{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:44:51Z","timestamp":1792025091292,"version":"4.4.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371367"],"award-info":[{"award-number":["82371367"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172331"],"award-info":[{"award-number":["82172331"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972028"],"award-info":[{"award-number":["81972028"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82402693"],"award-info":[{"award-number":["82402693"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fujian provincial health technology","award":["2024ZD01008"],"award-info":[{"award-number":["2024ZD01008"]}]},{"name":"Fujian Provincial Natural Science Foundation of China","award":["2024D023"],"award-info":[{"award-number":["2024D023"]}]},{"name":"Fujian Provincial Natural Science Foundation of China","award":["2024D024"],"award-info":[{"award-number":["2024D024"]}]},{"name":"Fujian Provincial Natural Science Foundation of China","award":["2022J011349"],"award-info":[{"award-number":["2022J011349"]}]},{"DOI":"10.13039\/100016808","name":"Natural Science Foundation of Xiamen, China","doi-asserted-by":"publisher","award":["3502Z20227267"],"award-info":[{"award-number":["3502Z20227267"]}],"id":[{"id":"10.13039\/100016808","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Treponema pallidum (T. pallidum) can invade the central nervous system (CNS) during early infection. However, whether blood\u2013brain barrier (BBB) disruption is required for spirochetal traversal remains unresolved.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To determine whether T. pallidum can traverse the BBB without disrupting its integrity, we established an intracisternal (i.c.) rabbit model. Systemic serological responses and T. pallidum DNA in peripheral tissues were assessed as evidence of spirochetal egress from the CNS to the periphery. BBB integrity was monitored throughout by the albumin quotient (QAlb)\u2014a validated BBB integrity marker \u2014with reference intervals derived from 20 healthy rabbits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The i.c. live T. pallidum group developed serological responses between day 7 and day 14, with kinetics similar to the intravenous live T. pallidum group, whereas the the i.c. heat-inactivated T. pallidum and i.c. control groups remained negative. T. pallidum DNA was detected in the brain and peripheral tissues (kidney, liver, spleen) of all i.c. live T. pallidum rabbits, but not in other groups. Throughout the 63 days, QAlb values in all i.c. groups remained within normal reference intervals, with no significant differences among groups (P\u202f&amp;gt;\u202f0.05).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>T. pallidum can disseminate from the CNS to peripheral tissues without disrupting BBB integrity. This challenges the view that BBB disruption is required for spirochetal traversal and highlights non-disruptive egress pathways.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiag367","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T11:50:19Z","timestamp":1783770619000},"page":"620-626","source":"Crossref","is-referenced-by-count":0,"title":["An Intracisternal Rabbit Model Reveals\n                    <i>Treponema pallidum<\/i>\n                    Egress Across an Intact Blood\u2013Brain Barrier"],"prefix":"10.1093","volume":"234","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4385-1534","authenticated-orcid":false,"given":"Shu-Hao","family":"Fan","sequence":"first","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xie","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhong","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Xue","family":"Zheng","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory, The Second Affiliated Hospital of Xiamen Medical College, Xiamen Medical College , Xiamen ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin-Feng","family":"Guo","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zheng","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Li","family":"Liu","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man-Li","family":"Tong","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4503-9382","authenticated-orcid":false,"given":"Li-Rong","family":"Lin","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Institute of Infectious Disease, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Xiamen Clinical Laboratory Quality Control Center , Xiamen, Fujian Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"2026101419575566000_jiag367-B1","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.ajog.2022.07.041","article-title":"Syphilis in pregnancy: an ongoing public health threat","volume":"227","author":"Eppes","year":"2022","journal-title":"Am J Obstet Gynecol"},{"key":"2026101419575566000_jiag367-B2","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1001\/jama.2025.17362","article-title":"Syphilis: a review","volume":"334","author":"Chevalier","year":"2025","journal-title":"JAMA"},{"key":"2026101419575566000_jiag367-B3","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1056\/NEJMra1906228","article-title":"Neurosyphilis","volume":"381","author":"Ropper","year":"2019","journal-title":"N Engl J Med"},{"key":"2026101419575566000_jiag367-B4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1097\/WCO.0000000000001404","article-title":"Neurosyphilis in 2025","volume":"38","author":"Sethi","year":"2025","journal-title":"Curr Opin Neurol"},{"key":"2026101419575566000_jiag367-B5","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.jiac.2017.11.007","article-title":"Frequency of treponema pallidum invasion into cerebrospinal fluid in primary or secondary early-stage syphilis","volume":"24","author":"Hagihara","year":"2018","journal-title":"J Infect Chemother"},{"key":"2026101419575566000_jiag367-B6","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.cca.2016.11.031","article-title":"Re-evaluating the sensitivity of the rabbit infectivity test for treponema pallidum in modern era","volume":"464","author":"Tong","year":"2017","journal-title":"Clin Chim Acta"},{"key":"2026101419575566000_jiag367-B7","doi-asserted-by":"crossref","first-page":"855","DOI":"10.7326\/0003-4819-109-11-855","article-title":"Invasion of the central nervous system by treponema pallidum: implications for diagnosis and treatment","volume":"109","author":"Lukehart","year":"1988","journal-title":"Ann Intern Med"},{"key":"2026101419575566000_jiag367-B8","volume-title":"Enabling novel treatments for nervous system disorders by improving methods for traversing the blood\u2013brain barrier: proceedings of a workshop","author":"National Academies Of Sciences, Engineering, And