Defect in early lung defence against Pseudomonas aeruginosa in DBA/2 mice is associated with acute inflammatory lung injury and reduced bactericidal activity in naïve macrophages

Wilson, Kari R.; Napper, Jennifer M.; Denvir, James; Sollars, Vincent E.; Yu, Hongwei D.

doi:10.1099/mic.0.2006/002261-0

Cited by 27 publications

(43 citation statements)

References 41 publications

(30 reference statements)

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“…Since DBA/2 mice are one of several C5-deficient inbred mouse strains (55), thus predicting a reduction in neutrophil recruitment to the lung tissues, the increased influx of inflammatory leukocytes we observed suggested that the loss of C5a may be compensated by the host by increasing the production of redundant/alternative neutrophil chemotactic factors.…”

Section: Discussionmentioning

confidence: 83%

“…Different techniques have been employed to introduce pathogens into the lung, such as intratracheal instillation (10), intranasal application (54), and application via aerosol (55,56). Intratracheal administration allows the colonization of the lung by a large fraction of the inoculum, with a potentially low level of extrapulmonary contamination.…”

Section: Discussionmentioning

confidence: 99%

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Role of Excessive Inflammatory Response to Stenotrophomonas maltophilia Lung Infection in DBA/2 Mice and Implications for Cystic Fibrosis

et al. 2010

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Stenotrophomonas maltophilia is a pathogen that causes infections mainly in immunocompromised patients. Despite increased S. maltophilia isolation from respiratory specimens of patients with cystic fibrosis (CF), the real contribution of the microorganism to CF pathogenesis still needs to be clarified. The aim of the present study was to evaluate the pathogenic role of S. maltophilia in CF patients by using a model of acute respiratory infection in DBA/2 mice following a single exposure to aerosolized bacteria. The pulmonary bacterial load was stable until day 3 and then decreased significantly from day 3 through day 14, when the bacterial load became undetectable in all infected mice. Infection disseminated in most mice, although at a very low level. Severe effects (swollen lungs, large atelectasis, pleural adhesion, and hemorrhages) of lung pathology were observed on days 3, 7, and 14. The clearance of S. maltophilia observed in DBA/2 mouse lungs was clearly associated with an early and intense bronchial and alveolar inflammatory response, which is mediated primarily by neutrophils. Significantly higher levels of interleukin-1␤ (IL-1␤), IL-6, IL-12, gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), GRO␣/KC, MCP-1/JE, MCP-5, macrophage inflammatory protein 1␣ (MIP-1␣), MIP-2, and TARC were observed in infected mice on day 1 with respect to controls. Excessive pulmonary infection and inflammation caused systemic effects, manifested by weight loss, and finally caused a high mortality rate. Taken together, our results show that S. maltophilia is not just a bystander in CF patients but has the potential to contribute to the inflammatory process that compromises respiratory function.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Role of Excessive Inflammatory Response to Stenotrophomonas maltophilia Lung Infection in DBA/2 Mice and Implications for Cystic Fibrosis

et al. 2010

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“…Following intratracheal infection, resistant mice showed a rapid influx of neutrophils (within 24 h) that was associated with clearance of bacteria. In contrast, Wilson et al (44) showed that, despite a similar neutrophil influx in both susceptible DBA/2 and resistant C57BL/6 mice during the initial phase of infection, only resistant mice cleared the bacteria, suggesting that there is a requirement for other host factors. Further, these authors showed that, although macrophages from susceptible mice are initially more phagocytic than C57BL/6 macrophages, they are defective for clearing or controlling bacterial colonization, indicating that rather than delaying the neutrophilic response, defective macrophages contribute to the susceptibility of DBA/2 mice to bacterial infection.…”

Section: Vol 78 2010mentioning

confidence: 90%

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

Chattoraj

Murthy²,

Ganesan³

et al. 2010

Infect Immun

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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...

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“…in S. aureus, the key factors are encoded by the Tnfaip8 and Seh1l loci (Ahn et al, 2010;Qiu et al, 2009), and in L. pneumophila, the critical marker is Naip5/Bircle (Zamboni et al, 2006). Third, the susceptibility of DBA/2 mice to the replication of some bacteria, including P. aeruginosa, is also not linked to the C5 deficiency (Wilson et al, 2007). Based upon our data, genetic crosses between the permissive and non-permissive mice can map and then help define host factors that govern susceptibility to S. maltophilia, with the potential for discovering new attributes of host susceptibility that have implications for explaining human cases of S. maltophilia disease.…”

Section: Resultsmentioning

confidence: 99%

Stenotrophomonas maltophilia strains replicate and persist in the murine lung, but to significantly different degrees

et al. 2011

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The environmental bacterium Stenotrophomonas maltophilia is increasingly described as a multidrug-resistant pathogen of humans, being associated with pneumonia, among other diseases. But the degree to which S. maltophilia is capable of replicating in a mammalian host has been an issue of controversy. Using a model of intranasal inoculation into adult A/J mice, we now document that S. maltophilia strain K279a, the clinical isolate of S. maltophilia whose complete genome sequence was recently determined, is in fact capable of replicating in lungs, displaying as much as a 10-fold increase in c.f.u. in the first 8 h of infection. Importantly, as few as 104 c.f.u. deposited into the A/J lung was sufficient to promote bacterial outgrowth. Bacterial replication in the lungs of the A/J mice was followed by elevations in pro-inflammatory cytokines and also promoted resistance to subsequent challenge. We also found that DBA/2 mice were permissive for S. maltophilia K279a replication, although the level of growth and persistence in these animals was less than it was in the A/J mice. In contrast, the BALB/c and C57BL/6 mouse strains were non-permissive for S. maltophilia K279a growth. Interestingly, when five additional clinical isolates were introduced into the A/J lung, marked differences in survival were observed, with some strains being much less infective than K279a and others being appreciably more infective. These data suggest that the presence of major virulence determinants is variable among clinical isolates. Overall, this study confirms the infectivity of S. maltophilia for the mammalian host, and illustrates how both host and bacterial factors affect the outcome of Stenotrophomonas infection.

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Defect in early lung defence against Pseudomonas aeruginosa in DBA/2 mice is associated with acute inflammatory lung injury and reduced bactericidal activity in naïve macrophages

Abstract: Defect in early lung defence against Pseudomonas aeruginosa in DBA/2 mice is associated with acute inflammatory lung injury and reduced bactericidal activity in naïve macrophages

Cited by 27 publications

References 41 publications

Role of Excessive Inflammatory Response to Stenotrophomonas maltophilia Lung Infection in DBA/2 Mice and Implications for Cystic Fibrosis

Role of Excessive Inflammatory Response to Stenotrophomonas maltophilia Lung Infection in DBA/2 Mice and Implications for Cystic Fibrosis

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

Stenotrophomonas maltophilia strains replicate and persist in the murine lung, but to significantly different degrees

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