SARS-CoV-2 exploits steroidogenic machinery, triggers lipid metabolism for viral replication and induces immune response in Leydig cells of K18-hACE2 mice

DOI record: { "DOI": "10.3389/fcimb.2025.1538461", "ISSN": [ "2235-2988" ], "URL": "http://dx.doi.org/10.3389/fcimb.2025.1538461", "abstract": "<jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>During COVID-19 pandemic, men had reduced serum testosterone and higher mortality rate than women. Variations in high density lipoprotein (HDL) levels were detected in severe COVID-19 individuals. We evaluated the response of testicular macrophages, steroidogenic activity and lipid metabolism of Leydig cells in SARS-CoV-2-infected K18-hACE2 mice.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>\n Testes were analyzed under light and electron microscope. Immunolocalization of human angiotensin converting enzyme (hACE2) and viral proteins (spike and nucleocapsid) were evaluated in association with the expression of viral recognition receptor\n <jats:italic>, Rigi</jats:italic>\n . Steroidogenesis was evaluated by the expression of\n <jats:italic>steroidogenic factor-1</jats:italic>\n (\n <jats:italic>Sf1</jats:italic>\n ), and the immunolocalization of steroidogenic proteins and testosterone. Pro-inflammatory (TNF-α, IL-1β, IL-6), anti-inflammatory (IL-10) cytokines, macrophages (CD68 and CD163) and macrophage inhibitory factor (MIF) were detected by immunolocalization and Western blot. The expression of lipid metabolism genes (\n <jats:italic>Srebp, Dgat1 and Scarb1</jats:italic>\n ) were investigated by RT-qPCR.\n </jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>\n In the infected animals, the Leydig cells showed enhanced immunolocalization of hACE2, spike and nucleocapsid. The expression of\n <jats:italic>Rigi</jats:italic>\n , pro-inflammatory cytokines and number of macrophages increased, confirming viral infection.\n <jats:italic>Sf1</jats:italic>\n expression, steroidogenic proteins and testosterone were reduced whereas the expression of\n <jats:italic>Dgat1, Srebp and Scarb1</jats:italic>\n increased. Lipid droplets-enriched Leydig cells and viral particles in lipids were observed. The infected Leydig cells also showed enhanced pro-inflammatory cytokines immunolabeling.\n </jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusion</jats:title>\n <jats:p>SARS-CoV-2 infects Leydig cells, activates its immune response and impairs steroidogenesis. The virus uses the steroidogenic machinery and induces lipid metabolism pathways for its survival and replication in these cells. These findings support the low testosterone and HDL levels in men with severe COVID-19.</jats:p>\n </jats:sec>", "alternative-id": [ "10.3389/fcimb.2025.1538461" ], "article-number": "1538461", "author": [ { "affiliation": [], "family": "de Oliveira", "given": "Salmo Azambuja", "sequence": "first" }, { "affiliation": [], "family": "da Silva", "given": "André Acácio Souza", "sequence": "additional" }, { "affiliation": [], "family": "Hinton", "given": "Barry T.", "sequence": "additional" }, { "affiliation": [], "family": "Gomes", "given": "Giovanni Freitas", "sequence": "additional" }, { "affiliation": [], "family": "Cunha", "given": "Thiago Mattar", "sequence": "additional" }, { "affiliation": [], "family": "Cerri", "given": "Paulo Sérgio", "sequence": "additional" }, { "affiliation": [], "family": "Sasso-Cerri", "given": "Estela", "sequence": "additional" } ], "container-title": "Frontiers in Cellular and Infection Microbiology", "container-title-short": "Front. Cell. Infect. Microbiol.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2025, 5, 27 ] ], "date-time": "2025-05-27T01:24:34Z", "timestamp": 1748309074000 }, "deposited": { "date-parts": [ [ 2026, 1, 5 ] ], "date-time": "2026-01-05T16:26:37Z", "timestamp": 1767630397000 }, "indexed": { "date-parts": [ [ 2026, 1, 9 ] ], "date-time": "2026-01-09T23:04:25Z", "timestamp": 1767999865185, "version": "3.49.0" }, "is-referenced-by-count": 2, "issued": { "date-parts": [ [ 2025, 5, 27 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 5, 27 ] ], "date-time": "2025-05-27T00:00:00Z", "timestamp": 1748304000000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fcimb.2025.1538461/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", "original-title": [], "prefix": "10.3389", "published": { "date-parts": [ [ 2025, 5, 27 ] ] }, "published-online": { "date-parts": [ [ 2025, 5, 27 ] ] }, "publisher": "Frontiers Media SA", "reference": [ { "DOI": "10.3390/ijms21103544", "article-title": "The role of lipid metabolism in COVID-19 virus infection and as a drug target", "author": "Abu-Farha", "doi-asserted-by": "publisher", "journal-title": "Int. J. Mol. Sci.", "key": "B1", "volume": "21", "year": "2020" }, { "DOI": "10.5534/wjmh.200170", "article-title": "Histopathology