MyD88 and TLR9 dependent immune responses mediate resistance to Leishmania guyanensis infections, irrespective of Leishmania RNA virus burden

Annette Ives; Slavica Masina; Patrik Castiglioni; Florence Prével; Mélanie Revaz-Breton; Mary-Anne Hartley; Pascal Launois; Nicolas Fasel; Catherine Ronet

doi:10.1371/journal.pone.0096766

MyD88 and TLR9 dependent immune responses mediate resistance to Leishmania guyanensis infections, irrespective of Leishmania RNA virus burden

PLoS One. 2014 May 6;9(5):e96766. doi: 10.1371/journal.pone.0096766. eCollection 2014.

Authors

Annette Ives¹, Slavica Masina¹, Patrik Castiglioni¹, Florence Prével¹, Mélanie Revaz-Breton², Mary-Anne Hartley¹, Pascal Launois², Nicolas Fasel¹, Catherine Ronet³

Affiliations

¹ Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
² Department of Biochemistry, World Health Organization Immunology Research and Training center (WHO-IRTC), Epalinges, Switzerland.
³ Department of Biochemistry, University of Lausanne, Epalinges, Switzerland; Department of Biochemistry, World Health Organization Immunology Research and Training center (WHO-IRTC), Epalinges, Switzerland.

Abstract

Infections with Leishmania parasites of the Leishmania Viannia subgenus give rise to both localized cutaneous (CL), and metastatic leishmaniasis. Metastasizing disease forms including disseminated (DCL) and mutocutaneous (MCL) leishmaniasis result from parasitic dissemination and lesion formation at sites distal to infection and have increased inflammatory responses. The presence of Leishmania RNA virus (LRV) in L. guyanensis parasites contributes to the exacerbation of disease and impacts inflammatory responses via activation of TLR3 by the viral dsRNA. In this study we investigated other innate immune response adaptor protein modulators and demonstrated that both MyD88 and TLR9 played a crucial role in the development of Th1-dependent healing responses against L. guyanensis parasites regardless of their LRV status. The absence of MyD88- or TLR9-dependent signaling pathways resulted in increased Th2 associated cytokines (IL-4 and IL-13), which was correlated with low transcript levels of IL-12p40. The reliance of IL-12 was further confirmed in IL12AB-/- mice, which were completely susceptible to infection. Protection to L. guyanensis infection driven by MyD88- and TLR9-dependent immune responses arises independently to those induced due to high LRV burden within the parasites.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Susceptibility
Immunity, Innate*
Interleukin-12 Subunit p35 / deficiency
Interleukin-12 Subunit p35 / genetics
Interleukin-12 Subunit p35 / metabolism
Interleukin-12 Subunit p40 / deficiency
Interleukin-12 Subunit p40 / genetics
Interleukin-12 Subunit p40 / metabolism
Interleukin-13 / metabolism
Interleukin-4 / metabolism
Leishmania guyanensis / physiology
Leishmania guyanensis / virology*
Leishmaniasis, Mucocutaneous / immunology
Leishmaniasis, Mucocutaneous / pathology
Leishmaniasis, Mucocutaneous / veterinary
Lymph Nodes / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88 / deficiency
Myeloid Differentiation Factor 88 / genetics
Myeloid Differentiation Factor 88 / metabolism*
RNA Viruses / physiology*
Signal Transduction
Th1 Cells / immunology
Th1 Cells / metabolism
Th2 Cells / immunology
Th2 Cells / metabolism
Toll-Like Receptor 9 / deficiency
Toll-Like Receptor 9 / genetics
Toll-Like Receptor 9 / metabolism*

Substances

Interleukin-12 Subunit p35
Interleukin-12 Subunit p40
Interleukin-13
Myeloid Differentiation Factor 88
Toll-Like Receptor 9
Interleukin-4

Grants and funding

This work was funded by the grants FNRS N° 3100A0-116665/1 (NF), IZ70Z0-131421 (NF) and the association Institute for Arthritis Research (NF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.