Kawasaki disease (KD) is the most common form of acquired heart disease in children, both the etiology and molecular mechanisms leading to the associated coronary arteritis remain unknown. Injection of a cell wall extract derived from Lactobacillus casei; LCCWE, into mice causes coronary arteritis that is histopathologically similar to the arteritis seen in KD, yet injection of a cell wall extract from a closely related strain Lactobacillus paracasei; LpCCWE, does not. The overall goal of this project is to define the molecular mechanisms by which LCCWE causes coronary arteritis, and to explain why LpCCWE does not. Our published data indicate that LCCWE potently induces NF-kB via TLR2 and MyD88 but not TLR4 in vitro (in murine and human macrophages and ECs) and in vivo (TLR2-/- and MyD88-/- mice do not develop coronary lesions). Our recent studies in humans and mice show marked accumulation of mature dendritic cells (DCs) in clinical KD lesions and in mouse arterial lesions after inoculation with LCCWE, suggesting that DCs play an important mechanistic role in coronary arteritis in both clinical KD and in the mouse model of LCCWE-induced arteritis. The hypotheses:(1) lipoteichoic acids and/or peptidoglycans specific to L. casei but not L. paracasei produce coronary arteritis but extracts from L. paracasei do not;(2) DCs are activated by these molecular components, and orchestrate immune response leading to coronary arteritis, and that DCs are essential in triggering this response. Thus, DCs may also play a similarly important function in clinical KD and could respond to DC-targeted therapies.
Specific Aims :(1) To define the bioactive component(s) of LCCWE that mediate inflammatory responses and coronary arteritis in this model, and to determine the molecular basis for the differences in response between L. casei and L. paracasei cell wall extracts;(2) To determine whether L. casei and/or L. paracasei cell wall extracts can induce DC activation in vitro using wild type, TLR2-/-, TLR4-/-, and MyD88-/- DCs and to explore the role of DCs in mediating coronary arteritis in vivo using a DC depletion mouse model. Significance: Improved understanding of the molecular mechanisms by which LCCWE leads to coronary arteritis and the role of the innate immune system and DCs in this mouse models may yield important insights into the pathogenesis of arterial inflammatory diseases, and suggest new targets for intervention and prevention of coronary artery pathology in KD. ? ? ? ?