and ultrastructural findings of fatal COVID-19 infections on testis", "author": "Achua", "doi-asserted-by": "publisher", "first-page": "65", "journal-title": "World J. Mens Health", "key": "B2", "volume": "39", "year": "2021" }, { "DOI": "10.2174/092986712799320538", "article-title": "Molecular pathways involved in the early and late damage induced by testis ischemia: evidence for a rational pharmacological modulation", "author": "Altavilla", "doi-asserted-by": "publisher", "first-page": "1219", "journal-title": "Curr. Med. Chem.", "key": "B3", "volume": "19", "year": "2012" }, { "DOI": "10.1016/j.clinsp.2024.100344", "article-title": "Reduced HDL-cholesterol in long COVID-19: A key metabolic risk factor tied to disease severity", "author": "Al-Zadjali", "doi-asserted-by": "publisher", "journal-title": "Clinics (Sao Paulo)", "key": "B4", "volume": "79", "year": "2024" }, { "DOI": "10.1038/s41586-020-2312-y", "article-title": "The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice", "author": "Bao", "doi-asserted-by": "publisher", "first-page": "830", "journal-title": "Nature", "key": "B5", "volume": "583", "year": "2020" }, { "DOI": "10.1093/qjmed/hcy163", "article-title": "Oral squamous carcinoma cells promote macrophage polarization in an MIF-dependent manner", "author": "Barbosa De Souza Rizzo", "doi-asserted-by": "publisher", "first-page": "769", "journal-title": "QJM", "key": "B6", "volume": "111", "year": "2018" }, { "DOI": "10.1016/j.mayocp.2020.06.018", "article-title": "Targeting TMPRSS2 in SARS-coV-2 infection", "author": "Baughn", "doi-asserted-by": "publisher", "first-page": "1989", "journal-title": "Mayo Clin. Proc.", "key": "B7", "volume": "95", "year": "2020" }, { "DOI": "10.1016/j.exger.2015.02.014", "article-title": "Leydig cell aging and hypogonadism", "author": "Beattie", "doi-asserted-by": "publisher", "first-page": "87", "journal-title": "Exp. Gerontol.", "key": "B8", "volume": "68", "year": "2015" }, { "DOI": "10.1016/j.kint.2021.01.004", "article-title": "Best practices for correctly identifying coronavirus by transmission electron microscopy", "author": "Bullock", "doi-asserted-by": "publisher", "first-page": "824", "journal-title": "Kidney Int.", "key": "B9", "volume": "99", "year": "2021" }, { "DOI": "10.3389/fimmu.2023.1161067", "article-title": "The multifaceted nature of IL-10: regulation, role in immunological homeostasis and its relevance to cancer, COVID-19 and post-COVID conditions", "author": "Carlini", "doi-asserted-by": "publisher", "journal-title": "Front. Immunol.", "key": "B10", "volume": "14", "year": "2023" }, { "DOI": "10.1016/j.bbalip.2021.159043", "article-title": "Hormone-sensitive lipase deficiency affects the expression of SR-BI, LDLr, and ABCA1 receptors/transporters involved in cellular cholesterol uptake and efflux and disturbs fertility in mouse testis", "author": "Casado", "doi-asserted-by": "publisher", "journal-title": "Biochim. Biophys. Acta Mol. Cell Biol. Lipids", "key": "B11", "volume": "1866", "year": "2021" }, { "DOI": "10.1016/j.bbrc.2020.02.071", "article-title": "Structure analysis of the receptor binding of 2019-nCoV", "author": "Chen", "doi-asserted-by": "publisher", "first-page": "135", "journal-title": "Biochem. Biophys. Res. Commun.", "key": "B12", "volume": "525", "year": "2020" }, { "DOI": "10.1016/j.jgg.2022.11.011", "article-title": "Infection of SARS-CoV-2 causes severe pathological changes in mouse testis", "author": "Chen", "doi-asserted-by": "publisher", "first-page": "99", "journal-title": "J. Genet. Genomics", "key": "B13", "volume": "50", "year": "2023" }, { "DOI": "10.3389/fimmu.2021.666543", "article-title": "Innate immune responses to wildtype and attenuated sheeppox virus mediated through RIG-1 sensing in PBMC in-vitro", "author": "Chibssa", "doi-asserted-by": "publisher", "journal-title": "Front. Immunol.", "key": "B14", "volume": "12", "year": "2021" }, { "DOI": "10.1016/j.chom.2020.11.003", "article-title": "Integrative imaging reveals SARS-coV-2-induced reshaping of subcellular morphologies", "author": "Cortese", "doi-asserted-by": "publisher", "first-page": "853", "journal-title": "Cell Host Microbe", "key": "B15", "volume": "28", "year": "2020" }, { "DOI": "10.1186/s12915-022-01497-8", "article-title": "High SARS-CoV-2 tropism and activation of immune cells in the testes of non-vaccinated deceased COVID-19 patients", "author": "Costa", "doi-asserted-by": "publisher", "first-page": "36", "journal-title": "BMC Biol.", "key": "B16", "volume": "21", "year": "2023" }, { "DOI": "10.1210/jcem.82.5.3938", "article-title": "Human Leydig cells and Sertoli cells are producers of interleukins-1 and -6", "author": "Cudicini", "doi-asserted-by": "publisher", "first-page": "1426", "journal-title": "J. Clin. Endocrinol. Metab.", "key": "B17", "volume": "82", "year": "1997" }, { "DOI": "10.3389/fimmu.2022.867260", "article-title": "The role of M1/M2 macrophage polarization in rheumatoid arthritis synovitis", "author": "Cutolo", "doi-asserted-by": "publisher", "journal-title": "Front. Immunol.", "key": "B18", "volume": "13", "year": "2022" }, { "DOI": "10.1007/s40618-023-02055-x", "article-title": "SARS-CoV-2 and male infertility: from short- to long-term impacts", "author": "Dai", "doi-asserted-by": "publisher", "first-page": "1491", "journal-title": "J. Endocrinol. Invest.", "key": "B19", "volume": "46", "year": "2023" }, { "DOI": "10.1111/andr.13755", "article-title": "hACE2 upregulation and participation of macrophages and clear cells in the immune response of epididymis to SARS-CoV-2 in K18-hACE2 mice", "author": "da Silva", "doi-asserted-by": "publisher", "journal-title": "Andrology", "key": "B20", "year": "2024" }, { "DOI": "10.1007/s00418-021-02023-7", "article-title": "Impaired macrophages and failure of steroidogenesis and spermatogenesis in rat testes with cytokines deficiency induced by diacerein", "author": "de Oliveira", "doi-asserted-by": "publisher", "first-page": "561", "journal-title": "Histochem. Cell Biol.", "key": "B21", "volume": "156", "year": "2021" }, { "DOI": "10.1016/j.lfs.2021.120069", "article-title": "Venlafaxine-induced adrenergic signaling stimulates Leydig cells steroidogenesis via Nur77 overexpression: A possible role of EGF", "author": "de Santi", "doi-asserted-by": "publisher", "journal-title": "Life Sci.", "key": "B22", "volume": "289", "year": "2022" }, { "DOI": "10.1016/j.steroids.2018.02.009", "article-title": "Involvement of adenosine monophosphate activated kinase in interleukin-6 regulation of steroidogenic acute regulatory protein and cholesterol side chain cleavage enzyme in the bovine zona fasciculata and zona reticularis", "author": "De Silva", "doi-asserted-by": "publisher", "first-page": "53", "journal-title": "Steroids", "key": "B23", "volume": "134", "year": "2018" }, { "DOI": "10.1371/journal.ppat.1009127", "article-title": "Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators", "author": "Dias", "doi-asserted-by": "publisher", "journal-title": "PloS Pathog.", "key": "B24", "volume": "16", "year": "2020" }, { "DOI": "10.1371/journal.ppat.1005185", "article-title": "Modulation of the host lipid landscape to promote RNA virus replication: The picornavirus encephalomyocarditis virus converges on the pathway used by hepatitis C virus", "author": "Dorobantu", "doi-asserted-by": "publisher", "journal-title": "PloS Pathog.", "key": "B25", "volume": "11", "year": "2015" }, { "DOI": "10.1111/andr.13073", "article-title": "Testicular pathology in fatal COVID-19: A descriptive autopsy study", "author": "Duarte-Neto", "doi-asserted-by": "publisher", "first-page": "13", "journal-title": "Andrology", "key": "B26", "volume": "10", "year": "2022" }, { "DOI": "10.1038/s41585-021-00542-5", "article-title": "Implications of testicular ACE2 and the renin-angiotensin system for SARS-CoV-2 on testis function", "author": "Edenfield", "doi-asserted-by": "publisher", "first-page": "116", "journal-title": "Nat. Rev. Urol.", "key": "B27", "volume": "19", "year": "2022" }, { "DOI": "10.3389/fmed.2020.563893", "article-title": "ACE2 expression in kidney and testis may cause kidney and testis infection in COVID-19 patients", "author": "Fan", "doi-asserted-by": "publisher", "journal-title": "Front. Med. (Lausanne)", "key": "B28", "volume": "7", "year": "2021" }, { "DOI": "10.1016/j.beem.2023.101751", "article-title": "The bidirectional interaction of COVID-19 infections and lipoproteins", "author": "Feingold", "doi-asserted-by": "publisher", "journal-title": "Best Pract. Res. Clin. Endocrinol. Metab.", "key": "B29", "volume": "37", "year": "2023" }, { "DOI": "10.1016/j.plipres.2019.100989", "article-title": "The biogenesis of lipid droplets: Lipids take center stage", "author": "Gao", "doi-asserted-by": "publisher", "journal-title": "Prog. Lipid Res.", "key": "B30", "volume": "75", "year": "2019" }, { "DOI": "10.1385/ENDO:28:2:165", "article-title": "Interleukin 1-beta injected into the testis acutely stimulates and later attenuates testicular steroidogenesis of the immature rat", "author": "Gerendai", "doi-asserted-by": "publisher", "first-page": "165", "journal-title": "Endocrine.", "key": "B31", "volume": "28", "year": "2005" }, { "DOI": "10.1371/journal.ppat.1011409", "article-title": "In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury", "author": "Giannakopoulos", "doi-asserted-by": "publisher", "journal-title": "PloS