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Macrophages (M\u03a6), the target cells of Leishmania parasites, are phagocytes that play a crucial role in the innate immune microbial defense and are antigen-presenting cells driving the activation of the acquired immune response. Exploring parasite\u2013host communication may be key in restraining parasite dissemination in the host. Extracellular vesicles (EVs) constitute a group of heterogenous cell-derived membranous structures, naturally produced by all cells and with immunomodulatory potential over target cells. This study examined the immunogenic potential of EVs shed by L. shawi and L. guyanensis in M\u03a6 activation by analyzing the dynamics of major histocompatibility complex (MHC), innate immune receptors, and cytokine generation. L. shawi and L. guyanensis EVs were incorporated by M\u03a6 and modulated innate immune receptors, indicating that EVs cargo can be recognized by M\u03a6 sensors. Moreover, EVs induced M\u03a6 to generate a mix of pro- and anti-inflammatory cytokines and favored the expression of MHCI molecules, suggesting that EVs antigens can be present to T cells, activating the acquired immune response of the host. Since nano-sized vesicles can be used as vehicles of immune mediators or immunomodulatory drugs, parasitic EVs can be exploited by bioengineering approaches for the development of efficient prophylactic or therapeutic tools for leishmaniasis.<\/jats:p>","DOI":"10.3390\/cells12081101","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T03:15:57Z","timestamp":1681096557000},"page":"1101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Insights on Host\u2013Parasite Immunomodulation Mediated by Extracellular Vesicles of Cutaneous Leishmania shawi and Leishmania guyanensis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6504-4384","authenticated-orcid":false,"given":"Juliana In\u00eas","family":"Weber","sequence":"first","affiliation":[{"name":"Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4261-3879","authenticated-orcid":false,"given":"Armanda Viana","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0273-4353","authenticated-orcid":false,"given":"Ana","family":"Val\u00e9rio-Bolas","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]},{"given":"Telmo","family":"Nunes","sequence":"additional","affiliation":[{"name":"Microscopy Center, Faculty of Sciences, University of Lisbon, Campo Grande, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6028-4717","authenticated-orcid":false,"given":"Manuela","family":"Carvalheiro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, iMed, Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"given":"Wilson","family":"Antunes","sequence":"additional","affiliation":[{"name":"Unidade Militar Laboratorial de Defesa Biol\u00f3gica e Qu\u00edmica (UMLDBQ), 1849-012 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9462-4679","authenticated-orcid":false,"given":"Gra\u00e7a","family":"Alexandre-Pires","sequence":"additional","affiliation":[{"name":"CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade T\u00e9cnica, 1300-477 Lisbon, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 2825-466 Set\u00fabal, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6632-1224","authenticated-orcid":false,"given":"Isabel Pereira","family":"da Fonseca","sequence":"additional","affiliation":[{"name":"CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade T\u00e9cnica, 1300-477 Lisbon, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 2825-466 Set\u00fabal, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9264-3887","authenticated-orcid":false,"given":"Gabriela","family":"Santos-Gomes","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.jinf.2014.07.016","article-title":"Leishmaniasis","volume":"69","author":"Pace","year":"2014","journal-title":"J. Infect."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Akuffo, H., Costa, C., van Griensven, J., Burza, S., Moreno, J., and Herrero, M. (2018). 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