{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:15:30Z","timestamp":1790309730860,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2020,7,11]],"date-time":"2020-07-11T00:00:00Z","timestamp":1594425600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND AND AIMS<\/jats:title>\n                    <jats:p>\n                      To date, conflicting data exist as to whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first contact between HBV and primary human hepatocytes (PHH)\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>APPROACH AND RESULTS<\/jats:title>\n                    <jats:p>\n                      The exposure of PHH to HBV particles resulted in nuclear translocation of NF\u03baB, followed by the expression and secretion of inflammatory cytokines (IL [interleukin] 1B, IL6, and TNF [tumor necrosis factor]). Ultraviolet irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune\u2010inducing agent. Purified HBV particles on the whole, which were prepared from HBV DNA\u2010positive and protein\u2010rich fractions after heparin column separation, still had immune\u2010inducing capacity in PHH. The HBV\u2010induced gene expression profile was similar to that induced by toll\u2010like receptor 2 (TLR2) ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7\u20109. Treatment of PHH with both HBV particles and Pam3Cys led to phosphorylation of ERK (extracellular signal\u2013regulated kinase), JNK, and p38 mitogen\u2010activated protein kinases as well as NF\u03baB (nuclear factor kappa B). Finally, HBV\u2010induced gene expression could be neutralized by TLR2\u2010specific antibodies. Of note, pretreatment with an HBV entry inhibitor attenuated the TLR2\u2010mediated response to HBV, suggesting a receptor binding\u2010related mechanism. In liver\u2010humanized uPA\/severe combined immunodeficient (SCID)\/beige mice challenged with HBV\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , immune induction could only marginally be seen.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>\n                      PHHs are able to sense HBV particles through TLR2, leading to an activation of anti\u2010HBV immune responses\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . These findings challenge the previously described stealth properties of HBV.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31112","type":"journal-article","created":{"date-parts":[[2020,1,11]],"date-time":"2020-01-11T08:16:11Z","timestamp":1578730571000},"page":"829-844","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":51,"title":["Hepatitis B Virus Particles Activate Toll\u2010Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes"],"prefix":"10.1097","volume":"72","author":[{"given":"Zhenhua","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"},{"name":"Institute of Virology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Trippler","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine I.","family":"Real","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xufeng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Schefczyk","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thekla","family":"Kemper","sequence":"additional","affiliation":[{"name":"Institute of Virology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olympia E.","family":"Anastasiou","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"},{"name":"Institute of Virology,University Hospital Essen, University Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Ladiges","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juergen","family":"Treckmann","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery,University Hospital Essen,University of Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Paul","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery,University Hospital Essen,University of Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo A.","family":"Baba","sequence":"additional","affiliation":[{"name":"Department of Pathology,University Hospital Essen, University of Duisburg\u2010Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Allweiss","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Dandri","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Gerken","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Essen, University 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