Pathog.", "key": "B32", "volume": "19", "year": "2023" }, { "DOI": "10.1001/jama.2020.5394", "article-title": "Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy", "author": "Grasselli", "doi-asserted-by": "publisher", "first-page": "1574", "journal-title": "JAMA", "key": "B33", "volume": "323", "year": "2020" }, { "DOI": "10.1093/molehr/gaaa073", "article-title": "Relevance of angiogenesis in autoimmune testis inflammation", "author": "Gualdoni", "doi-asserted-by": "publisher", "journal-title": "Mol. Hum. Reprod.", "key": "B34", "volume": "27", "year": "2021" }, { "DOI": "10.1210/endo.131.5.1425417", "article-title": "Interleukin-1 inhibits Leydig cell steroidogenesis primarily by decreasing 17 alpha-hydroxylase/C17–20 lyase cytochrome P450 expression", "author": "Hales", "doi-asserted-by": "publisher", "first-page": "2165", "journal-title": "Endocrinology", "key": "B35", "volume": "131", "year": "1992" }, { "DOI": "10.1016/S0165-0378(02)00020-7", "article-title": "Testicular macrophage modulation of Leydig cell steroidogenesis", "author": "Hales", "doi-asserted-by": "publisher", "first-page": "3", "journal-title": "J. Reprod. Immunol.", "key": "B36", "volume": "57", "year": "2002" }, { "DOI": "10.1007/s12020-016-1043-1", "article-title": "SF-1 deficiency causes lipid accumulation in Leydig cells via suppression of STAR and CYP11A1", "author": "Hatano", "doi-asserted-by": "publisher", "first-page": "484", "journal-title": "Endocrine", "key": "B37", "volume": "54", "year": "2016" }, { "DOI": "10.15252/msb.20209610", "article-title": "The protein expression profile of ACE2 in human tissues", "author": "Hikmet", "doi-asserted-by": "publisher", "first-page": "7", "journal-title": "Mol. Syst. Biol.", "key": "B38", "volume": "16", "year": "2020" }, { "DOI": "10.1111/his.14264", "article-title": "Hunting coronavirus by transmission electron microscopy – a guide to SARS-CoV-2-associated ultrastructural pathology in COVID-19 tissues", "author": "Hopfer", "doi-asserted-by": "publisher", "first-page": "358", "journal-title": "Histopathology", "key": "B39", "volume": "78", "year": "2021" }, { "DOI": "10.1038/ncomms3883", "article-title": "MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice", "author": "Horie", "doi-asserted-by": "publisher", "first-page": "2883", "journal-title": "Nat. Commun.", "key": "B40", "volume": "4", "year": "2013" }, { "DOI": "10.1007/978-1-4939-7837-3_12", "article-title": "Polarizing macrophages in vitro", "author": "Huang", "doi-asserted-by": "publisher", "first-page": "119", "journal-title": "Methods Mol. Biol.", "key": "B41", "volume": "1784", "year": "2018" }, { "DOI": "10.1007/BF00302977", "article-title": "Development of cytoplasmic digitations between Leydig cells and testicular macrophages of the rat", "author": "Hutson", "doi-asserted-by": "publisher", "first-page": "385", "journal-title": "Cell Tissue Res.", "key": "B42", "volume": "267", "year": "1992" }, { "DOI": "10.1177/153537020623100101", "article-title": "Physiologic interactions between macrophages and Leydig cells", "author": "Hutson", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "Exp. Biol. Med. (Maywood)", "key": "B43", "volume": "231", "year": "2006" }, { "DOI": "10.1038/nature04734", "article-title": "Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses", "author": "Kato", "doi-asserted-by": "publisher", "first-page": "101", "journal-title": "Nature", "key": "B44", "volume": "441", "year": "2006" }, { "DOI": "10.1016/j.bbamcr.2013.05.018", "article-title": "The role of phospholipids in the biological activity and structure of the endoplasmic reticulum", "author": "Lagace", "doi-asserted-by": "publisher", "first-page": "2499", "journal-title": "Biochim. Biophys. Acta", "key": "B45", "volume": "1833", "year": "2013" }, { "DOI": "10.3389/fendo.2021.694083", "article-title": "Testosterone deficiency is a risk factor for severe COVID-19", "author": "Lanser", "doi-asserted-by": "publisher", "journal-title": "Front. Endocrinol. (Lausanne)", "key": "B46", "volume": "12", "year": "2021" }, { "DOI": "10.1016/j.jare.2022.05.013", "article-title": "SCAP deficiency facilitates obesity and insulin resistance through shifting adipose tissue macrophage polarization", "author": "Lee", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "J. Adv. Res.", "key": "B47", "volume": "45", "year": "2023" }, { "DOI": "10.1186/s12958-018-0341-2", "article-title": "The in vitro modulation of steroidogenesis by inflammatory cytokines and insulin in TM3 Leydig cells", "author": "Leisegang", "doi-asserted-by": "publisher", "first-page": "26", "journal-title": "Reprod. Biol. Endocrinol.", "key": "B48", "volume": "16", "year": "2018" }, { "DOI": "10.3390/cells12081198", "article-title": "SARS-CoV-2 enters human Leydig cells and affects testosterone