Leishmania guyanensis parasites block the activation of the inflammasome by inhibiting maturation of IL-1β

Authors:

Mary-Anne Hartley1,¶, Remzi O. Eren1,¶, Matteo Rossi1, Florence Prevel1, Patrik Castiglioni1, Nathalie Isorce1, Chantal Desponds1, Lon-Fye Lye2, Stephen M. Beverley2, Stefan K. Drexler1,&, Nicolas Fasel1,&

doi: 10.15698/mic2018.03.619
Volume 5, pp. 137 to 149, published 14/01/2018.

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Affiliations:

1 Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

2 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.

These authors equally contributed to this work.

& These authors also equally contributed to this work.

Keywords: 

Leishmania, Leishmania-virus, metastatic leishmaniasis, inflammasome, NOD-like receptors, RIG-like receptors, A20

Corresponding Author(s):

Nicolas Fasel, Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, Epalinges, Switzerland, CH-1066; Tel: 0041 21 692 5732; nicolas.fasel@unil.ch

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Mary-Anne Hartley, Remzi O. Eren, Matteo Rossi, Florence Prevel, Patrik Castiglioni, Nathalie Isorce, Chantal Desponds, Lon-Fye Lye, Stephen M. Beverley, Stefan K. Drexler, Nicolas Fasel (2018). Leishmania guyanensis parasites block the activation of the inflammasome by inhibiting maturation of IL-1β. Microbial Cell 5(3): 137-149. doi: 10.15698/mic2018.03.619

© 2018 Hartley et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

The various symptomatic outcomes of cutaneous leishmaniasis relates to the type and potency of its underlying inflammatory responses. Presence of the cytoplasmic Leishmania RNA virus-1 (LRV1) within Leishmania guyanensis, worsens lesional inflammation and parasite burden, as the viral dsRNA genome acts as a potent innate immunogen stimulating Toll-Like-Receptor-3 (TLR3). Here we investigated other innate pattern recognition receptors capable of reacting to dsRNA and potentially contributing to LRV1-mediated inflammatory pathology. We included the cytoplasmic dsRNA sensors, namely, the RIG-like receptors (RLRs) and the inflammasome-dependent and -independent Nod-like-receptors (NLRs). Our study found no role for RLRs or inflammasome-dependent NLRs in the pathology of L. guyanensis infection irrespective of its LRV1-status. Further, neither LRV1-bearing L. guyanensis (LgyLRV1+) nor LRV1-negative L. guyanensis (LgyLRV1-) activated the inflammasome in vitro. Interestingly, similarly to L. donovani, L. guyanensis infection induced the up-regulation of the A20 protein, known to be involved in the evasion of inflammasome activation. Moreover, we observed that LgyLRV1+ promoted the transcription of inflammasome-independent NLRC2 (also called NOD2) and NLRC5. However, only NLRC2 showed some contribution to LRV1-dependent pathology. These data confirmed that the endosomal TLR3 pathway is the dominant route of LRV1-dependent signalling, thus excluding the cytosolic and inflammasome pathways. We postulate that avoidance of the inflammasome pathways is likely an important mechanism of virulence in Leishmania infection irrespective of the LRV1-status.