title: Lack of MyD88 protects the immunodeficient host against fatal lung inflammation triggered by the opportunistic bacteria Burkholderia cenocepacia.
abstract: 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. TLR and their key signaling intermediate MyD88 play a central role in the detection of microbial molecular patterns and in the initiation of an effective immune response. We performed a study to better understand the role of TLR-MyD88 signaling in B. cenocepacia-induced pathogenesis in the immunocompromised host, using an experimental murine model. 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. Notably, when compared with wild-type mice, infected MyD88(-/-) animals displayed significantly reduced levels of inflammatory mediators (including KC, TNF-alpha, 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 involved the proinflammatory cytokine TNF-alpha and could be prevented by corticosteroids. Altogether, our findings demonstrate that a MyD88-dependent pathway can critically contribute to a detrimental host inflammatory response that leads to fatal pneumonia.
authors.affiliation: Institut Pasteur, Paris, France.
authors.forename: Grasiella M de C
authors.initials: GM
authors.lastname: Ventura
authors.forename: Viviane
authors.initials: V
authors.lastname: Balloy
authors.forename: Reuben
authors.initials: R
authors.lastname: Ramphal
authors.forename: Huot
authors.initials: H
authors.lastname: Khun
authors.forename: Michel
authors.initials: M
authors.lastname: Huerre
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Maria-Cristina M
authors.initials: MC
authors.lastname: Plotkowski
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
mesh_terms: D000818:Animals; D019121:Burkholderia Infections / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D016956:Burkholderia cepacia / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity; D016867:Immunocompromised Host / Q000235:genetics* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D009894:Opportunistic Infections / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D007166:Immunosuppressive Agents; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D014409:Tumor Necrosis Factor-alpha