{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T10:30:31Z","timestamp":1784716231826,"version":"3.55.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T00:00:00Z","timestamp":1721001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-159765, ER1-143489, PJT-148821"],"award-info":[{"award-number":["PJT-159765, ER1-143489, PJT-148821"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Exosomes produced by the protozoan parasite <jats:italic>Leishmania<\/jats:italic> (LeishEXO) are well-established drivers of virulence, though mechanisms underlying their exacerbation of experimental leishmaniasis remain elusive. Expression of Annexin A1 (ANXA1), a protein implicated in exosome-mediated pathologies and viral internalization, has been shown to correlate with cutaneous leishmaniasis severity. Given ANXA1\u2019s regulation of myeloid cells \u2013 the canonical hosts for <jats:italic>Leishmania<\/jats:italic> \u2013 we studied the potential role of ANXA1 and its receptors FPR1\/2 in exerting LeishEXO\u2019s effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Murine and <jats:italic>in vitro<\/jats:italic> ANXA1<jats:sup>-\/-<\/jats:sup> models were used to study the generation of protective T<jats:sub>H<\/jats:sub>1 responses during experimental <jats:italic>L. major<\/jats:italic> infection with and without LeishEXO. Recruitment of inflammatory cells was assessed using a peritoneal cell recruitment assay and immunophenotyping, and production of inflammatory mediators was measured using a cytokine and chemokine array. Treatment of experimental models with FPR2 antagonist WRW4 and FPR1\/2 agonist WKYMVm was used to delineate the role of the FPR\/ANXA1 axis in LeishEXO-mediated hyperpathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We established that ANXA1 deficiency prohibits LeishEXO-mediated pathogenesis and myeloid cell infection, with minimal alterations to adaptive and innate immune phenotypes. FPR2 blockade with WRW4 similarly inhibited leishmanial hyperpathogenesis, while direct activation of FPRs with WKYMVm enhanced infection and recapitulated the LeishEXO-mediated phenotype. This research describes LeishEXO\u2019s utilization of the ANXA1\/FPR axis to facilitate parasitic internalization and pathogenesis, which may be leveraged in the development of therapeutics for leishmaniasis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1436151","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T04:53:56Z","timestamp":1721019236000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Implication of the Annexin 1\/FPR axis in leishmanial exosome-mediated Leishmania major skin hyperpathogenesis"],"prefix":"10.3389","volume":"15","author":[{"given":"Alonso","family":"da Silva Lira Filho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Lafleur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciriaco A.","family":"Piccirillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Olivier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,15]]},"reference":[{"key":"B1","volume-title":"Leishmaniasis","year":"2023"},{"key":"B2","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":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018724","article-title":"Temperature-induced protein secretion by leishmania mexicana modulates macrophage signalling and function","volume":"6","author":"Hassani","year":"2011","journal-title":"PloS One"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2012.05.014","article-title":"Leishmania virulence factors: focus on the metalloprotease GP63","volume":"14","author":"Olivier","year":"2012","journal-title":"Microbes Infect"},{"key":"B5","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1194\/jlr.R084343","article-title":"Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology","volume":"60","author":"Skotland","year":"2019","journal-title":"J Lipid Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.7150\/thno.19890","article-title":"Metabolomic profiling of extracellular vesicles and alternative normalization methods reveal enriched metabolites and strategies to study prostate cancer-related changes. 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