Abstracts (complete list) - Wissenschaft Online

Jan Liese, Ulrike Schleicher, Christian Bogdan
The role of TLR9 signalling in murine cutaneous leishmaniasis
In most strains of mice subcutaneous infections with Leishmania (L.) major lead to selfhealing
skin lesions. A prominent CD4+ T-helper cell (Th)-based interferon (IFN)gamma
response is associated with the ultimate resolution of the disease. The innate
immune respose against the pathogen is characterised by the expression of inducible
nitric oxide synthase (iNOS) and by the rapid induction of NK cell cytotoxicity and IFNgamma
production in the draining lymph node (LN). Mice deficient for the adaptor
molecule MyD88 are unable to control Leishmania parasites in vivo, indicating the
requirement of Toll-like receptor signalling for a protective immune reponse. TLR9,
which uses MyD88 for signalling, is located in the endosome, where it might interact
with intracellular L. major. Therefore, we investigated the immune response against
Leishmania in TLR9 deficient (TLR9-/-) C57BL/6 mice.
In the LN of L. major-infected TLR9-/- mice NK cell IFN-gamma expression and
cytotoxicity were strongly reduced as compared to wild type controls. In vitro, L. major
promastigotes as well as L. major DNA induced interleukin (IL)-12 in bone-marrow
derived myeloid dendritic cells (DCs) in a TLR9-dependent manner. IL-12p35-/- mice
were deficient for NK cell activation after L. major infection, suggesting that L. major
induces IL-12 via TLR9 in DCs which in turn triggers early NK cell activity in the LN.
TLR9-/- mice exhibited more severe dermal lesions during the acute phase of the
infection compared to wild type mice, but ultimately controlled the infection. TLR9-/-
and wild type mice showed no difference of the mRNA levels of IFN-gamma, IL-12p35,
IL-12p40 or iNOS in the skin or LN. However, TLR9-/- mice transiently expressed higher
levels of IL-4, IL-13, and arginase 1 mRNA, indicating an enhanced Th2 cytokine
production.
Thus, TLR9-/- mice have a deficient innate immune response to L. major, which is
associated with an aggravated clinical course of infection, but does not influence the
ultimate outcome of infection.