-title":"The coronavirus spike protein is a class I virus fusion protein: Structural and functional characterization of the fusion core complex","volume":"77","author":"Bosch","year":"2003","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41586-020-2665-2","article-title":"Structures and distributions of SARS-CoV-2 spike proteins on intact virions","volume":"588","author":"Ke","year":"2020","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5339","DOI":"10.1038\/s41596-021-00623-0","article-title":"Expression and characterization of SARS-CoV-2 spike proteins","volume":"16","author":"Schaub","year":"2021","journal-title":"Nat. Protoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.cell.2020.09.037","article-title":"Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology","volume":"183","author":"Piccoli","year":"2020","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Halma, M.T.J., Plothe, C., Marik, P., and Lawrie, T.A. (2023). Strategies for the Management of Spike Protein-Related Pathology. Microorganisms, 11.","DOI":"10.20944\/preprints202303.0344.v2"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nguyen, V., Zhang, Y., Gao, C., Cao, X., Tian, Y., Carver, W., Kiaris, H., Cui, T., and Tan, W. (2022). The Spike Protein of SARS-CoV-2 Impairs Lipid Metabolism and Increases Susceptibility to Lipotoxicity: Implication for a Role of Nrf2. Cells, 11.","DOI":"10.1101\/2022.04.19.488806"},{"key":"ref_17","unstructured":"Excellgene (2023, May 29). Developing a Variant-Proof SARS-CoV-2 Vaccine: A CEPI-Funded ExcellGene Partnership with Bharat Biotech and the University of Sydney. Available online: https:\/\/excellgene.com\/2022\/07\/developing-a-variant-proof-sars-cov-2-vaccine\/."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pino, P., Kint, J., Kiseljak, D., Agnolon, V., Corradin, G., Kajava, A.V., Rovero, P., Dijkman, R., den Hartog, G., and McLellan, J.S. (2020). Trimeric SARS-CoV-2 Spike Proteins Produced from CHO Cells in Bioreactors Are High-Quality Antigens. Processes, 8.","DOI":"10.1101\/2020.11.15.382044"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tumpara, S., Grunding, A.R., Sivaraman, K., Wrenger, S., Olejnicka, B., Welte, T., Wurm, M.J., Pino, P., Kiseljak, D., and Wurm, F.M. (2021). Boosted Pro-Inflammatory Activity in Human PBMCs by Lipopolysaccharide and SARS-CoV-2 Spike Protein Is Regulated by alpha-1 Antitrypsin. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22157941"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ouyang, W., Xie, T., Fang, H., Gao, C., Stantchev, T., Clouse, K.A., Yuan, K., Ju, T., and Frucht, D.M. (2021). Variable Induction of Pro-Inflammatory Cytokines by Commercial SARS CoV-2 Spike Protein Reagents: Potential Impacts of LPS on In Vitro Modeling and Pathogenic Mechanisms In Vivo. Int. J. Mol. Sci., 22.","DOI":"10.1101\/2021.05.26.445843"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"40889","DOI":"10.1038\/srep40889","article-title":"Unsaturated lipid bodies as a hallmark of inflammation studied by Raman 2D and 3D microscopy","volume":"7","author":"Czamara","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e147057","DOI":"10.1172\/jci.insight.147057","article-title":"Fatty acid mobilization from adipose tissue is mediated by CD36 posttranslational modifications and intracellular trafficking","volume":"6","author":"Daquinag","year":"2021","journal-title":"JCI Insight"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pacia, M.Z., Sternak, M., Mateuszuk, L., Stojak, M., Kaczor, A., and Chlopicki, S. (2020). Heterogeneity of chemical composition of lipid droplets in endothelial inflammation and apoptosis. Biochim. Biophys. Acta Mol. Cell Res., 1867.","DOI":"10.1016\/j.bbamcr.2020.118681"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/JLB.4MR0119-035R","article-title":"Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation","volume":"106","author":"Teixeira","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1369\/0022155411404073","article-title":"Lipid bodies in inflammatory cells: Structure, function, and current imaging techniques","volume":"59","author":"Melo","year":"2011","journal-title":"J. Histochem. Cytochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e68563","DOI":"10.7554\/eLife.68563","article-title":"SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-kappaB pathway","volume":"10","author":"Khan","year":"2021","journal-title":"eLife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/s41421-022-00453-8","article-title":"Surface translocation of ACE2 and TMPRSS2 upon TLR4\/7\/8 activation is required for SARS-CoV-2 infection in circulating monocytes","volume":"8","author":"Yao","year":"2022","journal-title":"Cell Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1350","DOI":"10.1002\/cti2.1350","article-title":"Endothelial cells are not productively infected by SARS-CoV-2","volume":"10","author":"Schimmel","year":"2021","journal-title":"Clin. Transl. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.virol.2008.08.026","article-title":"Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2","volume":"381","author":"Glende","year":"2008","journal-title":"Virology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8722","DOI":"10.1128\/JVI.00253-07","article-title":"Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted","volume":"81","author":"Inoue","year":"2007","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41580-018-0085-z","article-title":"Dynamics and functions of lipid droplets","volume":"20","author":"Olzmann","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/j.bbalip.2017.07.006","article-title":"Lipid droplet functions beyond energy storage","volume":"1862","author":"Welte","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/s41574-023-00845-0","article-title":"Lipid droplet biogenesis and functions in health and disease","volume":"19","author":"Zadoorian","year":"2023","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1161\/CIRCRESAHA.119.316424","article-title":"LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis: Insight From Mouse Models","volume":"127","author":"Metso","year":"2020","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"569","DOI":"10.7150\/ijbs.14027","article-title":"Dysregulation of the Low-Density Lipoprotein Receptor Pathway Is Involved in Lipid Disorder-Mediated Organ Injury","volume":"12","author":"Zhang","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.bbalip.2009.04.002","article-title":"PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores","volume":"1791","author":"Bickel","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1016\/S0022-2275(20)34939-7","article-title":"Adipose differentiation-related protein is an ubiquitously expressed lipid storage droplet-associated protein","volume":"38","author":"Brasaemle","year":"1997","journal-title":"J. Lipid Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"40855","DOI":"10.1038\/srep40855","article-title":"PLIN2 is a Key Regulator of the Unfolded Protein Response and Endoplasmic Reticulum Stress Resolution in Pancreatic beta Cells","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4098","DOI":"10.1038\/s41598-017-04498-8","article-title":"A snake venom group IIA PLA(2) with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ(2) in macrophages","volume":"7","author":"Giannotti","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.atherosclerosis.2021.04.016","article-title":"Upregulated monocyte expression of PLIN2 is associated with early arterial injury in children with overweight\/obesity","volume":"327","author":"Pisano","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"42841","DOI":"10.1074\/jbc.M506569200","article-title":"Post-translational regulation of adipose differentiation-related protein by the ubiquitin\/proteasome pathway","volume":"280","author":"Xu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1194\/jlr.M090969","article-title":"CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway","volume":"60","author":"Li","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4765","DOI":"10.1038\/s41467-020-18565-8","article-title":"CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis","volume":"11","author":"Hao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Fader Kaiser, C.M., Romano, P.S., Vanrell, M.C., Pocognoni, C.A., Jacob, J., Caruso, B., and Delgui, L.R. (2021). Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.826248"},{"key":"ref_45","first-page":"435","article-title":"Lipid Droplets and the Management of Cellular Stress","volume":"92","author":"Jarc","year":"2019","journal-title":"Yale J. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.1172\/JCI34587","article-title":"Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes","volume":"118","author":"Song","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.jcis.2021.06.056","article-title":"SARS-CoV-2 spike protein removes lipids from model membranes and interferes with the capacity of high density lipoprotein to exchange lipids","volume":"602","author":"Correa","year":"2021","journal-title":"J. Colloids Interface Sci."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/11\/2683\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:15:38Z","timestamp":1760130938000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/11\/2683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,1]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["microorganisms11112683"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms11112683","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,1]]}}}