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British Medical Bulletin 61:81-96 (2002)
© 2002 Oxford University Press

Persistent and aggressive bacteria in the lungs of cystic fibrosis children

C Anthony Hart and Craig Winstanley

Department of Medical Microbiology and Genitourinary Medicine, University of Liverpool, Liverpool, UK


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Pseudomonas aeruginosa
 Burkholderia
 References
 
There have been enormous improvements in life expectancy of patients with cystic fibrosis, especially with improved nutrition and better understanding of the basic cellular defects. However, infection in particular with Pseudomonas aeruginosa and Burkholderia cepacia, has the greatest effect in decreasing life expectancy. Although infections can be prevented by rigorous infection control procedures, early aggressive antimicrobial chemotherapy and established infection managed by antibiotics, they are not completely effective. A greater understanding of how the bacteria evade the host defences and produce infection is needed.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Pseudomonas aeruginosa
 Burkholderia
 References
 
Cystic fibrosis (CF) is an autosomal recessive disorder resulting from mutations in a gene on the long arm of chromosome 71Go. The gene product is the cystic fibrosis transmembrane conductance regulator (CFTR) which regulates and facilitates transport of electrolytes across epithelial cell and other membranes. The mutations, (over 1000 described so far), can be by frameshift, deletion or by base substitution leading to amino acid substitution, however 60% of CF patients have {Delta}F508 (a three base [codon] deletion at phenylalanine 508). Although the mutations give abnormal electrolyte transport, how this explains the complete pathophysiology, especially in the lung, is unclear (Table 1). What is clear, however, is the mucus in the CF airways is highly viscid, sulphated and readily forms aggregates2Go.


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  		Table 1. Some factors promoting bacterial persistence and damage in the CF lung

 
In the normal lung, the mucus layer acts to trap inhaled particles such as bacteria and is propelled upwards towards the pharynx by cilia (the mucociliary escalator), and then expectorated or swallowed. This defence mechanism is so potent that, despite heavy bacterial colonization of the upper airways (above the vocal cords), the lower airway is normally sterile. In the CF lung, the viscid mucous cannot be propelled so easily and the escalator fails, leading to an accumulation of mucus and trapped bacteria3Go. In addition, it has recently been shown that while extracellular fluid from cultured normal airways epithelia can kill bacteria, that from CF airways epithelia cannot4Go. A number of antimicrobial substances are excreted into the airways. These include lysozyme (which hydrolyses the peptidoglycan backbone of the bacterial cell wall), lactoferrin (which is an iron chelator), phospholipase A2, proteases, complement and secretory IgA. A recent discovery has been that antibacterial cationic peptides are synthesized and secreted by epithelial cells of the airways and elsewhere. These peptides intercalate into bacterial membranes, permeabilise them and cause bacterial death. Among these are the ß-defensins 1 and 2 and cathelicidins6GoGo–8Go. There is some evidence that, although these are expressed in the CF lung, they are not active in the airway surface liquid found there. However, if, for example, cathelicidin is over-expressed then this effect can be overcome8Go. There is, nevertheless, an intense inflammatory response in the CF bronchial tree with large amounts of neutrophils, macrophages and inflammatory mediators such as tumour necrosis factor-{alpha} (TNF), interleukin-1 (IL-1) and IL-8. Indeed secretion of IL-8, which is a neutrophil chemokine, seems to be triggered by exposure of bronchial submucous glands from CF patients to raised Cl– ions. This causes accumulation of activated neutrophils which release {alpha}-defensins, reactive oxidants, and protease all of which potentiate lung damage. Although it appears that neutrophils from CF patients are not grossly deficient, there is evidence of altered intraneutrophil pH regulation9Go resulting in hypersecretion of granule contents including myeloperoxidase. CF sputum contains large amounts of myeloperoxidase and reactive oxygen and nitrogen intermediates which are toxic for tracheobronchial epithelial cells10Go. In an animal model, the malnutrition seen in CF contributes to poor bacterial clearance from the lungs and, by decreasing production of the anti-inflammatory cytokine IL-10, might result in excessive inflammation11Go. However, concentrations of one inflammatory mediator, nitric oxide (NO) which also has antibacterial activity, are low in the CF lung probably as a result of decreased inducible nitric oxide synthetase (iNOs) expression12Go. There do not appear to be any gross deficiencies in the specific (T- and B-cell) immune system; indeed, high levels of serum and sputum antibacterial antibodies are found in CF patients. However, there is evidence that some CF patients with chronic Pseudomonas aeruginosa colonization have more of a Th2 response than uncolonized CF controls13Go. Nevertheless, it does appear that the prolonged microbial colonization/infection that is characteristic of the CF lung results from defects in the innate or non-specific immune system. This is characterized by chronic infection with Staphylococcus aureus and non-capsulate Haemophilus influenzae in early life, followed by Ps. aeruginosa and Burkholderia cepacia, and much later Stenotrophomonas maltophilia14Go, Alcaligenes xylosoxidans, non-tuberculous mycobacteria and some previously unidentified bacteria15Go. In this review, we will concentrate on mechanisms of persistence and aggression by the two most important CF lung pathogens – Ps. aeruginosa and B. cepacia.


