{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T14:43:20Z","timestamp":1792853000741,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"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><jats:title>Introduction<\/jats:title><jats:p>Syphilis is a complex disease with variable clinical presentation where symptomatic and potentially infectious stages alternate with periods of latency, representing a fascinating model to study immune evasion and host immune responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Immunohistochemistry (IHC), bulk, and single-cell RNA sequencing were performed on formalin-fixed paraffin-embedded skin biopsies collected from subjects with secondary syphilis. Additionally, PBMCs from healthy individuals and either primary or <jats:italic>MyD88<\/jats:italic> knock-out keratinocytes were exposed to live <jats:italic>Treponema pallidum<\/jats:italic> cells to define initial skin responses to the bacteria.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Immunohistochemistry of secondary syphilis skin lesions showed a polymorphous immune infiltrate with colocalization of T cells, B cells and antigen\u2013presenting cells. Single-cell analysis revealed distinct cellular contributions to the immune response, with prominent immune-stromal crosstalk accompanied by altered keratinocyte differentiation and decreased intraepidermal communication. Notably, prominent inflammatory signals were countered by concomitant regulatory responses, particularly in infiltrating myeloid cells. Exposure of PBMCs to live <jats:italic>T. pallidum<\/jats:italic> inhibited immune responses, while exposure to sonicated cells triggered <jats:italic>CXCL1<\/jats:italic> and <jats:italic>CXCL3<\/jats:italic> upregulation. Keratinocytes responded to both intact and sonicated <jats:italic>T. pallidum<\/jats:italic> with upregulation of type-I interferon responses that, however, were abolished in MYD88\u2013deficient but not in STING\u2013deficient keratinocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data provide novel insights into the contribution of epidermal TLR sensing through MYD88 to the host response to syphilis infection, highlighting mechanisms by which <jats:italic>T. pallidum<\/jats:italic> evades immune responses in skin that may facilitate transmission of this pathogen through the skin.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1549206","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T01:34:05Z","timestamp":1742952845000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Characterizing the immune infiltrate in secondary syphilis: implications for transmission and pathology"],"prefix":"10.3389","volume":"16","author":[{"given":"Ir\u00e8ne","family":"Gallais S\u00e9r\u00e9zal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Kirma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrinal K.","family":"Sarkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Cole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianying","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Bogle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Coon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey R.","family":"vanStraalen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Dobry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda H.","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Michelle","family":"Kahlenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W.","family":"Harms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison C.","family":"Billi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lam C.","family":"Tsoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Giacani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann E.","family":"Gudjonsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02348-0","article-title":"Syphilis","volume":"402","author":"Peeling","year":"2023","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.04.007","article-title":"Microbial vertical transmission during human pregnancy","volume":"21","author":"Arora","year":"2017","journal-title":"Cell Host Microbe"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2010.09.020","article-title":"Cellular architecture of treponema pallidum: novel flagellum, periplasmic cone, and cell envelope as revealed by cryo electron tomography","volume":"403","author":"Liu","year":"2010","journal-title":"J Mol Biol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1995.tb02332.x","article-title":"Treponema pallidum and the quest for outer membrane proteins","volume":"16","author":"Radolf","year":"1995","journal-title":"Mol Microbiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2016.141","article-title":"Treponema pallidum, the syphilis spirochete: Making a living as a stealth pathogen","volume":"14","author":"Radolf","year":"2016","journal-title":"Nat Rev Microbiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1086\/511822","article-title":"Treponema pallidum elicits innate and adaptive cellular immune responses in skin and blood during secondary syphilis: A flow-cytometric analysis","volume":"195","author":"Salazar","year":"2007","journal-title":"J Infect Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001717","article-title":"Immune evasion and recognition of the syphilis spirochete in blood and skin of secondary syphilis patients: Two immunologically distinct compartments","volume":"6","author":"Cruz","year":"2012","journal-title":"PloS Negl Trop Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.15349","article-title":"Possible inducible skin-associated lymphoid tissue (iSALT)-like structures with CXCL13 + fibroblast-like cells in secondary syphilis","volume":"177","author":"Kogame","year":"2017","journal-title":"Br J Dermatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/173.2.491","article-title":"Primary and secondary syphilis lesions contain mRNA for Th1 cytokines and activated cytolytic T cells","volume":"44","author":"Van Voorhis","year":"1996","journal-title":"J Investig Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"36","DOI":"10.3109\/01913123.2011.584498","article-title":"Cell and tissue interactions of treponema pallidum in primary and secondary syphilitic skin lesions: An ultrastructural study of serial sections","volume":"37","author":"Juanpere-Rodero","year":"2013","journal-title":"Ultrastruct Pathol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1172\/jci.insight.127291","article-title":"The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity","volume":"4","author":"Billi","year":"2019","journal-title":"JCI Insight"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e994","DOI":"10.1016\/S2666-5247(23)00219-7","article-title":"Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study","volume":"4","author":"Tantalo","year":"2023","journal-title":"Lancet Microbe"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI159393","article-title":"Keratinocytes sense and eliminate CRISPR DNA through STING\/IFN-\u03ba activation and APOBEC3G induction","volume":"133","author":"Sarkar","year":"2023","journal-title":"J Clin Invest"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0292-x","article-title":"CellPhoneDB: inferring cell\u2013cell communication from combined expression of multi-subunit ligand\u2013receptor complexes","volume":"15","author":"Efremova","year":"2020","journal-title":"Nat Protoc"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1136\/sti.69.2.102","article-title":"The localisation of treponemes and characterisation of the inflammatory infiltrate in skin biopsies from patients with primary or secondary syphilis, or early infectious yaws","volume":"69","author":"Engelkens","year":"1993","journal-title":"Genitourin Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/OLQ.0000000000000149","article-title":"Toll-like receptor polymorphisms are associated with increased neurosyphilis risk","volume":"41","author":"Marra","year":"2014","journal-title":"Sex Transm Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2007.11.003","article-title":"Immune responses induced by spirochetal outer membrane lipoproteins and glycolipids","volume":"213","author":"Schr\u00f6der","year":"2008","journal-title":"Immunobiology"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010481200","article-title":"Toll-like receptor-2 mediates treponema glycolipid and lipoteichoic acid-induced NF-\u03baB translocation","volume":"276","author":"Opitz","year":"2001","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5343.1612","article-title":"IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling","volume":"278","author":"Muzio","year":"1997","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80402-1","article-title":"MyD88: an adapter that recruits IRAK to the IL-1 receptor complex","volume":"7","author":"Wesche","year":"1997","journal-title":"Immunity"},{"key":"B21","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.yexcr.2017.09.040","article-title":"Treponema pallidum flagellins stimulate MMP-9 and MMP-13 expression via TLR5 and MAPK\/NF-\u03baB signaling pathways in human epidermal keratinocytes","volume":"361","author":"Jiang","year":"2017","journal-title":"Exp Cell Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2017.01.002","article-title":"Treponema pallidum flagellins elicit proinflammatory cytokines from human monocytes via TLR5 signaling pathway","volume":"222","author":"Xu","year":"2017","journal-title":"Immunobiology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.molimm.2016.11.005","article-title":"Treponema pallidum flagellin FlaA2 induces IL-6 secretion in THP-1 cells via the Toll-like receptor 2 signaling pathway","volume":"81","author":"Xie","year":"2017","journal-title":"Mol Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14617","article-title":"The N-terminal D1 domain of Treponema pallidum flagellin binding to TLR5 is required but not sufficient in activation of TLR5","volume":"23","author":"Xu","year":"2019","journal-title":"J Cell Mol Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2022.105879","article-title":"Treponema pallidum FlaA2 inducing the release of pro-inflammatory cytokines is mediated via TLR2 in keratinocytes","volume":"173","author":"Luo","year":"2022","journal-title":"Microb Pathog"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(02)00362-9","article-title":"Claudin-based barrier in simple and stratified cellular sheets","volume":"14","author":"Tsukita","year":"2002","journal-title":"Curr Opin Cell Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5701070","article-title":"Regulation of epidermal tight-junctions (TJ) during infection with exfoliative toxin-negative Staphylococcus strains","volume":"128","author":"Ohnemus","year":"2008","journal-title":"J Invest Dermatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/DAD.0b013e3181e8b587","article-title":"The immunopathobiology of syphilis: The manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity","volume":"33","author":"Carlson","year":"2011","journal-title":"Am J Dermatopathol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00296","article-title":"CXCR5, the defining marker for follicular B helper T (TFH) cells","volume":"6","author":"Moser","year":"2015","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.11.1545","article-title":"Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production","volume":"192","author":"Breitfeld","year":"2000","journal-title":"J Exp Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2309","article-title":"Regulation of T H2 development by CXCR5 + dendritic cells and lymphotoxin-expressing B cells","volume":"13","author":"Le\u00f3n","year":"2012","journal-title":"Nat Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00124-17","article-title":"Oral prion disease pathogenesis is impeded in the specific absence of CXCR5-expressing dendritic cells","volume":"91","author":"Bradford","year":"2017","journal-title":"J Virol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.18.1.205-216.2005","article-title":"Secondary syphilitic lesions","volume":"18","author":"Baughn","year":"2005","journal-title":"Clin Microbiol Rev"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/153.6.1014","article-title":"Role of circulating immune complexes in human secondary syphilis","volume":"153","author":"Jorizzo","year":"1986","journal-title":"J Infect Dis"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.136.4.1406","article-title":"Characterization of the antigenic determinants and host components in immune complexes from patients with secondary syphilis","volume":"136","author":"Baughn","year":"1986","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-1859(82)80042-3","article-title":"Persistent serum immune complexes in syphilis","volume":"56","author":"Engel","year":"1980","journal-title":"Br J Vener Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100615","article-title":"TpF1 from treponema pallidum activates inflammasome and promotes the development of regulatory T cells","volume":"187","author":"Babolin","year":"2011","journal-title":"J Immunol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1093\/bjd\/ljac088","article-title":"Skin programming of inflammatory responses to Staphylococcus aureus is compartmentalized according to epidermal keratinocyte differentiation status","volume":"188","author":"Clayton","year":"2023","journal-title":"Br J Dermatol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/iai.67.3.1220-1226.1999","article-title":"Treponema denticola outer membrane enhances the phagocytosis of collagen-coated beads by gingival fibroblasts","volume":"67","author":"Battikhi","year":"1999","journal-title":"Infect Immun"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1073\/pnas.2205378119","article-title":"Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events","volume":"119","author":"Tsukamoto","year":"2022","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1549206\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T01:34:09Z","timestamp":1742952849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1549206\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,25]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2025.1549206"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1549206","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,25]]},"article-number":"1549206"}}