production", "author": "Li", "doi-asserted-by": "publisher", "journal-title": "vitro. Cells", "key": "B49", "volume": "12", "year": "2023" }, { "DOI": "10.1093/cid/ciac142", "article-title": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by intranasal or intratesticular route induces testicular damage", "author": "Li", "doi-asserted-by": "publisher", "first-page": "e974", "journal-title": "Clin. Infect. Dis.", "key": "B50", "volume": "75", "year": "2022" }, { "DOI": "10.1210/endo.136.8.7628389", "article-title": "Tumor necrosis factor-alpha inhibition of 17 alpha-hydroxylase/C17–20 lyase gene (Cyp17) expression", "author": "Li", "doi-asserted-by": "publisher", "first-page": "3519", "journal-title": "Endocrinology", "key": "B51", "volume": "136", "year": "1995" }, { "DOI": "10.1016/j.tice.2023.102276", "article-title": "SARS-CoV-2 nucleocapsid protein promotes TMAO-induced NLRP3 inflammasome activation by SCAP-SREBP signaling pathway", "author": "Liu", "doi-asserted-by": "publisher", "journal-title": "Tissue Cell", "key": "B52", "volume": "86", "year": "2024" }, { "DOI": "10.3389/fendo.2017.00307", "article-title": "Cytokines in male fertility and reproductive pathologies: immunoregulation and beyond", "author": "Loveland", "doi-asserted-by": "publisher", "journal-title": "Front. Endocrinol.", "key": "B53", "volume": "8", "year": "2017" }, { "DOI": "10.3389/frph.2023.1229622", "article-title": "Testicular pathological alterations associated with SARS-CoV-2 infection", "author": "Ly", "doi-asserted-by": "publisher", "journal-title": "Front. Reprod. Health", "key": "B54", "volume": "5", "year": "2023" }, { "DOI": "10.1186/1477-7827-2-9", "article-title": "The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis and their involvement in testicular torsion and autoimmune orchitis", "author": "Lysiak", "doi-asserted-by": "publisher", "journal-title": "Reprod. Biol. Endocrinol.", "key": "B55", "volume": "2", "year": "2004" }, { "DOI": "10.1095/biolreprod.102.013318", "article-title": "Ischemia-reperfusion of the murine testis stimulates the expression of proinflammatory cytokines and activation of c-jun N-terminal kinase in a pathway to E-selectin expression", "author": "Lysiak", "doi-asserted-by": "publisher", "first-page": "202", "journal-title": "Biol. Reprod.", "key": "B56", "volume": "69", "year": "2003" }, { "DOI": "10.1016/j.cell.2016.11.016", "article-title": "Zika virus causes testis damage and leads to male infertility in mice", "author": "Ma", "doi-asserted-by": "publisher", "first-page": "1511", "journal-title": "Cell", "key": "B57", "volume": "167", "year": "2016" }, { "DOI": "10.1016/j.steroids.2003.07.009", "article-title": "Involvement of multiple transcription factors in the regulation of steroidogenic acute regulatory protein gene expression", "author": "Manna", "doi-asserted-by": "publisher", "first-page": "1125", "journal-title": "Steroids", "key": "B58", "volume": "68", "year": "2003" }, { "DOI": "10.1128/JVI.02012-06", "article-title": "Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus", "author": "McCray", "doi-asserted-by": "publisher", "first-page": "813", "journal-title": "J. Virol.", "key": "B59", "volume": "81", "year": "2007" }, { "DOI": "10.1016/j.domaniend.2015.05.006", "article-title": "Interleukin-6 inhibits adrenal androgen release from bovine adrenal zona reticularis cells by inhibiting the expression of steroidogenic proteins", "author": "McIlmoil", "doi-asserted-by": "publisher", "first-page": "108", "journal-title": "Domest. Anim. Endocrinol.", "key": "B60", "volume": "53", "year": "2015" }, { "DOI": "10.1016/j.bbalip.2007.02.012", "article-title": "Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter", "author": "Miller", "doi-asserted-by": "publisher", "first-page": "663", "journal-title": "Biochim. Biophys. Acta", "key": "B61", "volume": "1771", "year": "2007" }, { "DOI": "10.4269/ajtmh.20-0762", "article-title": "Evaluation of K18-hACE2 mice as a model of SARS-CoV-2 infection", "author": "Moreau", "doi-asserted-by": "publisher", "first-page": "1215", "journal-title": "Am. J. Trop. Med. Hyg.", "key": "B62", "volume": "103", "year": "2020" }, { "DOI": "10.1002/ar.1092040406", "article-title": "Morphometric analysis of testicular Leydig cells in normal adult mice", "author": "Mori", "doi-asserted-by": "publisher", "first-page": "333", "journal-title": "Anat. Rec.", "key": "B63", "volume": "204", "year": "1982" }, { "DOI": "10.1038/s41419-021-03527-9", "article-title": "Evidences for lipid involvement in SARS-CoV-2 cytopathogenesis", "author": "Nardacci", "doi-asserted-by": "publisher", "first-page": "263", "journal-title": "Cell Death Dis.", "key": "B64", "volume": "12", "year": "2021" }, { "DOI": "10.1111/bju.15573", "article-title": "Impact of the SARS-CoV-2 virus on male reproductive