{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T16:44:39Z","timestamp":1793378679367,"version":"4.5.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI 132674, AI 126343, AI 007526 , AI 153586 , AI060549"],"award-info":[{"award-number":["AI 132674, AI 126343, AI 007526 , AI 153586 , AI060549"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008013","name":"University of Texas Medical Branch at Galveston","doi-asserted-by":"publisher","award":["IHII Pilot Grant"],"award-info":[{"award-number":["IHII Pilot Grant"]}],"id":[{"id":"10.13039\/100008013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Scrub typhus is a life-threatening zoonosis caused by the obligate intracellular bacterium <jats:italic>Orientia tsutsugamushi<\/jats:italic> (<jats:italic>Ot<\/jats:italic>) that is transmitted by the infected larvae of trombiculid mites. However, the mechanism by which <jats:italic>Ot<\/jats:italic> disseminates from the bite site to visceral organs remains unclear; host innate immunity against bacterial dissemination and replication during early infection is poorly understood. In this study, by using an intradermal infection mouse model and fluorescent probe-labeled <jats:italic>Ot<\/jats:italic>, we assessed the dynamic pattern of innate immune cell responses at the inoculation site. We found that neutrophils were the first responders to <jats:italic>Ot<\/jats:italic> infection and migrated into the skin for bacterial uptake. <jats:italic>Ot<\/jats:italic> infection greatly induced neutrophil activation, and <jats:italic>Ot<\/jats:italic>-neutrophil interaction remarkably promoted cell death both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Depletion of neutrophils did not alter bacterial dissemination in mice, as evidenced by similar bacterial burdens in the skin and draining lymph nodes (dLN) at day 3, as well as in the lungs and brains at day 14, as compared to the control mice. Instead, dendritic cells (DCs) and macrophages played a role as a Trojan horse and transmitted <jats:italic>Ot<\/jats:italic> from the skin into dLN. Importantly, the absence of homing receptor CCR7 or neutralization of its ligand, CCL21, significantly impaired DC migration, resulting in reduced bacterial burdens in dLN. Taken together, our study sheds light on a CCR7\/dendritic cell-mediated mechanism of early <jats:italic>Ot<\/jats:italic> dissemination and provides new insights into therapeutic and vaccine development strategies for scrub typhus.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1061031","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T04:53:19Z","timestamp":1671684799000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["CCR7\/dendritic cell axis mediates early bacterial dissemination in Orientia tsutsugamushi-infected mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Yuejin","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey","family":"Gonzales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Thiriot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyanate","family":"Sunyakumthorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Melby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaren","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Soong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006657","article-title":"Orientia tsutsugamushi: A neglected but fascinating obligate intracellular bacterial pathogen","volume":"13","author":"Salje","year":"2017","journal-title":"PloS Pathog"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1608499","article-title":"Scrub typhus - scientific neglect, ever-widening impact","volume":"375","author":"Walker","year":"2016","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2020.02.014","article-title":"Orientia tsutsugamushi","volume":"28","author":"Wongsantichon","year":"2020","journal-title":"Trends Microbiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006062","article-title":"A review of the global epidemiology of scrub typhus","volume":"11","author":"Xu","year":"2017","journal-title":"PloS Negl Trop Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/tropicalmed3010008","article-title":"A review of scrub typhus (Orientia tsutsugamushi and related organisms): Then, now, and tomorrow","volume":"3","author":"Luce-Fedrow","year":"2018","journal-title":"Trop Med Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1086\/596576","article-title":"Scrub typhus: The geographic distribution of phenotypic and genotypic variants of","author":"Kelly","year":"2009","journal-title":"Orientia Tsutsugamushi. Clin Infect Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1603657","article-title":"Endemic scrub typhus in south America","volume":"375","author":"Weitzel","year":"2016","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003971","article-title":"A systematic review of mortality from untreated scrub typhus (Orientia tsutsugamushi)","volume":"9","author":"Taylor","year":"2015","journal-title":"PloS Negl Trop Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005838","article-title":"Estimating the burden of scrub typhus: A systematic review","volume":"11","author":"Bonell","year":"2017","journal-title":"PloS Negl Trop Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001466","article-title":"Orientia tsutsugamushi in human scrub typhus eschars shows tropism for dendritic cells and monocytes rather than endothelium","volume":"6","author":"Paris","year":"2012","journal-title":"PloS Negl Trop Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3880385","article-title":"Identification of the target cells of Orientia tsutsugamushi in human cases of scrub typhus","volume":"14","author":"Moron","year":"2001","journal-title":"Mod Pathol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ijid.2014.02.009","article-title":"Clinical profile and improving mortality trend of scrub typhus in south India","volume":"23","author":"Varghese","year":"2014","journal-title":"Int J Infect Dis"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.21037\/apm-21-1100","article-title":"Analysis of the epidemiological and clinical characteristics of 65 patients