{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T06:40:17Z","timestamp":1789800017827,"version":"4.0.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H02350"],"award-info":[{"award-number":["18H02350"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p><jats:italic>Vibrio vulnificus<\/jats:italic> is known to cause necrotizing soft tissue infections (NSTIs). However, the pathogenic mechanism causing cellulitis, necrotizing fasciitis, muscle necrosis, and rapidly developing septicemia in humans have not been fully elucidated. Here, we report a multilayer analysis of tissue damage after subcutaneous bacterial inoculation as a murine model of <jats:italic>V. vulnificus<\/jats:italic> NSTIs. Our histopathological examination showed the progression of cellulitis, necrotizing fasciitis, and muscle necrosis worsening as the infection penetrated deeper into the muscle tissue layers. The increase in vascular permeability was the primary cause of the swelling and congestion, which are acute signs of inflammation in soft tissue and characteristic of human NSTIs. Most importantly, our sequential analysis revealed for the first time that <jats:italic>V. vulnificus<\/jats:italic> not only spreads along the skin and subcutaneous tissues or fascia but also invades deeper muscle tissues beyond the fascia as the crucial process of its lethality. Also, increased vascular permeability enabled <jats:italic>V. vulnificus<\/jats:italic> to proliferate in muscle tissue and enter the systemic circulation, escalating the bacterium\u2019s lethality. Our finding may yield important clinical benefits to patients by helping physicians understand the impact of surgical debridement on the patient\u2019s quality of life. Furthermore, this study provides a promising system to accelerate studies of virulence factors and eventually help establish new therapies.<\/jats:p>","DOI":"10.3389\/fmicb.2022.849600","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T09:57:38Z","timestamp":1646733458000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Increased Vascular Permeability Due to Spread and Invasion of Vibrio vulnificus in the Wound Infection Exacerbates Potentially Fatal Necrotizing Disease"],"prefix":"10.3389","volume":"13","author":[{"given":"Kohei","family":"Yamazaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashige","family":"Kashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehiro","family":"Kado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Yoshioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/ni.2769","article-title":"Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection","volume":"15","author":"Abtin","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.chom.2014.12.001","article-title":"Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus","volume":"17","author":"Arezes","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1001\/archpedi.1982.03970430063018","article-title":"Group B Streptococcal Cellulitis-adenitis in infants","volume":"136","author":"Baker","year":"1982","journal-title":"Am. J. Dis. Child."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.idcr.2016.07.014","article-title":"Rapidly developing and fatal Vibrio vulnificus wound infection","volume":"6","author":"Baker-Austin","year":"2016","journal-title":"IDCases"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1111\/j.1758-2229.2009.00096.x","article-title":"Environmental occurrence and clinical impact of Vibrio vulnificus and Vibrio parahaemolyticus: a European perspective","volume":"2","author":"Baker-Austin","year":"2010","journal-title":"Environ. Microbiol. Rep."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/nclimate1628","article-title":"Emerging Vibrio risk at high latitudes in response to ocean warming","volume":"3","author":"Baker-Austin","year":"2013","journal-title":"Nat. Clim. Chang."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1086\/529148","article-title":"Nonfoodborne vibrio infections: an important cause of morbidity and mortality in the United States, 1997\u20132006","volume":"46","author":"Dechet","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref8","first-page":"654","article-title":"Fulminant wound infections due to Vibrio vulnificus","volume":"4","author":"Finkelstein","year":"2002","journal-title":"Isr. Med. Assoc. J."},{"key":"ref9","first-page":"118","article-title":"Molecular pathogenesis of Vibrio vulnificus","volume":"43","author":"Gulig","year":"2005","journal-title":"J. Microbiol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e241683","DOI":"10.1136\/bcr-2021-241683","article-title":"Group B streptococcus sepsis in an infant presented with cellulitis of soft tissue of neck","volume":"14","author":"Gulzar","year":"2021","journal-title":"BMJ Case Rep."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1067\/j.cpsurg.2014.06.001","article-title":"Necrotizing soft tissue infections: review and current concepts in treatment, systems of care, and outcomes","volume":"51","author":"Hakkarainen","year":"2014","journal-title":"Curr. Probl. Surg."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"122","DOI":"10.4236\/jdm.2012.21020","article-title":"Vibrio vulnificus septicemia and necrotizing fasciitis in the patients with liver cirrhosis and diabetes mellitus","volume":"2","author":"Ito","year":"2012","journal-title":"Int. J. Diabet. Mellit."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"5096","DOI":"10.1128\/IAI.68.9.5096-5106.2000","article-title":"Construction and phenotypic evaluation of a Vibrio vulnificus vvpE mutant for elastolytic protease","volume":"68","author":"Jeong","year":"2000","journal-title":"Infect. Immun."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e1002581","DOI":"10.1371\/journal.ppat.1002581","article-title":"Additive function of Vibrio vulnificus MARTXVv and VvhA cytolysins promotes rapid growth and epithelial tissue necrosis during intestinal infection","volume":"8","author":"Jeong","year":"2012","journal-title":"PLoS Pathog."