   Pseudomonas aeruginosa
Top
 Footnotes
 Abstract
 Introduction
 Pseudomonas aeruginosa
Burkholderia
 References
 
In recent years, the pseudomonads have been subdivided into a number of new genera on the basis of the genetic sequences of their 16S-rRNA genes, and the number of new species has increased exponentially (Table 2). Ps. aeruginosa is the most important member of rRNA homology group I, and a major pathogen in the CF lung. It is a Gram-negative, oxidase positive rod that is motile by means of polar flagella (Fig. 1). It is ubiquitous in the moist environment, and can even grow in distilled water and disinfectant solutions.


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  		Table 2. Medically important pseudomonads

 


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  		Fig. 1 Negative stain electron micrograph of Pseudomonas aeruginosa showing flagella (f) and pili (p). Bar = 500 nm.

 
Epidemiology

It is generally assumed that there is a hierarchy of colonization in the CF lung beginning with H. influenzae and Staph. aureus and subsequently with Ps. aeruginosa and B. cepacia. However, it is now clear that Ps. aeruginosa can affect the CF lung early in life; for example, 97.5% of children with CF in three centres in the US were infected by the age of 3 years16Go. In general, Ps. aeruginosa infection rates vary from 20–85% in most CF units, but with a higher prevalence in adult units17Go,18Go. What affects the prevalence and age of onset of Ps. aeruginosa infection is not entirely clear, but there is evidence that continuous administration of antistaphylococcal antibiotics is associated with a higher rate of acquisition of Ps. aeruginosa19Go. There is little doubt, however, that infection with Ps. aeruginosa has a deleterious effect in terms of declining lung function, increased hospital admission rates, and increased and more rapid mortality20GoGoGo–23Go. This is particularly apparent if Ps. aeruginosa infection occurs early in life21Go,23Go. In some units, there is now a policy of early aggressive antipseudomonal therapy as soon as infection is detected, since it is impossible to cure the infection once it is established. This policy does seem to be effective both in preventing colonization and mortality and morbidity24Go.

Ps. aeruginosa isolates can be typed for epidemiological purposes by phenotypic methods (such as pyocin typing, serotyping, phage typing, antibiogram) and genotypic methods such as pulsed field gel electrophoresis (PFGE) of macro-restricted chromosomal DNA, random amplified polymorphic DNA (RAP-D), ribotyping or flagellin gene polymorphisms25GoGoGoGo–29Go. In general, the genomic techniques are more sensitive and specific, but in reality no one method is completely reliable. During prolonged infection, the phenotype of Ps. aeruginosa can change from smooth, to rough, to highly mucoid colonial variants which may all be of the same genotype. During the early stages of disease, patients may be colonized intermittently and each patient has a unique genotype16Go. However, patients can be infected with two, three or more different genotypes concurrently or sequentially. The sources of the bacteria are many, and can include the inanimate environment both within and outside hospitals18Go,30Go,31Go. There is some evidence of cross-infection, especially between siblings, although the possibility of infection from a common source remains28Go. Outbreaks of infection with Ps. aeruginosa have been described in a number of CF units including Denmark26Go, Liverpool27Go, Manchester32Go and Melbourne33Go. Indeed, the Liverpool strain has been shown not only to cross-infect but also superinfect; that is, it colonizes patients already colonized by their own unique Ps. aeruginosa strain which it can displace34Go. Furthermore, this highly transmissible genotype was also able to cause pneumonia in the parents of a CF patient carrying the bacterium35Go. The complete genomic sequence of one strain of Ps. aeruginosa (PAO1) has now been published36Go. This is of great importance because it provides a point of reference with which to compare other strains including the highly transmissible lineages and will help our understanding of how they persist and cause disease.