with scrub typhus on the East coast of China","volume":"10","author":"Xu","year":"2021","journal-title":"Ann Palliat Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001981","article-title":"Orientia tsutsugamushi subverts dendritic cell functions by escaping from autophagy and impairing their migration","volume":"7","author":"Choi","year":"2013","journal-title":"PloS Negl Trop Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2020.577303","article-title":"Chronic encephalopathy and locked-in state due to scrub typhus related cns vasculitis","volume":"346","author":"Sharma","year":"2020","journal-title":"J Neuroimmunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701219","article-title":"Dysregulated Th1 immune and vascular responses in scrub typhus pathogenesis","volume":"200","author":"Soong","year":"2018","journal-title":"J Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003191","article-title":"Strong type 1, but impaired type 2, immune responses contribute to Orientia tsutsugamushi-induced pathology in mice","volume":"8","author":"Soong","year":"2014","journal-title":"PloS Negl Trop Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005765","article-title":"Type 1-skewed neuroinflammation and vascular damage associated with Orientia tsutsugamushi infection in mice","volume":"11","author":"Soong","year":"2017","journal-title":"PloS Negl Trop Dis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"121","DOI":"10.3390\/tropicalmed6030121","article-title":"Comparison of lethal and nonlethal mouse models of Orientia tsutsugamushi infection reveals T-cell population-associated cytokine signatures correlated with lethality and protection","volume":"6","author":"Luce-Fedrow","year":"2021","journal-title":"Trop Med Infect Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00816","article-title":"Dissemination of Orientia tsutsugamushi, a causative agent of scrub typhus, and immunological responses in the humanized draga mouse","volume":"9","author":"Jiang","year":"2018","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-019-1684-3","article-title":"Temporal analysis of mrna expression profiles in orientia infected C3heb\/Fej mouse","volume":"20","author":"Chao","year":"2020","journal-title":"BMC Microbiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.867924","article-title":"Distinct role of Tnfr1 and Tnfr2 in protective immunity against Orientia tsutsugamushi infection in mice","volume":"13","author":"Liang","year":"2022","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0007675","article-title":"Polarized lung inflammation and Tie2\/Angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection","volume":"14","author":"Trent","year":"2020","journal-title":"PloS Negl Trop Dis"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.19-0955","article-title":"Ideal criteria for accurate mouse models of vector-borne diseases with emphasis on scrub typhus and dengue","volume":"103","author":"Sarathy","year":"2020","journal-title":"Am J Trop Med Hyg"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054570","article-title":"An intradermal inoculation model of scrub typhus in Swiss cd-1 mice demonstrates more rapid dissemination of virulent strains of Orientia tsutsugamushi","volume":"8","author":"Sunyakumthorn","year":"2013","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003064","article-title":"Dissemination of Orientia tsutsugamushi and inflammatory responses in a murine model of scrub typhus","volume":"8","author":"Keller","year":"2014","journal-title":"PloS Negl Trop Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005453","article-title":"Murine models of scrub typhus associated with host control of Orientia tsutsugamushi infection","volume":"11","author":"Mendell","year":"2017","journal-title":"PloS Negl Trop Dis"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004884","article-title":"An intradermal inoculation mouse model for immunological investigations of acute scrub typhus and persistent infection","volume":"10","author":"Soong","year":"2016","journal-title":"PloS Negl Trop Dis"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2017.59","article-title":"Engineering of obligate intracellular bacteria: Progress, challenges and paradigms","volume":"15","author":"McClure","year":"2017","journal-title":"Nat Rev Microbiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.mimet.2016.08.022","article-title":"Live imaging of the genetically intractable obligate intracellular bacteria Orientia tsutsugamushi using a panel of fluorescent dyes","volume":"130","author":"Atwal","year":"2016","journal-title":"J Microbiol Methods"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200324690","article-title":"The chemokine receptor Ccr7 controls lymph node-dependent cytotoxic T cell priming in alloimmune responses","volume":"34","author":"Hopken","year":"2004","journal-title":"Eur J Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002966","article-title":"Hematogenously disseminated Orientia tsutsugamushi-infected murine model of scrub typhus","volume":"8","author":"Shelite","year":"2014","journal-title":"PloS Negl Trop Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2017.147","article-title":"Il-33 induces immunosuppressive neutrophils Via a type 2 innate lymphoid Cell\/Il-13\/Stat6 axis and protects the liver against injury in lcmv infection-induced viral hepatitis","volume":"16","author":"Liang","year":"2019","journal-title":"Cell Mol Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601891","article-title":"Retinoic acid regulates immune responses by promoting il-22 and modulating S100 proteins in viral hepatitis","volume":"198","author":"Jie","year":"2017","journal-title":"J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02022","article-title":"A type I interferon and il-10 induced by Orientia tsutsugamushi infection suppresses antigen-specific T cells and their memory responses","volume":"9","author":"Min","year":"2018","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aat4579","article-title":"Neutrophils: New insights and open