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The epididymis, divided into caput, corpus, and cauda, shows a region\u2010specific immunity. The K18\u2010hACE2 mouse expresses human angiotensin\u2010converting enzyme 2 (<jats:italic>hACE2<\/jats:italic>), the receptor that allows SARS\u2010CoV\u20102 infection. However, studies using this transgenic mouse to evaluate the impact of this viral infection in epididymis have not yet been performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We evaluated the expression of <jats:italic>hACE2<\/jats:italic> in the epididymis of SARS\u2010CoV\u20102\u2010infected K18\u2010hACE2 mice, and assessed the epididymal immune response, focusing on F4\/80<jats:sup>+<\/jats:sup> mononuclear phagocytes and tumor necrosis factor\u2010alpha expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>The following analyses were performed in the epididymal sections of infected mice: epithelial height and duct diameter, birefringent collagen, Terminal deoxynucleotidyl Transferase\u2010mediated dUTP Nick End Labelling, immunoreactions for detection of <jats:italic>hACE2<\/jats:italic>, spike, FGF, V\u2010ATPase, F4\/80, tumor necrosis factor\u2010alpha, and iNOS. Viral particles were identified under electron microscopy. <jats:italic>hACE2, Rigi, Tgfb1<\/jats:italic> and <jats:italic>Tnfa<\/jats:italic> expression were also evaluated by real\u2010time quantitative polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All epididymal regions expressed <jats:italic>hACE2<\/jats:italic>, which increased in all epididymal regions in the infected mice. However, the caput appeared to be the most infected region. Despite this, the caput region showed minimal changes while the cauda showed significant epithelial changes associated with increased iNOS immunoexpression. The F4\/80<jats:sup>+<\/jats:sup> mononuclear phagocyte area increased significantly in both stroma and epithelium. In addition to the epithelial and stromal mononuclear phagocytes, tumor necrosis factor\u2010alpha was also detected in clear cells, whose cytoplasm showed a significant increase of this cytokine in the infected animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and conclusion<\/jats:title><jats:p>The K18\u2010hACE2 mouse is a useful model for evaluating the impact of SARS\u2010CoV\u20102 infection in the epididymis. The infection induced <jats:italic>hACE2<\/jats:italic> upregulation, favoring the virulence in the epididymis. The epididymal regions responded differentially to infection, and the activation of F4\/80<jats:sup>+<\/jats:sup> mononuclear phagocytes associated with the increased tumor necrosis factor\u2010alpha immunolabeling in clear cells indicates a role of clear cells\/mononuclear phagocytes immunoregulatory mechanisms in the epididymal immune response to SARS\u2010CoV\u20102 infection.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.13755","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T00:25:29Z","timestamp":1728001529000},"page":"1509-1529","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["hACE2 upregulation and participation of macrophages and clear cells in the immune response of epididymis to SARS\u2010CoV\u20102 in K18\u2010hACE2 mice"],"prefix":"10.1111","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-2115","authenticated-orcid":false,"given":"Andr\u00e9 Ac\u00e1cio Souza","family":"da Silva","sequence":"first","affiliation":[{"name":"Department of Morphology and Genetics Federal University of S\u00e3o Paulo  Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0439-1331","authenticated-orcid":false,"given":"Salmo Azambuja","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Department of Morphology and Genetics Federal University of S\u00e3o Paulo  Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0490-9548","authenticated-orcid":false,"given":"Maria Agustina","family":"Battistone","sequence":"additional","affiliation":[{"name":"Department of Medicine Program in Membrane Biology, Nephrology Division Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7385-7895","authenticated-orcid":false,"given":"Barry Thomas","family":"Hinton","sequence":"additional","affiliation":[{"name":"Department of Cell Biology School of Medicine University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5756-5828","authenticated-orcid":false,"given":"Paulo S\u00e9rgio","family":"Cerri","sequence":"additional","affiliation":[{"name":"Department of Morphology Genetics, Orthodontics and Pediatric Dentistry, S\u00e3o Paulo State University (Unesp) School of Dentistry  Araraquara Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3101-4635","authenticated-orcid":false,"given":"Estela","family":"Sasso\u2010Cerri","sequence":"additional","affiliation":[{"name":"Department of Morphology Genetics, Orthodontics and Pediatric Dentistry, S\u00e3o Paulo State University (Unesp) School of Dentistry  Araraquara Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,3]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"World Health Organization.2023.\u201cCoronavirus (COVID\u201019) Dashboard >Cases.\u201d In: WHO [Internet]. 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