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

PLoS Negl Trop Dis. 2019 Jun 19;13(6):e0007500. doi: 10.1371/journal.pntd.0007500. eCollection 2019 Jun.

Abstract

Background: 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.

Methodology/principal findings: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bunyaviridae Infections / complications*
  • Cells, Cultured
  • Coinfection / immunology*
  • Disease Models, Animal
  • Disease Susceptibility*
  • Interferon-beta / metabolism*
  • Interleukin-10 / metabolism*
  • Leishmania / immunology
  • Leishmaniasis / immunology*
  • Mice, Inbred C57BL
  • Models, Theoretical
  • Phlebovirus / immunology
  • eIF-2 Kinase / metabolism*

Substances

  • IL10 protein, mouse
  • Interleukin-10
  • Interferon-beta
  • eIF-2 Kinase
  • protein kinase R, mouse

Grant support

UGL- National Council for Scientific and Technological Development (CNPq)- 400063/2017-4. Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro. CNE-09/2016 NF- National Council for Scientific and Technological Development. IZRJZ3_164176/1 and FNS grant No 310030_173180 The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.