{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T14:21:05Z","timestamp":1782915665438,"version":"3.54.5"},"reference-count":34,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It has been shown that vertical transmission of the SARS-CoV-2 strain is relatively rare, and there is still limited information on the specific impact of maternal SARS-CoV-2 infection on vertical transmission. The current study focuses on a transcriptomics analysis aimed at examining differences in gene expression between placentas from mother\u2013newborn pairs affected by COVID-19 and those from unaffected controls. Additionally, it investigates the in situ expression of molecules involved in placental inflammation. The Papa Giovanni XXIII Hospital in Bergamo, Italy, has recorded three instances of intrauterine transmission of SARS-CoV-2. The first two cases occurred early in the pandemic and involved pregnant women in their third trimester who were diagnosed with SARS-CoV-2. The third case involved an asymptomatic woman in her second trimester with a twin pregnancy, who unfortunately delivered two stillborn fetuses due to the premature rupture of membranes. Transcriptomic analysis revealed significant differences in gene expression between the placentae of COVID-19-affected mother\/newborn pairs and two matched controls. The infected and control placentae were matched for gestational age. According to the Benjamani\u2013Hochberg method, 305 genes met the criterion of an adjusted p-value of less than 0.05, and 219 genes met the criterion of less than 0.01. Up-regulated genes involved in cell signaling (e.g., CCL20, C3, MARCO) and immune response (e.g., LILRA3, CXCL10, CD48, CD86, IL1RN, IL-18R1) suggest their potential role in the inflammatory response to SARS-CoV-2. RNAscope\u00ae technology, coupled with image analysis, was utilized to quantify the surface area covered by SARS-CoV-2, ACE2, IL-1\u03b2, IL-6, IL-8, IL-10, and TNF-\u03b1 on both the maternal and fetal sides of the placenta. A non-statistically significant gradient for SARS-CoV-2 was observed, with a higher surface coverage on the fetal side (2.42 \u00b1 3.71%) compared to the maternal side (0.74 \u00b1 1.19%) of the placenta. Although not statistically significant, the surface area covered by ACE2 mRNA was higher on the maternal side (0.02 \u00b1 0.04%) compared to the fetal side (0.01 \u00b1 0.01%) of the placenta. IL-6 and IL-8 were more prevalent on the fetal side (0.03 \u00b1 0.04% and 0.06 \u00b1 0.08%, respectively) compared to the maternal side (0.02 \u00b1 0.01% and 0.02 \u00b1 0.02%, respectively). The mean surface areas of IL-1\u03b2 and IL-10 were found to be equal on both the fetal (0.04 \u00b1 0.04% and 0.01 \u00b1 0.01%, respectively) and maternal sides of the placenta (0.04 \u00b1 0.05% and 0.01 \u00b1 0.01%, respectively). The mean surface area of TNF-\u03b1 was found to be equal on both the fetal and maternal sides of the placenta (0.02 \u00b1 0.02% and 0.02 \u00b1 0.02%, respectively). On the maternal side, ACE-2 and all examined interleukins, but not TNF-\u03b1, exhibited an inverse mRNA amount compared to SARS-CoV-2. On the fetal side, ACE-2, IL-6 and IL-8 were inversely correlated with SARS-CoV-2 (r = \u22120.3, r = \u22120.1 and r = \u22120.4, respectively), while IL-1\u03b2 and IL-10 showed positive correlations (r = 0.9, p = 0.005 and r = 0.5, respectively). TNF-\u03b1 exhibited a positive correlation with SARS-CoV-2 on both maternal (r = 0.4) and fetal sides (r = 0.9) of the placenta. Further research is needed to evaluate the correlation between cell signaling and immune response genes in the placenta and the vertical transmission of SARS-CoV-2. Nonetheless, the current study extends our comprehension of the molecular and immunological factors involved in SARS-CoV-2 placental infection underlying maternal\u2013fetal transmission.<\/jats:p>","DOI":"10.3390\/ijms25168825","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T05:23:27Z","timestamp":1723613007000},"page":"8825","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In Situ Analyses of Placental Inflammatory Response to SARS-CoV-2 Infection in Cases of Mother\u2013Fetus Vertical Transmission"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3309-8011","authenticated-orcid":false,"given":"Denise","family":"Morotti","sequence":"first","affiliation":[{"name":"Pathology Department, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Tabano","sequence":"additional","affiliation":[{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"},{"name":"Department of Pathophysiology and Transplantation, University of Milan, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Gaudioso","sequence":"additional","affiliation":[{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6203-368X","authenticated-orcid":false,"given":"Tatjana","family":"Radaelli","sequence":"additional","affiliation":[{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio Alberto","family":"Croci","sequence":"additional","affiliation":[{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"},{"name":"Department of Pathophysiology and Transplantation, University of Milan, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Pathology Department, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Ghirardi","sequence":"additional","affiliation":[{"name":"Pathology Department, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2303-7394","authenticated-orcid":false,"given":"Andrea","family":"Gianatti","sequence":"additional","affiliation":[{"name":"Pathology Department, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-5866","authenticated-orcid":false,"given":"Luisa","family":"Patan\u00e8","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8731-2693","authenticated-orcid":false,"given":"Valeria","family":"Poletti de Chaurand","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7486-8545","authenticated-orcid":false,"given":"David A.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Perinatal Pathology Consulting, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7810-5011","authenticated-orcid":false,"given":"Mohamed A. 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A.","family":"Hagazi","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0925-742X","authenticated-orcid":false,"given":"Fabio","family":"Grizzi","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"ref_1","first-page":"1824","article-title":"Pharmacologic treatments for coronavirus disease 2019 (COVID-19)","volume":"323","author":"Sanders","year":"2020","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41591-020-0820-9","article-title":"The proximal origin of SARS-CoV-2","volume":"26","author":"Andersen","year":"2020","journal-title":"Nat. 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