Mammalian Innate Immune Response to a Leishmania-Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence.
Some strains of the protozoan parasite Leishmania guyanensis (L.g) harbor a viral endosymbiont called Leishmania RNA virus 1 (LRV1). LRV1 recognition by TLR-3 increases parasite burden and lesion swelling in vivo. However, the mechanisms by which anti-viral innate immune responses affect parasitic infection are largely unknown. Upon investigating the mammalian host's response to LRV1, we found that miR-155 was singularly and strongly upregulated in macrophages infected with LRV1+ L.g when compared to LRV1- L.g. LRV1-driven miR-155 expression was dependent on TLR-3/TRIF signaling. Furthermore, LRV1-induced TLR-3 activation promoted parasite persistence by enhancing macrophage survival through Akt activation in a manner partially dependent on miR-155. Pharmacological inhibition of Akt resulted in a decrease in LRV1-mediated macrophage survival and consequently decreased parasite persistence. Consistent with these data, miR-155-deficient mice showed a drastic decrease in LRV1-induced disease severity, and lesional macrophages from these mice displayed reduced levels of Akt phosphorylation.
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Remzi Onur
RO
Eren
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Marta
M
Reverte
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Matteo
M
Rossi
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Mary-Anne
MA
Hartley
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Patrik
P
Castiglioni
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Florence
F
Prevel
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Ricardo
R
Martin
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Chantal
C
Desponds
Department of Molecular Microbiology, School of Medicine, Washington University, St. Louis, MO 63110, USA.
Lon-Fye
LF
Lye
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Stefan K
SK
Drexler
Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
Walter
W
Reith
Department of Molecular Microbiology, School of Medicine, Washington University, St. Louis, MO 63110, USA.
Stephen M
SM
Beverley
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Catherine
C
Ronet
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland. Electronic address: nicolas.fasel@unil.ch.
Nicolas
N
Fasel
D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D007113:Immunity, Innate; D018334:Leishmania guyanensis / Q000472:pathogenicity / Q000502:physiology / Q000821:virology*; D007897:Leishmaniasis, Mucocutaneous / Q000469:parasitology / Q000473:pathology; D019199:Leishmaniavirus / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000469:parasitology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D051057:Proto-Oncogene Proteins c-akt
Akt; Leishmania; Leishmania RNA virus; TLR-3; macrophage survival; miR-155