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- Title
TLR9 Activation Is Triggered by the Excess of Stimulatory versus Inhibitory Motifs Present in Trypanosomatidae DNA.
- Authors
Khan, Mélissa Erin; Borde, Chloé; Rocha, Eduardo P.C.; Mériaux, Véronique; Maréchal, Vincent; Escoll, Pedro; Goyard, Sophie; Cavaillon, Jean-Marc; Manoury, Bénédicte; Doyen, Noëlle
- Abstract
DNA sequences purified from distinct organisms, e.g. non vertebrate versus vertebrate ones, were shown to differ in their TLR9 signalling properties especially when either mouse bone marrow-derived- or human dendritic cells (DCs) are probed as target cells. Here we found that the DC-targeting immunostimulatory property of Leishmania major DNA is shared by other Trypanosomatidae DNA, suggesting that this is a general trait of these eukaryotic single-celled parasites. We first documented, in vitro, that the low level of immunostimulatory activity by vertebrate DNA is not due to its limited access to DCs' TLR9. In addition, vertebrate DNA inhibits the activation induced by the parasite DNA. This inhibition could result from the presence of competing elements for TLR9 activation and suggests that DNA from different species can be discriminated by mouse and human DCs. Second, using computational analysis of genomic DNA sequences, it was possible to detect the presence of over-represented inhibitory and under-represented stimulatory sequences in the vertebrate genomes, whereas L. major genome displays the opposite trend. Interestingly, this contrasting features between L. major and vertebrate genomes in the frequency of these motifs are shared by other Trypanosomatidae genomes (Trypanosoma cruzi, brucei and vivax). We also addressed the possibility that proteins expressed in DCs could interact with DNA and promote TLR9 activation. We found that TLR9 is specifically activated with L. major HMGB1-bound DNA and that HMGB1 preferentially binds to L. major compared to mouse DNA. Our results highlight that both DNA sequence and vertebrate DNA-binding proteins, such as the mouse HMGB1, allow the TLR9-signaling to be initiated and achieved by Trypanosomatidae DNA. Author Summary: Distinct laboratory mouse based models have allowed elucidating some of the processes that account for so called resistance or vulnerability to the Leishmania major parasite cutaneous inoculation. The outcome ranges from rapid healing – C57BL/6 mice- to progressive nonhealing ones – BALB/c mice. Distinct cell lineages contribute to sense and process molecules derived from the L. major parasite. Previous studies revealed a role for intracellular Toll-like receptor 9 (TLR9) in host resistance to Leishmania major. L. major DNA is involved in innate immune response, since it induces TLR9 signaling and activation of dendritic cells. We were interested to further explore L. major DNA sequences focusing on their features as (a) either direct TLR9 agonists or antagonists (b) as well as once partnering with endogenous DNA binding proteins. We more specifically used mouse dendritic cells as sensing cells of L. major DNA as well as DNA from other Trypanosomatidae in comparison with vertebrate DNA. Overall, the data underscore a counter-selection of TLR9 agonist motifs in vertebrate DNA which is not found in Trypanosomatidae DNAs and suggest how TLR9 could discriminate between pathogen and self DNAs, to maintain the cellular integrity.
- Subjects
TRYPANOSOMATIDAE; DNA-binding proteins; TRYPANOSOMA; DNA sequencing; NUCLEOTIDE sequence; DNA; TRYPANOSOMA cruzi
- Publication
PLoS Neglected Tropical Diseases, 2014, Vol 8, Issue 11, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0003308