questions","volume":"3","author":"Ley","year":"2018","journal-title":"Sci Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe7729","article-title":"Neutrophils self-limit swarming to contain bacterial growth in vivo","volume":"372","author":"Kienle","year":"2021","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1126\/science.1159194","article-title":"In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies","volume":"321","author":"Peters","year":"2008","journal-title":"Science"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1162914","article-title":"Immunology. neutrophil soldiers or Trojan horses","volume":"321","author":"John","year":"2008","journal-title":"Science"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01012","article-title":"Neutrophils as Trojan horse vehicles for brucella abortus macrophage infection","volume":"10","author":"Gutierrez-Jimenez","year":"2019","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/s0966-842x(03)00075-1","article-title":"Neutrophil granulocytes\u2013Trojan horses for leishmania major and other intracellular microbes","volume":"11","author":"Laskay","year":"2003","journal-title":"Trends Microbiol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00037.2016","article-title":"Arginase: A multifaceted enzyme important in health and disease","volume":"98","author":"Caldwell","year":"2018","journal-title":"Physiol Rev"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0712349","article-title":"Myeloperoxidase: A front-line defender against phagocytosed microorganisms","volume":"93","author":"Klebanoff","year":"2013","journal-title":"J Leukoc Biol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.abb.2018.01.004","article-title":"Myeloperoxidase: Its role for host defense, inflammation, and neutrophil function","volume":"640","author":"Aratani","year":"2018","journal-title":"Arch Biochem Biophys"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1016\/j.immuni.2019.03.001","article-title":"A subset of type I conventional dendritic cells controls cutaneous bacterial infections through vegfalpha-mediated recruitment of neutrophils","volume":"50","author":"Janela","year":"2019","journal-title":"Immunity"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.06.014","article-title":"Ccr7 governs skin dendritic cell migration under inflammatory and steady-state conditions","volume":"21","author":"Ohl","year":"2004","journal-title":"Immunity"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.9.5153","article-title":"The multiple personalities of the chemokine receptor Ccr7 in dendritic cells","volume":"176","author":"Sanchez-Sanchez","year":"2006","journal-title":"J Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/ni1513","article-title":"Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells","volume":"8","author":"Link","year":"2007","journal-title":"Nat Immunol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"17373","DOI":"10.1038\/s41598-018-35775-9","article-title":"Ultrastructural visualization of Orientia tsutsugamushi in biopsied eschars and monocytes from scrub typhus patients in south Korea","volume":"8","author":"Ro","year":"2018","journal-title":"Sci Rep"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003990","article-title":"Increased nucleosomes and neutrophil activation link to disease progression in patients with scrub typhus but not murine typhus in Laos","volume":"9","author":"Paris","year":"2015","journal-title":"PloS Negl Trop Dis"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02065","article-title":"Scrub typhus pathogenesis: Innate immune response and lung injury during Orientia tsutsugamushi infection","volume":"10","author":"Trent","year":"2019","journal-title":"Front Microbiol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039042","article-title":"Intracellular invasion of Orientia tsutsugamushi activates inflammasome in asc-dependent manner","volume":"7","author":"Koo","year":"2012","journal-title":"PloS One"},{"key":"B53","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1128\/IAI.68.2.594-602.2000","article-title":"Expression of chemokine genes in murine macrophages infected with","volume":"68","author":"Cho","year":"2000","journal-title":"Orientia Tsutsugamushi. Infect Immun"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009782","article-title":"Orientia tsutsugamushi selectively stimulates the c-type lectin receptor mincle and type 1-skewed proinflammatory immune responses","volume":"17","author":"Fisher","year":"2021","journal-title":"PloS Pathog"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008674","article-title":"The role of dermis resident macrophages and their interaction with neutrophils in the early establishment of leishmania major infection transmitted by sand fly bite","volume":"16","author":"Chaves","year":"2020","journal-title":"PloS Pathog"},{"key":"B56","doi-asserted-by":"publisher","first-page":"399","DOI":"10.4236\/ojas.2021.113029","article-title":"The role of neutrophils in the interaction with leishmania: Far beyond a simple Trojan horse","volume":"11","author":"Carreira","year":"2021","journal-title":"Open J Anim Sci"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1A0314-170R","article-title":"The chemotaxis of M1 and M2 macrophages is regulated by different chemokines","volume":"97","author":"Xuan","year":"2015","journal-title":"J Leukoc Biol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001028","article-title":"Orientia tsutsugamushi stimulates an original gene expression program in monocytes: Relationship with gene expression in patients with scrub typhus","volume":"5","author":"Tantibhedhyangkul","year":"2011","journal-title":"PloS Negl Trop Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1061031\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T04:53:23Z","timestamp":1671684803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1061031\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,22]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2022.1061031"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1061031","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,22]]},"article-number":"1061031"}}