Pseudomonas aeruginosaAlginate PromotesBurkholderia cenocepaciaPersistence in Cystic Fibrosis Transmembrane Conductance Regulator Knockout Mice

Abstract

Pseudomonas aeruginosa, a major respiratory pathogen in cystic fibrosis (CF) patients, facilitates infection by other opportunistic pathogens. Burkholderia cenocepacia, which normally infects adolescent patients, encounters alginate elaborated by mucoid P. aeruginosa. To determine whether P. aeruginosa alginate facilitates B. cenocepacia infection in mice, cystic fibrosis transmembrane conductance regulator knockout mice were infected with B. cenocepacia strain BC7 suspended in either phosphate-buffered saline (BC7/PBS) or P. aeruginosa alginate (BC7/alginate), and the pulmonary bacterial load and inflammation were monitored. Mice infected with BC7/PBS cleared all of the bacteria within 3 days, and inflammation was resolved by day 5. In contrast, mice infected with BC7/alginate showed persistence of bacteria and increased cytokine levels for up to 7 days. Histological examination of the lungs indicated that there was moderate to severe inflammation and pneumonic consolidation in isolated areas at 5 and 7 days postinfection in the BC7/alginate group. Further, alginate decreased phagocytosis of B. cenocepacia by professional phagocytes both in vivo and in vitro. P. aeruginosa alginate also reduced the proinflammatory responses of CF airway epithelial cells and alveolar macrophages to B. cenocepacia infection. The observed effects are specific to P. aeruginosa alginate, because enzymatically degraded alginate or other polyuronic acids did not facilitate bacterial persistence. These observations suggest that P. aeruginosa alginate may facilitate B. cenocepacia infection by interfering with host innate defense mechanisms.Respiratory failure due to lung infection is the major cause of mortality in cystic fibrosis (CF) patients. CF airways are colonized by more than one opportunistic bacterial pathogen, and Pseudomonas aeruginosa is a major pathogen. The other opportunistic bacterial pathogens that are frequently isolated from CF airways include Haemophilus influenzae, Staphylococcus aureus, the Burkholderia cepacia complex (BCC), Stenotrophomonas maltophilia, and methicillin-resistant S. aureus (7). Most individuals with CF experience a characteristic agerelated pattern of pulmonary colonization and intermittent exacerbations involving H. influenzae and S. aureus, followed by P. aeruginosa (4, 5). Similarly, accumulating evidence suggests that P. aeruginosa can promote colonization by less commonly observed bacteria, such as S. maltophilia, Achromobacter xylosoxidans, and Mycobacterium abscessus (43). P. aeruginosa has also been implicated in promoting BCC pathogenesis by increasing the adherence of BCC to respiratory epithelial cells and upregulating the expression of BCC virulence factors (17,31,32).Chronic P. aeruginosa infections are often associated with a mucoid phenotype due to the production of large quantities of the acidic exopolysaccharide alginate (5). Alginate is an important extracellular virulence factor and has been shown to impair host innate defenses related to phagocytes (1,13,15,18,26,30). In CF ai...

Cystic Fibrosis

“…However, it is likely that CFTR dysfunction predisposes the host to infection with P. aeruginosa ; subsequent adaptation by the bacteria then allows for chronic infection and reduced opportunity for eradication. It is also likely that P. aeruginosa interacts with other bacterial pathogens including Staphylococcus aureus and Burkholderia cepacia complex in a way to further alter the inflammatory response 25,82 .…”

Insights into Cystic Fibrosis Polymicrobial Consortia: The Role of Species Interactions in Biofilm Development, Phenotype, and Response to In-Use Antibiotics

“…Nonetheless, the precise ways under which the many different organisms interact within the CF airways, and how these interactions influence the behavior of the individual species, the activity of the polymicrobial communities, and the relationship between host and microbes are poorly understood. Some studies have highlighted the potentially important roles of such interspecies interactions in disease phenotype and clinical outcome of CF infections (Amin et al, 2010; Chattoraj et al, 2010; Bragonzi et al, 2012; Lopes et al, 2012; Twomey et al, 2012). …”

Outcome and Prevention of Pseudomonas aeruginosa-Staphylococcus aureus Interactions During Pulmonary Infections in Cystic Fibrosis

“…Accordingly, and as previously underlined, infections of the CF airways is highly polymicrobic and there is growing evidence that many of these microorganisms interact (Sibley & Surette, 2011) as observed between P. aeruginosa and S. aureus (Biswas et al, 2009;Hoffman et al, 2006;Mitchell et al, 2010b;Qazi et al, 2006;Yang et al, 2011), P. aeruginosa and Burkholderia spp. (Bakkal et al, 2010;Chattoraj et al, 2010;Riedel et al, 2001;Weaver & Kolter, 2004), P. aeruginosa and S. maltophilia , P. aeruginosa and C. albicans (McAlester et al, 2008), and more generally with a large proportion of the organisms found in the CF airways (Duan et al, 2003;Sibley et al, 2008).…”