{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:03:03Z","timestamp":1789448583874,"version":"build-2803163510"},"reference-count":139,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"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:p>\n                    The global resurgence of syphilis, marked by a dramatic 150% increase in cases over the last decade and the rise of the dominant SS14-\u03a9 strain cluster, represents a critical threat to public health. This review explores the complex molecular mechanisms by which\n                    <jats:italic>Treponema pallidum<\/jats:italic>\n                    functions as a \u201cstealth pathogen,\u201d establishing suppressive chemotactic microenvironments that facilitate neuroinvasion and persistent central nervous system (CNS) damage. We delineate a biomechanical and molecular cascade wherein the spirochete utilizes its unique \u201cnaked\u201d outer membrane and hypervariable\n                    <jats:italic>Treponema pallidum<\/jats:italic>\n                    repeat protein K (TprK) to bypass host immune surveillance. Furthermore, we detail how the pathogen is increasingly understood to breach the blood-brain barrier (BBB) through the induction of pro-inflammatory signals like interleukin-1\u03b2 (IL-1\u03b2) and the recently identified upregulation of ADAMTS5, which degrades the endothelial glycocalyx. Addressing the significance of recent advances, this review highlights the transition from traditional animal models to sophisticated\n                    <jats:italic>in vitro<\/jats:italic>\n                    genetic engineering, which has begun to overcome historical research bottlenecks. We conclude that while standard penicillin therapy effectively achieves serological cure, it is often insufficient to arrest or reverse the established neuro-inflammatory cascades that lead to permanent cognitive and neuropsychiatric impairments. Future perspectives emphasize the necessity of proactive prophylactic models like doxycycline post-exposure prophylaxis (DoxyPEP) and the identification of novel drug targets, such as the extracellular loops of outer membrane proteins, to disrupt immune evasion and may help mitigate irreversible neurological sequelae.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1866420","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:27:28Z","timestamp":1789446448000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Treponema pallidum suppressive microenvironments and central nervous system damage: from mechanisms to tools and prevention"],"prefix":"10.3389","volume":"17","author":[{"given":"Muze","family":"Huang","sequence":"first","affiliation":[{"name":"School of Medicine, Xiamen University","place":["Xiamen, Fujian, China"]},{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine Xiamen","place":["Xiamen, Fujian, China"]},{"name":"Xiamen University, Xiamen, China; and Institute of Infectious Disease, School of Medicine, Xiamen University","place":["Xiamen, Fujian, China"]},{"name":"School of Basic Medicine, Fujian Medical University","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyuan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Stomatology, Xiamen Medical College","place":["Xiamen, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Han","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Xiamen Medical College","place":["Xiamen, Fujian, China"]},{"name":"University of Tsukuba","place":["Tsukuba, Ibaraki, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarena Jiayao","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Xiamen Medical College","place":["Xiamen, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaw-syan","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medical Science, Xiamen Medical College","place":["Xiamen, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medicine, Xiamen University","place":["Xiamen, Fujian, China"]},{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine Xiamen","place":["Xiamen, Fujian, China"]},{"name":"Xiamen University, Xiamen, China; and Institute of Infectious Disease, School of Medicine, Xiamen University","place":["Xiamen, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.20944\/preprints202308.2154.v1","article-title":"Advancing syphilis research: Exploring new frontiers in immunology and pharmacological interventions","volume":"2","author":"Fajemiroye","year":"2023","journal-title":"Venereology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006447","article-title":"Historic Treponema pallidum genomes from Colonial Mexico retrieved from archaeological remains","volume":"12","author":"Schuenemann","year":"2018","journal-title":"PloS NeglTrop Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1128\/mr.57.3.750-779.1993","article-title":"Polypeptides of Treponema pallidum: Progress toward understanding their structural, functional, and immunologic roles. 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