health", "author": "Nassau", "doi-asserted-by": "publisher", "first-page": "143", "journal-title": "BJU Int.", "key": "B65", "volume": "129", "year": "2022" }, { "DOI": "10.3389/fphys.2020.574761", "article-title": "Coronavirus disease-19 infection: Implications on male fertility and reproduction", "author": "Navarra", "doi-asserted-by": "publisher", "journal-title": "Front. Physiol.", "key": "B66", "volume": "11", "year": "2020" }, { "DOI": "10.1679/aohc1950.42.51", "article-title": "Electron microscopic study on the testicular interstitial cells in the mouse", "author": "Ohata", "doi-asserted-by": "publisher", "first-page": "51", "journal-title": "Arch. Histol. Jpn.", "key": "B67", "volume": "42", "year": "1979" }, { "DOI": "10.1530/REP-13-0199", "article-title": "Cell-type-specific regulation of genes involved in testicular lipid metabolism: fatty acid-binding proteins, diacylglycerol acyltransferases, and perilipin 2", "author": "Oresti", "doi-asserted-by": "crossref", "first-page": "471", "journal-title": "Reproduction.", "key": "B68", "volume": "146", "year": "2013" }, { "DOI": "10.1155/2019/2056085", "article-title": "Macrophage migration inhibitory factor promotes the interaction between the tumor, macrophages, and T cells to regulate the progression of chemically induced colitis-associated colorectal cancer", "author": "Pacheco-Fernández", "doi-asserted-by": "publisher", "journal-title": "Mediators Inflamm.", "key": "B69", "volume": "2019", "year": "2019" }, { "DOI": "10.1016/j.athplu.2023.01.002", "article-title": "Low HDL-c levels at admission are associated with greater severity and worse clinical outcomes in patients with COVID-19 disease", "author": "Parra", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "Atheroscler. Plus", "key": "B70", "volume": "52", "year": "2023" }, { "DOI": "10.1038/s41577-020-0288-3", "article-title": "RIG-I-like receptors: their regulation and roles in RNA sensing", "author": "Rehwinkel", "doi-asserted-by": "publisher", "first-page": "537", "journal-title": "Nat. Rev. Immunol.", "key": "B71", "volume": "20", "year": "2020" }, { "DOI": "10.1369/00221554231168916", "article-title": "Spatial distribution of SARS-CoV-2 receptors and proteases in testicular cells", "author": "Ribeiro", "doi-asserted-by": "publisher", "first-page": "169", "journal-title": "J. Histochem. Cytochem.", "key": "B72", "volume": "71", "year": "2023" }, { "DOI": "10.1038/s41586-022-04835-6", "article-title": "The role of NSP6 in the biogenesis of the SARS-CoV-2 replication organelle", "author": "Ricciardi", "doi-asserted-by": "publisher", "first-page": "761", "journal-title": "Nature", "key": "B73", "volume": "606", "year": "2022" }, { "DOI": "10.1001/jama.2020.6775", "article-title": "Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area", "author": "Richardson", "doi-asserted-by": "publisher", "first-page": "2052", "journal-title": "JAMA", "key": "B74", "volume": "323", "year": "2020" }, { "DOI": "10.3390/cells11162572", "article-title": "Impact of microbiota depletion by antibiotics on SARS-CoV-2 infection of K18-hACE2 mice", "author": "Rodrigues", "doi-asserted-by": "publisher", "journal-title": "Cells", "key": "B75", "volume": "11", "year": "2022" }, { "DOI": "10.1139/o05-149", "article-title": "The influence of cholesterol and lipid metabolism on host cell structure and hepatitis C virus replication", "author": "Sagan", "doi-asserted-by": "publisher", "first-page": "67", "journal-title": "Biochem. Cell Biol.", "key": "B76", "volume": "84", "year": "2006" }, { "DOI": "10.1111/andr.12993", "article-title": "Severely low testosterone in males with COVID-19: A case-control study", "author": "Salonia", "doi-asserted-by": "publisher", "first-page": "1043", "journal-title": "Andrology", "key": "B77", "volume": "9", "year": "2021" }, { "DOI": "10.1530/REP-17-0053", "article-title": "Follicular expression of pro-inflammatory cytokines tumour necrosis factor-α (TNFα), interleukin 6 (IL6) and their receptors in cattle: TNFα, IL6 and macrophages suppress thecal androgen production in vitro", "author": "Samir", "doi-asserted-by": "publisher", "first-page": "35", "journal-title": "Reproduction", "key": "B78", "volume": "154", "year": "2017" }, { "DOI": "10.1016/j.reprotox.2006.07.008", "article-title": "Morphological changes in the testis induced by diethylcarbamazine", "author": "Saraiva", "doi-asserted-by": "publisher", "first-page": "754", "journal-title": "Reprod. Toxicol.", "key": "B79", "volume": "22", "year": "2006" }, { "DOI": "10.1016/j.micron.2007.06.003", "article-title": "Changes in mouse Leydig cells ultrastructure and testosterone secretion after diethylcarbamazine