Abstract
BackgroundLeishmania 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.Methodology/Principal findingsWe 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.ConclusionsAltogether, 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.
Highlights
The World Health Organization acknowledges that leishmaniasis is prevalent in 98 countries and estimates the occurrence of one million new cases of cutaneous leishmaniasis (CL) annually [1]
Using a phlebovirus isolated from L. amazonensis rodents reservoirs (Icoaraci), we demonstrated that Icoaraci coinfection enhanced the parasite load, both in vivo and in vitro
Leishmania (L.) amazonensis is endemic in Brazil and is the causative agent of local CL and anergic diffuse cutaneous leishmaniasis (ADCL), a more severe form of the disease
Summary
The World Health Organization acknowledges that leishmaniasis is prevalent in 98 countries and estimates the occurrence of one million new cases of cutaneous leishmaniasis (CL) annually [1]. Leishmania (L.) amazonensis is endemic in Brazil and is the causative agent of local CL and anergic diffuse cutaneous leishmaniasis (ADCL), a more severe form of the disease. According to the current model, LRV-mediated development of exacerbated lesions in vertebrates resulted from aggravation of the inflammatory response by activation of Phlebovirus enhances Leishmania infection the endosomal double-stranded RNA sensor Toll-like receptor 3 (TLR3) and production of type I interferon and other cytokines [6]. 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
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