Clinical Significance of Microbial Infection and Adaptation in Cystic Fibrosis

Hauser, Alan R.; Jain, Manu; Bar-Meir, Maskit; McColley, Susanna A.

doi:10.1128/cmr.00036-10

Cited by 362 publications

(427 citation statements)

References 672 publications

(731 reference statements)

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“…Antibiotic treatment regimes for exacerbations are determined based on these culture results plus antimicrobial susceptibility testing (Hauser et al, 2011). This treatment strategy is inherently biased towards aerobic microbes that grow on media selected by clinical microbiologists (Burns and Rolain, 2014).…”

Section: Introductionmentioning

confidence: 99%

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

et al. 2014

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There is a poor understanding of how the physiology of polymicrobial communities in cystic fibrosis (CF) lungs contributes to pulmonary exacerbations and lung function decline. In this study, a microbial culture system based on the principles of the Winogradsky column (WinCF system) was developed to study the physiology of CF microbes. The system used glass capillary tubes filled with artificial sputum medium to mimic a clogged airway bronchiole. Chemical indicators were added to observe microbial physiology within the tubes. Characterization of sputum samples from seven patients showed variation in pH, respiration, biofilm formation and gas production, indicating that the physiology of CF microbial communities varied among patients. Incubation of homogenized tissues from an explant CF lung mirrored responses of a Pseudomonas aeruginosa pure culture, supporting evidence that end-stage lungs are dominated by this pathogen. Longitudinal sputum samples taken through two exacerbation events in a single patient showed that a two-unit drop in pH and a 30% increase in gas production occurred in the tubes prior to exacerbation, which was reversed with antibiotic treatment. Microbial community profiles obtained through amplification and sequencing of the 16S rRNA gene showed that fermentative anaerobes became more abundant during exacerbation and were then reduced during treatment where P. aeruginosa became the dominant bacterium. Results from the WinCF experiments support the model where two functionally different CF microbial communities exist, the persistent Climax Community and the acute Attack Community. Fermentative anaerobes are hypothesized to be the core members of the Attack Community and production of acidic and gaseous products from fermentation may drive developing exacerbations. Treatment targeting the Attack Community may better resolve exacerbations and resulting lung damage.

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Section: Introductionmentioning

confidence: 99%

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

et al. 2014

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“…Bacterial airways infection varies significantly with the age of patients and Staphylococcus aureus (SA) is the most commonly isolated bacterium from young CF patients [10][11][12] . With the increase of age of patients, Pseudomonas aeruginosa (PA) becomes predominant and in the adult patients represents over 80% of bacteria in the lung 8,12,13 . However, the mechanisms responsible for this age-related infection switch from SA to PA remained unclear.…”

mentioning

confidence: 99%

“…The F508del-CFTR is the most frequent mutation in CFTR present in CF patients 5 . Pulmonary disease in CF is the major problem that determines the life span and life quality of patients 6 and contributes to 80-95% death of CF patients [7][8][9] . In the lungs, mutations of CFTR cause depletion of airway surface liquid and mucus dehydration, which provide an appropriate niche for chronic bacterial infection by opportunistic pathogens.…”

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confidence: 99%

Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity

et al. 2014

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Young cystic fibrosis (CF) patients' airways are mainly colonized by Staphylococcus aureus, while Pseudomonas aeruginosa predominates in adults. However, the mechanisms behind this infection switch are unclear. Here, we show that levels of type-IIA-secreted phospholipase A2 (sPLA2-IIA, a host enzyme with bactericidal activity) increase in expectorations of CF patients in an age-dependent manner. These levels are sufficient to kill S. aureus, with marginal effects on P. aeruginosa strains. P. aeruginosa laboratory strains and isolates from CF patients induce sPLA2-IIA expression in bronchial epithelial cells from CF patients (these cells are a major source of the enzyme). In an animal model of lung infection, P. aeruginosa induces sPLA2-IIA production that favours S. aureus killing. We suggest that sPLA2-IIA induction by P. aeruginosa contributes to S. aureus eradication in CF airways. Our results indicate that a bacterium can eradicate another bacterium by manipulating the host immunity.

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“…Most P. aeruginosa strains rely on a multitude of virulence factors to control host cellular pathways, including effectors delivered by the T3SS. However, in a cystic fibrosis context, colonizing strains modulate levels of expression of some of these virulence factors (Hauser et al , 2011), namely down‐regulation of the T3SS (Jain et al , 2004) and undergo a remarkable accumulation of pathoadaptive mutations (Marvig et al , 2014). The PA7‐related P. aeruginosa strains lack the 20‐Kb‐long genomic region encoding the T3SS core components and all genes encoding secreted effectors but contains several additional genomic islands and potential novel virulence factors (Pirnay et al , 2009; Roy et al , 2010; Cadoret et al , 2014; Freschi et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors

et al. 2017

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Bacterial pathogens often subvert the innate immune system to establish a successful infection. The direct inhibition of downstream components of innate immune pathways is particularly well documented but how bacteria interfere with receptor proximal events is far less well understood. Here, we describe a Toll/interleukin 1 receptor (TIR) domain‐containing protein (PumA) of the multi‐drug resistant Pseudomonas aeruginosa PA7 strain. We found that PumA is essential for virulence and inhibits NF‐κB, a property transferable to non‐PumA strain PA14, suggesting no additional factors are needed for PumA function. The TIR domain is able to interact with the Toll‐like receptor (TLR) adaptors TIRAP and MyD88, as well as the ubiquitin‐associated protein 1 (UBAP1), a component of the endosomal‐sorting complex required for transport I (ESCRT‐I). These interactions are not spatially exclusive as we show UBAP1 can associate with MyD88, enhancing its plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes both cytokine and TLR receptor signalling, highlighting a novel strategy for innate immune evasion.

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Clinical Significance of Microbial Infection and Adaptation in Cystic Fibrosis

Cited by 362 publications

References 672 publications

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity

A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors

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