Macrophage responses to CF pathogens: JNK MAP kinase signaling by Burkholderia cepacia complex lipopolysaccharide

Abstract

Chronic bacterial colonization of the airways with opportunistic pathogens is the primary cause of morbidity and mortality in cystic fibrosis (CF) patients. Burkholderia cepacia complex (Bcc) organisms pose a particular challenge in CF lung disease, due in part to their ability to trigger a fulminant pneumonia. This study compares the U937 macrophage response to two Bcc species, B. cenocepacia and Burkholderia multivorans, against Pseudomonas aeruginosa and Staphylococcus aureus. The two Bcc strains demonstrated higher levels of U937 macrophage internalization compared with both P. aeruginosa and S. aureus. Both the Bcc strains also stimulated significantly greater levels of tumor necrosis factor-α and interleukin-1β from macrophages when compared with P. aeruginosa. Further examination of the macrophage response to B. multivorans demonstrated that the lipopolysaccharide component of these bacteria was a potent inducer of proinflammatory cytokines and was shown to signal predominantly through the c-Jun N-terminal kinase mitogen-activated protein kinase pathway. These studies further characterize the host response to Bcc and in particular B. multivorans, now the predominant Bcc species in many CF populations.

IFN-γ Stimulates Autophagy-Mediated Clearance of Burkholderia cenocepacia in Human Cystic Fibrosis Macrophages

“…CF macrophages excessively produce the pro-inflammatory cytokine IL-1β in response to B. cenocepacia infection [19], [50]. Human bronchial epithelial cells do not produce IL-1β in response to B. cenocepacia [51].…”

Exaggerated inflammatory responses mediated by Burkholderia cenocepacia in human macrophages derived from Cystic fibrosis patients

“…Previous studies have shown normal IL-1β levels in young CF patients not infected with B. cenocepacia [14,25], elevated levels in adult CF alveolar macrophages not infected with B. cenocepacia [26], and increased IL-1β in non CF macrophages in response to B. cenocepacia [15]. Therefore, it is not clear if IL-1B is specifically increased in CF macrophages upon B. cenocepacia infection.…”

“…Longitudinal studies have shown very little change in IL-1β production over the first years of life [14], whereas others have shown increased IL-1β within subsets of CF patients infected with viruses or various bacterial pathogens [3]. In addition, non CF human macrophages have demonstrated increased IL-1β in response to B. cenocepacia [15], but it is unclear how this response compares to CF macrophages and the overall impact on inflammation in CF. In this study, using the virulent B. cenocepacia J2315 strain, we found increased levels of IL-1β, IL-10, MCP-1, and IFN-γ in infected human CF macrophages, along with increases in cell death and bacterial survival compared to non CF macrophages…”

Comparative Genomics of Environmental and Clinical Burkholderia cenocepacia Strains Closely Related to the Highly Transmissible Epidemic ET12 Lineage

“…Briefly, expression of the cable pilus ( cblA ), as well as a 22 kDa adhesion, are required for the initial adhesion of the bacteria to the surface of lung epithelial cells ( McClean and Callaghan, 2009 ). Moreover, a functional flagella and lipase are necessary for cell invasion ( Tomich et al, 2002 ; Mullen et al, 2007 ), and several other virulence factors enhance the B. cenocepacia pathogenicity, like LPS, metalloprotease, siderophores or secretion systems ( Leitao et al, 2010 ; McKeon et al, 2010 ). Cell-cell communication by quorum sensing (QS), have been described in B. cenocepacia to coordinate expression of these different virulence factors, most of them being necessary for the virulence and also for the normal physiology of B. cenocepacia ( Leitao et al, 2010 ).…”