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Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chancre self-healing, a typical clinical phenomenon of primary syphilis, is essentially wound healing. The first response to a wound is constriction of the injured blood vessels and activation of platelets to form a fibrin clot. However, the role of <jats:italic>Treponema pallidum<\/jats:italic> in platelet activation and clot formation remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We aimed to elucidate the role of the outer membrane <jats:italic>Treponema pallidum<\/jats:italic> lipoprotein Tp0136 in human platelet activation and aggregation and explore the related mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A series of experiments were performed to assess the effects of Tp0136 on human platelet activation and aggregation <jats:italic>in vitro<\/jats:italic>. The effect of Tp0136 on platelet receptors was studied by detecting PAR1 protein levels and studying related receptor sites. The involvement of the G<jats:sub>q<\/jats:sub>\/G<jats:sub>i<\/jats:sub> signaling pathway downstream of PAR1 was explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Tp0136 significantly accelerated the formation of human platelet clots as well as platelet adhesion to and diffusion on fibrinogen to promote platelet aggregation. Tp0136 also potentiated P-selectin expression and PF4 release to promote platelet activation and downregulated PAR1 expression. The activation and aggregation induced by Tp0136 were reverted by the specific PAR1 antagonist RWJ56110 and the human PAR1 antibody. In addition, Tp0136 significantly enhanced G<jats:sub>q<\/jats:sub> and G<jats:sub>i<\/jats:sub> signaling activation, thereby triggering p38 phosphorylation and Akt-PI3K activation, increasing the release of intraplatelet Ca<jats:sup>2+<\/jats:sup> and attenuating the release of cytosolic cAMP. Furthermore, the specific PAR1 antagonist RWJ56110 significantly suppressed G<jats:sub>q<\/jats:sub> and G<jats:sub>i<\/jats:sub> signaling activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results showed that the <jats:italic>Treponema pallidum<\/jats:italic> Tp0136 protein stimulated human platelet activation and aggregation by downregulating PAR1 and triggered PAR1-dependent G<jats:sub>q<\/jats:sub> and G<jats:sub>i<\/jats:sub> pathway activation. These findings may contribute to our understanding of the self-healing of chancroid in early syphilis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.818151","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T04:54:45Z","timestamp":1646024085000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["The Outer Membrane Lipoprotein Tp0136 Stimulates Human Platelet Activation and Aggregation Through PAR1 to Enhance Gq\/Gi Signaling"],"prefix":"10.3389","volume":"13","author":[{"given":"Qiu-Yan","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Rong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Ci","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu087","article-title":"Analysis of 3 Algorithms for Syphilis Serodiagnosis and Implications for Clinical Management","volume":"58","author":"Tong","year":"2014","journal-title":"Clin Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"17073","DOI":"10.1038\/nrdp.2017.73","article-title":"Syphilis","volume":"3","author":"Peeling","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1152\/physrev.00067.2017","article-title":"Wound Healing: A Cellular Perspective","volume":"99","author":"Rodrigues","year":"2019","journal-title":"Physiol Rev"},{"key":"B4","doi-asserted-by":"publisher","first-page":"xxi","DOI":"10.1046\/j.1523-1747.2003.12575.x","article-title":"Fibrin Is a Many Splendored Thing","volume":"121","author":"Clark","year":"2003","journal-title":"J Invest Dermatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00016.2011","article-title":"New Fundamentals in Hemostasis","volume":"93","author":"Versteeg","year":"2013","journal-title":"Physiol Rev"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00717","article-title":"Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer","volume":"10","author":"Sebert","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6042","article-title":"Protease-Activated Receptors 1 and 4 Mediate Activation of Human Platelets by Thrombin","volume":"103","author":"Kahn","year":"1999","journal-title":"J Clin Invest"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/35025229","article-title":"Thrombin Signalling and Protease-Activated Receptors","volume":"407","author":"Coughlin","year":"2000","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0007401","article-title":"Analysis of Host Cell Binding Specificity Mediated by the Tp0136 Adhesin of the Syphilis Agent Treponema Pallidum Subsp. 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