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Leishmania parasites infect thousands of people worldwide and cause from single cutaneous self-healing lesions to massive mucosal destructive lesions. The transmission to vertebrates requires the bite of Phlebotomine sandflies, which can also transmit Phlebovirus. We have demonstrated that Leishmania infection requires and triggers the Endoplasmic stress (ER stress) response in infected macrophages. In the present paper, we tested the hypothesis that ER stress is increased and required for the aggravation of Leishmania infection due to coinfection with Phlebovirus. We demonstrated that Phlebovirus Icoaraci induces the ER stress program in macrophages mediated by the branches IRE\/XBP1 and PERK\/ATF4. The coinfection with L. amazonensis potentiates and sustains the ER stress, and the inhibition of IRE1\u03b1 or PERK results in poor viral replication and decreased parasite load in macrophages. Importantly, we observed an increase in viral replication during the coinfection with Leishmania. Our results demonstrated the role of ER stress branches IRE1\/XBP1 and PERK\/ATF4 in the synergic effect on the Leishmania increased load during Phlebovirus coinfection and suggests that Leishmania infection can also increase the replication of Phlebovirus in macrophages.<\/jats:p>","DOI":"10.3390\/v14091948","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T20:50:27Z","timestamp":1662670227000},"page":"1948","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Endoplasmic Stress Affects the Coinfection of Leishmania Amazonensis and the Phlebovirus (Bunyaviridae) Icoaraci"],"prefix":"10.3390","volume":"14","author":[{"given":"Jos\u00e9 V.","family":"dos Santos","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Parasitology, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia F.","family":"Freixo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1islan de C.","family":"Vivarini","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge M.","family":"Medina","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1187-557X","authenticated-orcid":false,"given":"Lucio A.","family":"Caldas","sequence":"additional","affiliation":[{"name":"Laboratory of Ultrastructure Hertha Meyer Cellular, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcia","family":"Attias","sequence":"additional","affiliation":[{"name":"Laboratory of Ultrastructure Hertha Meyer Cellular, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karina L. Dias","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Virginia, Pinn Hall, Charlottesville, VA 22908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa Cristina C.","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulisses G.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Parasitology, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00018-015-2052-6","article-title":"The endoplasmic reticulum: Structure, function and response to cellular signaling","volume":"73","author":"Schwarz","year":"2016","journal-title":"Cell. 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