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"4047","DOI":"10.4049\/jimmunol.0901541","article-title":"Neutrophil-derived hyperresistinemia in severe acute streptococcal infections","volume":"183","author":"Johansson","year":"2009","journal-title":"J. Immunol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"934","DOI":"10.3390\/microorganisms9050934","article-title":"MukB is a gene necessary for rapid proliferation of Vibrio vulnificus in the systemic circulation but not at the local infection site in the mouse wound infection model","volume":"9","author":"Kashimoto","year":"2021","journal-title":"Microorganisms"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1128\/IAI.00654-13","article-title":"Contribution of six flagellin genes to the flagellum biogenesis of Vibrio vulnificus and in vivo invasion","volume":"82","author":"Kim","year":"2014","journal-title":"Infect. Immun."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"318","DOI":"10.7326\/0003-4819-109-4-318","article-title":"Syndromes of Vibrio vulnificus infections: clinical and epidemiologic features in Florida cases, 1981-1987","volume":"109","author":"Klontz","year":"1988","journal-title":"Ann. Intern. Med."},{"key":"ref19","first-page":"305","article-title":"Septicaemia secondary to Vibrio vulnificus cellulitis","volume":"29","author":"Lewis","year":"2005","journal-title":"Commun. Dis. Intell. Q. Rep."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1866","DOI":"10.1093\/infdis\/jir070","article-title":"RTX toxin enhances the survival of Vibrio vulnificus during infection by protecting the organism from phagocytosis","volume":"203","author":"Lo","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1111\/j.1346-8138.2006.00139.x","article-title":"Vibrio vulnificus infection and metalloprotease","volume":"33","author":"Miyoshi","year":"2006","journal-title":"J. Dermatol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nature12655","article-title":"Staphylococcus \u03b4-toxin induces allergic skin disease by activating mast cells","volume":"503","author":"Nakamura","year":"2013","journal-title":"Nature"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"S391","DOI":"10.1093\/cid\/cis243","article-title":"Increasing rates of Vibriosis in the United States, 1996\u20132010: review of surveillance data from 2 systems","volume":"54","author":"Newton","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.VE-0001-2014","article-title":"The biology of Vibrio vulnificus","volume":"3","author":"Oliver","year":"2015","journal-title":"Microbiol. Spectr."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"2873","DOI":"10.1128\/iai.64.7.2873-2876.1996","article-title":"Pulmonary damage by Vibrio vulnificus cytolysin","volume":"64","author":"Park","year":"1996","journal-title":"Infect. Immun."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/nri3646","article-title":"Mechanisms regulating skin immunity and inflammation","volume":"14","author":"Pasparakis","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e50062","DOI":"10.3791\/50062","article-title":"An in vivo assay to test blood vessel permeability","volume":"16","author":"Radu","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/1749-7922-6-46","article-title":"Necrotizing fasciitis: literature review of contemporary strategies for diagnosing and management with three case reports: torso, abdominal wall, upper and lower limbs","volume":"6","author":"Roje","year":"2011","journal-title":"World J. Emerg. Surg."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.jamcollsurg.2008.10.032","article-title":"Necrotizing fasciitis: current concepts and review of the literature","volume":"208","author":"Sarani","year":"2009","journal-title":"J. Am. Coll. Surg."},{"key":"ref30","year":"2006"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"e87882","DOI":"10.1172\/jci.insight.87882","article-title":"Biofilm in group A streptococcal necrotizing soft tissue infections","volume":"1","author":"Siemens","year":"2016","journal-title":"JCI Insight."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/0002-9343(92)90583-W","article-title":"Cellulitis after axillary lymph node dissection for carcinoma of the breast","volume":"93","author":"Simon","year":"1992","journal-title":"Am. J. Med."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1128\/iai.55.1.269-272.1987","article-title":"Correlation between virulence and colony morphology in Vibrio vulnificus","volume":"55","author":"Simpson","year":"1987","journal-title":"Infect. Immun."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2253","DOI":"10.1056\/NEJMra1600673","article-title":"Necrotizing soft-tissue infections","volume":"377","author":"Stevens","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1056\/NEJMcp031807","article-title":"Cellulitis","volume":"350","author":"Swartz","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1128\/jcm.19.2.197-199.1984","article-title":"Wound infections caused by Vibrio vulnificus, a marine vibrio, in inland areas of the United States","volume":"19","author":"Tacket","year":"1984","journal-title":"J. Clin. Microbiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1080\/21505594.2020.1782707","article-title":"Chemotactic invasion in deep soft tissue by Vibrio vulnificus is essential for the progression of necrotic lesions","volume":"11","author":"Yamazaki","year":"2020","journal-title":"Virulence"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fmicb.2019.00123","article-title":"Identification of in vivo essential genes of Vibrio vulnificus for establishment of wound infection by signature-tagged mutagenesis","volume":"10","author":"Yamazaki","year":"2019","journal-title":"Front. Microbiol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.849600\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T09:57:43Z","timestamp":1646733463000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.849600\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,8]]},"references-count":38,"alternative-id":["10.3389\/fmicb.2022.849600"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.849600","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,8]]},"article-number":"849600"}}