{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:55:50Z","timestamp":1790502950754,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009638","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T00:00:00Z","timestamp":1628121600000}}],"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"canadian institutes of health research","doi-asserted-by":"publisher","award":["PJT-159765"],"award-info":[{"award-number":["PJT-159765"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2018-03849"],"award-info":[{"award-number":["RGPIN-2018-03849"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The leishmaniases are a group of sandfly-transmitted diseases caused by species of the protozoan parasite, <jats:italic>Leishmania<\/jats:italic>. With an annual incidence of 1 million cases, 1 billion people living in <jats:italic>Leishmania<\/jats:italic>-endemic regions, and nearly 30,000 deaths each year, leishmaniasis is a major global public health concern. While phlebotomine sandflies are well-known as vectors of <jats:italic>Leishmania<\/jats:italic>, they are also the vectors of various phleboviruses, including Sandfly Fever Sicilian Virus (SFSV).<\/jats:p>\n<jats:p>Cutaneous leishmaniasis (CL), caused by <jats:italic>Leishmania major<\/jats:italic> (<jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic>), among other species, results in development of skin lesions on the infected host. Importantly, there exists much variation in the clinical manifestation between individuals. We propose that phleboviruses, vectored by and found in the same sandfly guts as <jats:italic>Leishmania<\/jats:italic>, may be a factor in determining CL severity. It was reported by our group that <jats:italic>Leishmania<\/jats:italic> exosomes are released into the gut of the sandfly vector and co-inoculated during blood meals, where they exacerbate CL skin lesions. We hypothesized that, when taking a blood meal, the sandfly vector infects the host with <jats:italic>Leishmania<\/jats:italic> parasites and exosomes as well as phleboviruses, and that this viral co-infection results in a modulation of leishmaniasis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/Principal findings<\/jats:title>\n<jats:p><jats:italic>In vitro<\/jats:italic>, we observed modulation by SFSV in MAP kinase signaling as well as in the IRF3 pathway that resulted in a pro-inflammatory phenotype. Additionally, we found that SFSV and <jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic> co-infection resulted in an exacerbation of leishmaniasis <jats:italic>in vivo<\/jats:italic>, and by using endosomal (Toll-like receptor) TLR3, and MAVS knock-out mice, deduced that SFSV\u2019s hyperinflammatory effect was TLR3- and MAVS-dependent. Critically, we observed that <jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic> and SFSV co-infected C57BL\/6 mice demonstrated significantly higher parasite burden than mice solely infected with <jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic>. Furthermore, viral presence increased leukocyte influx <jats:italic>in vivo<\/jats:italic>. This influx was accompanied by elevated total extracellular vesicle numbers. Interestingly, <jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic> displayed higher infectiveness with coincident phleboviral infection compared to <jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic> infection alone.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusion\/Significance<\/jats:title>\n<jats:p>Overall our work represents novel findings that contribute towards understanding the causal mechanisms governing cutaneous leishmaniasis pathology. Better comprehension of the potential role of viral co-infection could lead to treatment regimens with enhanced effectiveness.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0009638","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T17:35:36Z","timestamp":1627320936000},"page":"e0009638","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7645-0102","authenticated-orcid":true,"given":"Ellen","family":"Heirwegh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9272-0985","authenticated-orcid":true,"given":"Emily","family":"MacLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlei","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4304-636X","authenticated-orcid":true,"given":"Shaden","family":"Kamhawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8484-3632","authenticated-orcid":true,"given":"Selena M.","family":"Sagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3901-6638","authenticated-orcid":true,"given":"Martin","family":"Olivier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,7,26]]},"reference":[{"issue":"5","key":"pntd.0009638.ref001","doi-asserted-by":"crossref","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence.","volume":"7","author":"J Alvar","year":"2012","journal-title":"PLoS One"},{"key":"pntd.0009638.ref002","unstructured":"WHO. 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