{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:44:40Z","timestamp":1790689480547,"version":"4.1.0"},"reference-count":73,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"National Autopsy Network","award":["01KX2524"],"award-info":[{"award-number":["01KX2524"]}]},{"name":"BONFOR","award":["O-115.0074"],"award-info":[{"award-number":["O-115.0074"]}]},{"DOI":"10.13039\/100014933","name":"aTyr","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014933","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2025,11,25]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Coronavirus disease 2019 (COVID-19) is associated with hyperinflammation, endothelialitis, hypoxemia, and hypercoagulation, contributing to thrombosis in acute severe and long COVID. While ACE2 is the primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, its low expression in certain infected cell types suggests alternative co-receptors. Neuropilins (NRP1 and NRP2), widely expressed, have been proposed as co-factors for viral entry. We analyzed NRP1 and NRP2 expression in autopsy tissues from heart, lung, and hematolymphoid organs using immunohistochemistry (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 20) and compared findings with public single-cell RNA sequencing (scRNAseq) data. Selected cases were further examined by spatial multiplex immunofluorescence (CODEX).\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      binding of NRP1\/NRP2 to SARS-CoV-2 spike fragments S1 and S1\u2032 was assessed by immunofluorescence microscopy. NRP1 was abundantly expressed in myocardial capillary endothelial cells (ECs) and macrophages in the heart and lung; NRP2 was found in alveolar macrophages and mast cells. scRNAseq re-analysis confirmed these\n                      <jats:italic toggle=\"yes\">in situ<\/jats:italic>\n                      patterns.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      , NRP1 exclusively bound S1, while NRP2 bound both S1 and S1\u2032. SARS-CoV-2 RNA was detected in neuropilin-positive,\n                      <jats:italic toggle=\"yes\">ACE2<\/jats:italic>\n                      \/\n                      <jats:italic toggle=\"yes\">TMPRSS2<\/jats:italic>\n                      -negative vascular EC and mast cells. The detection of SARS-CoV-2 RNA in neuropilin-positive but\n                      <jats:italic toggle=\"yes\">ACE2<\/jats:italic>\n                      \/\n                      <jats:italic toggle=\"yes\">TMPRSS2<\/jats:italic>\n                      -negative cell clusters supports that neuropilins are involved in systemic viral dissemination. NRP1 on vascular EC may contribute to angiogenesis, vascular damage, and microangiopathy, while NRP2 represents a potential immunomodulatory target to regulate macrophage activity, resolve inflammation, and potentially prevent the progression of pulmonary fibrosis and limit excessive mast cell activation in long COVID.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The well-known severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, angiotensin-converting enzyme 2 (ACE2), exhibits low expression in key cell types implicated in coronavirus disease 2019 (COVID-19) pathology, such as endothelial cells and B cells, macrophages, and mast cells. In contrast, neuropilins, identified as co-receptors for SARS-CoV-2, are abundantly expressed in these cells under physiological conditions and may be involved in virus-host interactions. This study presents a detailed\n                        <jats:italic toggle=\"yes\">in situ<\/jats:italic>\n                        analysis of Neuropilin 1 (NRP1) and Neuropilin 2 (NRP2) expression in fatal COVID-19 cases using immunohistochemistry and spatial multiplex immunofluorescence phenotyping, complemented by single cell RNA sequencing. Additionally, it demonstrates differential binding affinities of NRP1 and NRP2 to SARS-CoV-2 spike protein fragments S1 and S1\u2032\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        , suggesting distinct roles for these neuropilins in viral recognition. This study highlights the impact of the unique furin cleavage site in SARS-CoV-2, which may contribute to increased pathogenicity through its interaction with NRP1.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01384-25","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T13:01:25Z","timestamp":1761742885000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Differential expression of viral entry protein neuropilin 1 (NRP1) and neuropilin 2 (NRP2) in fatal COVID-19"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5318-832X","authenticated-orcid":false,"given":"A.","family":"Dette","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xnwqx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, University Hospital Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Moers","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xnwqx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, University Hospital Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2900-1782","authenticated-orcid":false,"given":"T.","family":"Mayr","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xnwqx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, University Hospital Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. v.","family":"Stillfried","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02cqe8q68","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, RWTH Aachen University Hospital","place":["Aachen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Bernhardt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xnwqx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, University Hospital Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"F\u00f6rster","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xnwqx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, University Hospital Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Werlein","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00f2yqf98","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, Hannover Medical School","place":["Hanover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Ackermann","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02cqe8q68","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, RWTH Aachen University Hospital","place":["Aachen, Germany"]},{"id":[{"id":"https:\/\/ror.org\/02r8sh830","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology and Department of Molecular Pathology, Helios University Clinic Wuppertal","place":["Wuppertal, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. H.","family":"Muders","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xnwqx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, University Hospital Bonn","place":["Bonn, Germany"]},{"name":"Asklepios Medical Care Center Pathology","place":["Gauting, Germany"]},{"name":"Precipoint Innovation GmbH","place":["Garching, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Kristiansen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xnwqx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, University Hospital Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Boor","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02cqe8q68","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, RWTH Aachen University Hospital","place":["Aachen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2609-3095","authenticated-orcid":true,"given":"I.","family":"G\u00fctgemann","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xnwqx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pathology, University Hospital Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.992384"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2507"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118102"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.001"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2024.02.013"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01601-2"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00846-2"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.4103\/atm.atm_7_23"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00418-x"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40249-020-00662-x"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101744"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.2c00184"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd2985"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.052824"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd3072"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.052"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908201106"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.3390\/v15071498"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2112457118"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01228"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2017.08.010"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-022-10048-0"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.2147\/BTT.S307352"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.05.013"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1006-19.2019"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2022.07.013"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2015432"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16096"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.010"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03570-8"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells10081900"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-022-09860-7"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa078"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.113.17.3073"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg6229"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.30.17779"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36140-9"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/all.14429"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjac021"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40560-020-00453-4"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200324799"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1070994"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01724-6"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4773"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03695-0"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2015.01.018"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03237-4"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00753-22"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-022-00998-0"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20209610"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/359843a0"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2021.106829"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-424713"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104296"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13051446"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16101924"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110858"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.10.065"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167280"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1159\/000109195"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2006-0439OC"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01576-9"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231810864"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.5415\/apallergy.0000000000000022"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5RU0614-296R"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.18563"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1089\/mab.2023.0007"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00556-8"},{"key":"e_1_3_5_71_2","unstructured":"van RG Drake FL. 2010. The Python language reference Release 3.0.1 [Repr.]. Python Software Foundation Hampton NH."},{"key":"e_1_3_5_72_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"e_1_3_5_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02382-y"},{"key":"e_1_3_5_74_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.27056"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/jvi.01384-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/jvi.01384-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T14:03:09Z","timestamp":1764079389000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/jvi.01384-25"}},"subtitle":[],"editor":[{"given":"Stacey","family":"Schultz-Cherry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":73,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11,25]]}},"alternative-id":["10.1128\/jvi.01384-25"],"URL":"https:\/\/doi.org\/10.1128\/jvi.01384-25","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]},"assertion":[{"value":"2025-08-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01384-25"}}