Medicine, Health And Medicine Division, Board On Health Sciences Policy, Forum On Neuroscience And Nervous System Disorders","year":"2018"},{"key":"2026101419575566000_jiag367-B9","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/mmi.12482","article-title":"The multifunctional role of the pallilysin-associated treponema pallidum protein, Tp0750, in promoting fibrinolysis and extracellular matrix component degradation","volume":"91","author":"Houston","year":"2014","journal-title":"Mol Microbiol"},{"key":"2026101419575566000_jiag367-B10","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1111\/jdv.19899","article-title":"Endothelial dysfunction of syphilis: pathogenesis","volume":"38","author":"Liu","year":"2024","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"2026101419575566000_jiag367-B11","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2022.108657","article-title":"The whole process of macrophage-treponema pallidum interactions: opsonic phagocytosis, nonopsonic phagocytosis and active invasion","volume":"107","author":"Chen","year":"2022","journal-title":"Int Immunopharmacol"},{"key":"2026101419575566000_jiag367-B12","doi-asserted-by":"crossref","DOI":"10.1016\/j.micpath.2021.105143","article-title":"Listeria monocytogenes crosses blood brain barrier through rho GTPases induced migration of macrophages and inflammatory interleukin expression","volume":"159","author":"Shahid","year":"2021","journal-title":"Microb Pathogen"},{"key":"2026101419575566000_jiag367-B13","doi-asserted-by":"crossref","DOI":"10.1111\/nan.12789","article-title":"The blood-CSF-brain route of neurological disease: the indirect pathway into the brain","volume":"48","author":"Cousins","year":"2022","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2026101419575566000_jiag367-B14","article-title":"Recombinant treponema pallidum protein Tp0965 activates endothelial cells and increases the permeability of endothelial cell monolayer","volume":"9","author":"Zhang","year":"2014","journal-title":"PLoS One"},{"key":"2026101419575566000_jiag367-B15","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1093\/infdis\/jiae008","article-title":"Characteristic profiling of soluble factors in the cerebrospinal fluid of patients with neurosyphilis","volume":"230","author":"Xu","year":"2024","journal-title":"J Infect Dis"},{"key":"2026101419575566000_jiag367-B16","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1128\/iai.11.6.1296-1299.1975","article-title":"Isolation and purification of treponema pallidum from syphilitic lesions in rabbits","volume":"11","author":"Hardy","year":"1975","journal-title":"Infect Immun"},{"key":"2026101419575566000_jiag367-B17","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1093\/infdis\/163.4.825","article-title":"An experimental model of early central nervous system syphilis","volume":"163","author":"Marra","year":"1991","journal-title":"J Infect Dis"},{"key":"2026101419575566000_jiag367-B18","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1086\/426510","article-title":"Treponema pallidum strain-specific differences in neuroinvasion and clinical phenotype in a rabbit model","volume":"191","author":"Tantalo","year":"2005","journal-title":"J Infect Dis"},{"key":"2026101419575566000_jiag367-B19","doi-asserted-by":"crossref","DOI":"10.1128\/spectrum.05198-22","article-title":"Red blood cell lysis pretreatment can significantly improve the yield of treponema pallidum DNA from blood","volume":"11","author":"Wei","year":"2023","journal-title":"Microbiol Spectrum"},{"key":"2026101419575566000_jiag367-B20","article-title":"Altered CSF albumin quotient links peripheral inflammation and brain damage in MS","volume":"8","author":"Puthenparampil","year":"2021","journal-title":"Neurol(R) Neuroimmunol Neuroinflammation"},{"key":"2026101419575566000_jiag367-B21","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1177\/1352458520912379","article-title":"Neurofilament levels are associated with blood-brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis","volume":"27","author":"Uher","year":"2021","journal-title":"Mult Scler"},{"key":"2026101419575566000_jiag367-B22","volume-title":"Defining, establishing and verifying reference intervals in the clinical laboratory: approved guideline. 3","author":"Clinical And Laboratory Standards Institute","year":"2010"},{"key":"2026101419575566000_jiag367-B23","volume-title":"Reference intervals: a user's Guide","author":"Horn","year":"2005"},{"key":"2026101419575566000_jiag367-B24","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.it.2015.08.006","article-title":"Revisiting the mechanisms of CNS immune privilege","volume":"36","author":"Louveau","year":"2015","journal-title":"Trends Immunol"},{"key":"2026101419575566000_jiag367-B25","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1111\/jdv.14681","article-title":"Biological false-positive venereal disease research laboratory test in cerebrospinal fluid in the diagnosis of neurosyphilis\u2014a case-control study","volume":"32","author":"Zheng","year":"2018","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"2026101419575566000_jiag367-B26","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s12576-016-0516-6","article-title":"Time-course investigation of blood-brain barrier permeability and tight junction protein changes in a rat model of permanent focal ischemia","volume":"68","author":"Liu","year":"2018","journal-title":"J Physiol Sci"},{"key":"2026101419575566000_jiag367-B27","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1177\/1352458516672015","article-title":"Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: their possible role on blood-brain barrier disruption","volume":"23","author":"Uchida","year":"2017","journal-title":"Mult Scler"},{"key":"2026101419575566000_jiag367-B28","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.intimp.2015.02.028","article-title":"Tp17 membrane protein of treponema pallidum activates endothelial cells in vitro","volume":"25","author":"Zhang","year":"2015","journal-title":"Int Immunopharmacol"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiag367\/68928084\/jiag367.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/234\/4\/620\/68928084\/jiag367.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/234\/4\/620\/68928084\/jiag367.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:58:06Z","timestamp":1792022286000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/234\/4\/620\/8735143"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,7,16]]},"published-print":{"date-parts":[[2026,10,15]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiag367","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,10,15]]},"published":{"date-parts":[[2026,7,16]]}}}