Lack of MyD88 protects the immunodeficient host against fatal lung inflammation triggered by the opportunistic bacteria Burkholderia cenocepacia.
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.
Ventura
Grasiella M de C
GM
Institut Pasteur, Paris, France.
Balloy
Viviane
V
Ramphal
Reuben
R
Khun
Huot
H
Huerre
Michel
M
Ryffel
Bernhard
B
Plotkowski
Maria-Cristina M
MC
Chignard
Michel
M
Si-Tahar
Mustapha
M
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
D007166:Immunosuppressive Agents; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D014409:Tumor Necrosis Factor-alpha