Amazonian Phlebovirus (Bunyaviridae) potentiates the infection of Leishmania (Leishmania) amazonensis: Role of the PKR/IFN1/IL-10 axis

• Published in: PLoS neglected tropical diseases Vol. 13; no. 6; p. e0007500
• Main Authors: Rath, Carolina Torturella, Schnellrath, Laila Castro, Damaso, Clarissa R, de Arruda, Luciana Barros, Vasconcelos, Pedro Fernando da Costa, Gomes, Claudia, Laurenti, Marcia Dalastra, Calegari Silva, Teresa Cristina, Vivarini, Áislan de Carvalho, Fasel, Nicolas, Pereira, Renata Meirelles Santos, Lopes, Ulisses Gazos
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-06-2019; Public Library of Science (PLoS)
• Subjects: Activation; Animals; Antiviral agents; Biology and Life Sciences; Bunyaviridae; Bunyaviridae Infections - complications; Cells, Cultured; Coinfection - immunology; Dengue; Dengue fever; Disease Models, Animal; Disease Susceptibility; Double-stranded RNA; eIF-2 Kinase - metabolism; Human diseases; Infections; Interferon; Interferon-beta - metabolism; Interleukin 10; Interleukin-10 - metabolism; Kinases; Leishmania; Leishmania - immunology; Leishmaniasis - immunology; Macrophages; Medicine and Health Sciences; Mice, Inbred C57BL; Models, Theoretical; Modulators; Nucleic acids; Parasites; Parasitic diseases; Parasitism; Pathology; Phlebovirus - immunology; Protozoa; Receptors; RNA; RNA viruses; Rodents; Sensors; Subgroups; TLR3 protein; Toll-like receptors; Tropical diseases; Vector-borne diseases; Vectors; Vertebrates; Viral diseases; Viruses; Visceral leishmaniasis; β-Interferon; Brazil; Rio de Janeiro Brazil; Amazon Basin
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0007500

Leishmania parasites are transmitted to vertebrate hosts by phlebotomine sandflies and, in humans, may cause tegumentary or visceral leishmaniasis. The role of PKR (dsRNA activated kinase) and Toll-like receptor 3 (TLR3) activation in the control of Leishmania infection highlights the importance of the engagement of RNA sensors, which are usually involved in the antiviral cell response, in the fate of parasitism by Leishmania. We tested the hypothesis that Phlebovirus, a subgroup of the Bunyaviridae, transmitted by sandflies, would interfere with Leishmania infection.
We tested two Phlebovirus isolates, Icoaraci and Pacui, from the rodents Nectomys sp. and Oryzomys sp., respectively, both natural sylvatic reservoir of Leishmania (Leishmania) amazonensis from the Amazon region. Phlebovirus coinfection with L. (L.) amazonensis in murine macrophages led to increased intracellular growth of L. (L.) amazonensis. Further studies with Icoaraci coinfection revealed the requirement of the PKR/IFN1 axis on the exacerbation of the parasite infection. L. (L.) amazonensis and Phlebovirus coinfection potentiated PKR activation and synergistically induced the expression of IFNβ and IL-10. Importantly, in vivo coinfection of C57BL/6 mice corroborated the in vitro data. The exacerbation effect of RNA virus on parasite infection may be specific because coinfection with dengue virus (DENV2) exerted the opposite effect on parasite load.
Altogether, our data suggest that coinfections with specific RNA viruses shared by vectors or reservoirs of Leishmania may enhance and sustain the activation of host cellular RNA sensors, resulting in aggravation of the parasite infection. The present work highlights new perspectives for the investigation of antiviral pathways as important modulators of protozoan infections.