{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:05:50Z","timestamp":1790057150392,"version":"4.0.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                      , the causative agent of Chagas disease, enters the host through the skin. While natural killer (NK) cell antimicrobial activity against\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      -infected keratinocytes in the epidermis has previously been shown, NK cell interactions with dermal fibroblasts, a primary target of parasite replication at the skin entry site, remain poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Bulk RNA-sequencing of mock- and\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      -infected human dermal fibroblasts (HDF) and the BJ fibroblast cell line was performed to identify infection-induced ligand changes. HVEM-CD160 binding and NK cell effector functions were assessed in vitro using fibroblast co-cultures with or without CD160 receptor blockade.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , RAG\n                      <jats:sup>-\/-<\/jats:sup>\n                      and RAG\n                      <jats:sup>-\/-<\/jats:sup>\n                      CD160\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice were infected intradermally with\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      ; NK cell degranulation and cytokine production were analyzed by flow cytometry, and parasite burden in skin and muscle was quantified by qPCR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RNA-sequencing revealed upregulation of herpesvirus entry mediator (HVEM, TNFRSF14) in infected human dermal fibroblasts, confirmed at the protein level. HVEM was functionally engaged by CD160, and CD160 blockade reduced NK cell degranulation and secretion of cytotoxic mediators in fibroblast co-cultures. CD160 deficiency impaired NK cell activation\n                      <jats:italic>in vivo<\/jats:italic>\n                      ; NK cell degranulation in the skin showed a trend toward inverse correlation with local parasite burden, and early skin parasite load predicted subsequent dissemination to muscle. HVEM was robustly upregulated in murine skin during acute infection, mirroring the human fibroblast data.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings establish the HVEM-CD160 axis as a key regulator of NK cell effector function in the skin during acute\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      infection, contributing to local parasite control. This conserved human-mouse regulatory response may offer broader insight into NK cell-mediated defense against pathogens that invade through the skin.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1872132","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:40:02Z","timestamp":1790055602000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CD160 mediated NK cell activation shapes host defense against acute Trypanosoma cruzi infection in the skin"],"prefix":"10.3389","volume":"17","author":[{"given":"Jessica","family":"Barton","sequence":"first","affiliation":[{"name":"Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cari","family":"Lehmann","sequence":"additional","affiliation":[{"name":"Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulricke","family":"Richardt","sequence":"additional","affiliation":[{"name":"Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1niel","family":"Cadar","sequence":"additional","affiliation":[{"name":"Virus Metagenomics and Evolution, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]},{"name":"Arbovirology and Entomology, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Volkmer","sequence":"additional","affiliation":[{"name":"Skin Cancer Center, Division of Molecular Cell Biology, Elbe Klinikum Buxtehude","place":["Elbe Klinikum Stade-Buxtehude, Buxtehude, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"Greinert","sequence":"additional","affiliation":[{"name":"Skin Cancer Center, Division of Molecular Cell Biology, Elbe Klinikum Buxtehude","place":["Elbe Klinikum Stade-Buxtehude, Buxtehude, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa Isela","family":"G\u00e1lvez","sequence":"additional","affiliation":[{"name":"Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-4632.2011.05380.x","article-title":"Trypanosoma cruzi infection: a review with emphasis on cutaneous manifestations","volume":"51","author":"Hemmige","year":"2012","journal-title":"Int J Dermatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiph.2017.07.017","article-title":"Chagas disease: Importance of rats as reservoir hosts of Trypanosoma cruzi (Chagas, 1909) in western Mexico","volume":"11","author":"Rosal","year":"2018","journal-title":"J Infection Public Health"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijppaw.2020.03.004","article-title":"Trypanosoma cruzi infections and associated pathology in urban-dwelling Virginia opossums (Didelphis virginiana)","volume":"11","author":"Zecca","year":"2020","journal-title":"Int J For Parasitology: Parasites Wildlife"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3024.1993.tb00591.x","article-title":"The 35\/50 kDa surface antigen of Trypanosoma cruzi metacyclic trypomastigotes, an adhesion molecule involved in host cell invasion","volume":"15","author":"Ruiz","year":"1993","journal-title":"Parasite Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(05)80061-3","article-title":"Lysosome recruitment and fusion are early events required for trypanosome invasion of mammalian cells","volume":"71","author":"Tardieux","year":"1992","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4894(73)90087-8","article-title":"Trypanosoma cruzi: Interaction with vertebrate cells in vitro: I. 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