administration", "author": "Saraiva", "doi-asserted-by": "publisher", "first-page": "580", "journal-title": "Micron", "key": "B80", "volume": "39", "year": "2008" }, { "DOI": "10.1186/1477-7827-6-18", "article-title": "Morphological evidences indicate that the interference of cimetidine on the peritubular components is responsible for detachment and apoptosis of Sertoli cells", "author": "Sasso-Cerri", "doi-asserted-by": "publisher", "journal-title": "Reprod. Biol. Endocrinol.", "key": "B81", "volume": "6", "year": "2008" }, { "DOI": "10.1016/j.exppara.2022.108343", "article-title": "Biogenic silver nanoparticles (AgNp-Bio) restore testosterone levels and increase TNF-α and IL-6 in Leydig cells infected with Toxoplasma gondii", "author": "Semedo", "doi-asserted-by": "publisher", "journal-title": "Exp. Parasitol.", "key": "B82", "volume": "241", "year": "2022" }, { "DOI": "10.1016/j.yexcr.2015.11.024", "article-title": "Lipid droplets and steroidogenic cells", "author": "Shen", "doi-asserted-by": "publisher", "first-page": "209", "journal-title": "Exp. Cell Res.", "key": "B83", "volume": "340", "year": "2016" }, { "DOI": "10.1073/pnas.1611424113", "article-title": "SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP", "author": "Shimizu-Albergine", "doi-asserted-by": "publisher", "first-page": "E5685", "journal-title": "Proc. Natl. Acad. Sci. U.S.A.", "key": "B84", "volume": "113", "year": "2016" }, { "DOI": "10.26508/lsa.202302049", "article-title": "Inhibition of the SREBP pathway prevents SARS-CoV-2 replication and inflammasome activation", "author": "Soares", "doi-asserted-by": "publisher", "journal-title": "Life Sci. Alliance", "key": "B85", "volume": "6", "year": "2023" }, { "DOI": "10.1111/and.14036", "article-title": "Impacts of n-acetyl cysteine on gibberellic acid-induced testicular dysfunction through regulation of inflammatory cytokines, steroid and antioxidant activity", "author": "Soliman", "doi-asserted-by": "publisher", "journal-title": "Andrologia", "key": "B86", "volume": "53", "year": "2021" }, { "DOI": "10.1186/s12964-022-01026-8", "article-title": "Zika virus triggers autophagy to exploit host lipid metabolism and drive viral replication", "author": "Stoyanova", "doi-asserted-by": "publisher", "first-page": "114", "journal-title": "Cell Commun. Signal.", "key": "B87", "volume": "21", "year": "2023" }, { "DOI": "10.1021/bi960057r", "article-title": "Steroidogenic factor 1-dependent promoter activity of the human steroidogenic acute regulatory protein (StAR) gene", "author": "Sugawara", "doi-asserted-by": "publisher", "first-page": "9052", "journal-title": "Biochemistry", "key": "B88", "volume": "35", "year": "1996" }, { "DOI": "10.1016/S2213-8587(20)30216-3", "article-title": "Association between high serum total cortisol concentrations and mortality from COVID-19", "author": "Tan", "doi-asserted-by": "publisher", "first-page": "659", "journal-title": "Lancet Diabetes Endocrinol.", "key": "B89", "volume": "8", "year": "2020" }, { "DOI": "10.1111/imr.13022", "article-title": "The molecular mechanism of RIG-I activation and signaling", "author": "Thoresen", "doi-asserted-by": "publisher", "first-page": "154", "journal-title": "Immunol. Rev.", "key": "B90", "volume": "304", "year": "2021" }, { "DOI": "10.15252/embj.2021107826", "article-title": "SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation", "author": "Thorne", "doi-asserted-by": "publisher", "journal-title": "EMBO J.", "key": "B91", "volume": "40", "year": "2021" }, { "DOI": "10.1093/nar/gks596", "article-title": "Primer3—new capabilities and interfaces", "author": "Untergasser", "doi-asserted-by": "publisher", "first-page": "e115", "journal-title": "Nucleic Acids Res.", "key": "B92", "volume": "40", "year": "2012" }, { "DOI": "10.1126/sciadv.1602899", "article-title": "Zika virus causes testicular atrophy", "author": "Uraki", "doi-asserted-by": "publisher", "journal-title": "Sci. Adv.", "key": "B93", "volume": "3", "year": "2017" }, { "DOI": "10.1016/0303-7207(88)90031-7", "article-title": "Interleukin-1 stimulates steroidogenesis in cultured rat Leydig cells", "author": "Verhoeven", "doi-asserted-by": "publisher", "first-page": "51", "journal-title": "Mol. Cell Endocrinol.", "key": "B94", "volume": "57", "year": "1988" }, { "DOI": "10.4049/jimmunol.1700162", "article-title": "Characterization of the micro-environment of the testis that shapes the phenotype and function of testicular macrophages", "author": "Wang", "doi-asserted-by": "publisher", "first-page": "4327", "journal-title": "J. Immunol.", "key": "B95", "volume": "198", "year": "2017" }, { "DOI": "10.1210/endocr/bqab180", "article-title": "Differential effects of viral nucleic acid sensor signaling pathways on testicular Sertoli and Leydig