Lack of MyD88 protects the immunodeficient host against fatal lung inflammation triggered by the opportunistic bacteria Burkholderia cenocepacia

Abstract

Introduction Burkholderia cenocepacia is an opportunistic pathogen of major concern for cystic fibrosis patients as well as immunocompromised cancer patients and transplant recipients. The mechanisms by which B cenocepacia triggers a rapid health deterioration of the susceptible host have yet to be characterized. Toll-like receptors (TLR) and their key signaling intermediate myeloid differentiation (MyD)88 play a central role in the detection of microbial molecular patterns and in the initiation of an effective immune response. Here, we designed an investigation to better understand the role of TLR-MyD88 signaling in B cenocepacia -induced pathogenesis in the immunocompromized host, using an experimental murine model. Methodology The time-course of several dynamic parameters, including animal survival, bacterial load and secretion of critical inflammatory mediators, was compared in infected and immunosuppressed wild-type and MyD88 -/- mice. Results When compared to wild-type mice, infected MyD88 -/- animals displayed significantly reduced levels of inflammatory mediators (including KC, TNFα, IL-6, MIP-2 and G-CSF) in blood and lung airspaces. Moreover, despite a higher transient bacterial load in the lungs, immunosuppressed mice deficient in MyD88 had an unexpected survival advantage. Finally, we showed that this B cenocepacia -induced life-threatening infection of wild-type mice could be prevented by corticosteroids. Conclusions Our findings demonstrate that a MyD88-dependent pathway can critically contribute to a detrimental host inflammatory response that leads to fatal pneumonia.