cells", "author": "Wang", "doi-asserted-by": "publisher", "journal-title": "Endocrinology", "key": "B96", "volume": "162", "year": "2021" }, { "DOI": "10.3390/cells9040920", "article-title": "scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells", "author": "Wang", "doi-asserted-by": "publisher", "journal-title": "Cells", "key": "B97", "volume": "9", "year": "2020" }, { "article-title": "Tumor necrosis factor and interleukin-1 stimulate testosterone secretion in adult male rat Leydig cells in vitro", "author": "Warren", "first-page": "353", "journal-title": "J. Androl", "key": "B98", "volume": "11", "year": "1990" }, { "DOI": "10.1146/annurev-immunol-032713-120156", "article-title": "Innate immune sensing and signaling of cytosolic nucleic acids", "author": "Wu", "doi-asserted-by": "publisher", "first-page": "461", "journal-title": "Annu. Rev. Immunol.", "key": "B99", "volume": "32", "year": "2014" }, { "DOI": "10.1038/srep19507", "article-title": "Mumps virus-induced innate immune responses in mouse Sertoli and Leydig cells", "author": "Wu", "doi-asserted-by": "publisher", "journal-title": "Sci. Rep.", "key": "B100", "volume": "6", "year": "2016" }, { "DOI": "10.1001/jamanetworkopen.2020.5619", "article-title": "Clinical characteristics of patients who died of coronavirus disease 2019 in China", "author": "Xie", "doi-asserted-by": "publisher", "journal-title": "JAMA Netw Open", "key": "B101", "volume": "3", "year": "2020" }, { "DOI": "10.1210/endo.132.6.8504748", "article-title": "The role of tumor necrosis factor-alpha in the regulation of mouse Leydig cell steroidogenesis", "author": "Xiong", "doi-asserted-by": "publisher", "first-page": "2438", "journal-title": "Endocrinology", "key": "B102", "volume": "132", "year": "1993" }, { "DOI": "10.3390/v11010073", "article-title": "Characterization of the lipidomic profile of human coronavirus-infected cells: Implications for lipid metabolism remodeling upon coronavirus replication", "author": "Yan", "doi-asserted-by": "publisher", "journal-title": "Viruses", "key": "B103", "volume": "11", "year": "2019" }, { "DOI": "10.1194/jlr.R800018-JLR200", "article-title": "Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis", "author": "Yen", "doi-asserted-by": "publisher", "first-page": "2283", "journal-title": "J. Lipid Res.", "key": "B104", "volume": "49", "year": "2008" }, { "DOI": "10.1038/s41421-021-00338-2", "article-title": "SARS-CoV-2 exploits host DGAT and ADRP for efficient replication", "author": "Yuan", "doi-asserted-by": "publisher", "first-page": "100", "journal-title": "Cell Discov.", "key": "B105", "volume": "7", "year": "2021" }, { "DOI": "10.1210/me.2013-1075", "article-title": "RIG-I-like receptors mediate innate antiviral response in mouse testis", "author": "Zhu", "doi-asserted-by": "publisher", "first-page": "1455", "journal-title": "Mol. Endocrinol.", "key": "B106", "volume": "27", "year": "2013" }, { "DOI": "10.1095/biolreprod.114.119396", "article-title": "p204-initiated innate antiviral response in mouse Leydig cells", "author": "Zhu", "doi-asserted-by": "publisher", "first-page": "8", "journal-title": "Biol. Reprod.", "key": "B107", "volume": "91", "year": "2014" }, { "DOI": "10.1016/j.isci.2022.104430", "article-title": "Alternative polarization of resident macrophages improves hyperglycemia-associated male infertility", "author": "Zhu", "doi-asserted-by": "publisher", "journal-title": "iScience", "key": "B108", "volume": "25", "year": "2022" }, { "DOI": "10.1002/jmv.26139", "article-title": "Increasing host cellular receptor-angiotensin-converting enzyme 2 expression by coronavirus may facilitate 2019-nCoV (or SARS-CoV-2) infection", "author": "Zhuang", "doi-asserted-by": "publisher", "first-page": "2693", "journal-title": "J. Med. Virol.", "key": "B109", "volume": "92", "year": "2020" }, { "DOI": "10.1016/j.dci.2021.104076", "article-title": "MAVS splicing variants associated with TRAF3 and TRAF6 in NF-κB and IRF3 signaling pathway in large yellow croaker Larimichthys crocea", "author": "Zou", "doi-asserted-by": "publisher", "journal-title": "Dev. Comp. Immunol.", "key": "B110", "volume": "121", "year": "2021" } ], "reference-count": 110, "references-count": 110, "relation": {}, "resource": { "primary": { "URL": "https://www.frontiersin.org/articles/10.3389/fcimb.2025.1538461/full" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "SARS-CoV-2 exploits steroidogenic machinery, triggers lipid metabolism for viral replication and induces immune response in Leydig cells of K18-hACE2 mice", "type": "journal-article", "update-policy": "https://doi.org/10.3389/crossmark-policy", "updated-by": [ { "DOI": "10.3389/fcimb.2025.1702430", "label": "Correction", "source": "publisher", "type": "correction", "updated": { "date-parts": [ [ 2026, 1, 5 ] ], "date-time": "2026-01-05T00:00:00Z", "timestamp": 1767571200000 } } ], "volume": "15" }