Persistence

The initial stage in infection is attachment of bacteria to mucosal surfaces and/or the altered CF mucin. A confusing plethora of ligand-receptor systems have been described for binding of Ps. aeruginosa to epithelial cells. These include pili (protein spikes that protrude from the bacterial surface), outer membrane proteins and even lipopolysaccharide on the bacterium37Go38Go–39Go and gangliosides (asialo-GM-1), fucose residues, heparan sulphate proteoglycans or even the mutant CFTR itself40GoGoGo–43Go on the epithelial cell. In addition, Ps. aeruginosa binds to CF mucin via outer membrane proteins44Go. It has been demonstrated that CF epithelial cells express a greater density of an asialylated ganglioside receptor, GM-1, on their apical surface perhaps as a result of poor acidification of the Golgi where the gangliosides are processed45Go. It is suggested that binding of Ps. aeruginosa to this receptor might then, as a result of release of bacterial neuraminidase, expose more receptors. It has also been postulated that, in the normal lung, the first extracellular domain of CFTR (amino acids 108–117) acts as a receptor for Ps. aeruginosa (via lipopolysaccharide) and this binding results in internalization of bacteria39Go,43Go. This, it is proposed, is a mechanism for clearance of Ps. aeruginosa from the lung, since the epithelial cells die perhaps by apoptosis46Go and dead cells plus internalized bacteria are removed. In the CF lung, the mutant CFTR is not expressed (in the case of {Delta}F508) so there is no receptor for internalization and Ps. aeruginosa accumulates43Go. This hypothesis has been questioned by others, who found no correlation between expression of CFTR (human or murine) and binding or clearance of Ps. aeruginosa to or from epithelial cells in vivo or in vitro47Go. Heparan sulphate proteoglycans are expressed on the basolateral rather than apical surfaces of epithelial cells. It is postulated that the inflammatory process in the CF lung loosens the tight junctions between cells thus exposing the receptors and allowing greater adherence by Ps. aeruginosa42Go. From the above, it is clear that there is no one unifying hypothesis to explain how Ps. aeruginosa colonizes the CF airways. It is likely that the bacteria have a number of different strategies for attachment depending on the strain, stage of infection, and CFTR mutation.

Once established in colonization, Ps. aeruginosa must resist attempts by the immune system to dislodge it. It is already at an advantage in that three major components – the mucociliary escalator, peptide-mediated killing, and NO production – are impaired. However, the CF airway is a very harsh environment with large numbers of neutrophils, cytokines, chemokines, complement, T-cells, B-cells and specific antibody9Go,10Go,13Go,48GoGo–50Go. Indeed, attachment of Ps. aeruginosa to a lung pneumocyte cell-line or epithelial cells from CF airways itself induces release of a number of cytokines and regulatory proteins51GoGoGo–54Go. Pyocyanin, a phenazine redox active molecule that gives Ps. aeruginosa its greenish pigment, can also increase IL-8 expression in airway epithelial cells55Go. Nevertheless, the bacterium is not eliminated. This may result from alterations in neutrophil activity12Go and inhibition of opsonophagocytosis by digestion of specific antibody by bacterial proteases such as elastase. Non-opsonic phagocytosis of Ps. aeruginosa involves at least two different receptors (CD14 and CR3) and it appears that mutants of Ps. aeruginosa can arise to escape this route of bacterial killing56Go. Thus, despite a florid inflammatory response, Ps. aeruginosa is able to persist in the CF airways.

During prolonged infection, the bacteria change tremendously, for example, changing from smooth to rough colonial morphology by loss of polysaccharide chains from lipopolysaccharide, by loss of flagella and thus motility, and production of a mucoid exopolysaccharide (alginate)57Go. The latter is particularly important in that it imparts further resistance to neutrophil-mediated killing58Go, and contributes to the production of a biofilm59Go. This ability to evolve rapidly is a survival trait that enables Ps. aeruginosa to survive for years in the CF lung. For example, 36% of Ps. aeruginosa strains from 30 CF patients were found to be hypermutators, whereas this phenomenon was not found in 75 strains from non-CF patients60Go. Under normal circumstances, hypermutability carries a cost which limits survival; but, clearly in the CF lung, the cost of hypermutability is offset by the need to survive in such a harsh environment. Hypermutability often results from mutations in genes encoding DNA repair and error avoidance genes (mutS, mutY) and this was so for the CF isolates. Thus, in this case, the ability to mutate rapidly in the harsh environment of the CF lung gives a survival advantage.

Another mechanism for survival is the production of a biofilm, and there are morphological and genetic data indicating biofilm production by Ps. aeruginosa in the CF lung59Go,61Go. At high densities, bacteria secrete high concentrations of a diffusible auto-inducer such as an N-acyl-homoserine lactone (HSL). This is produced by an enzyme which is a member of the LuxI family62Go,63Go. In the case of Ps. aeruginosa, two enzymes (RhlI and LasI) direct the synthesis of N-butyryl HSL and N-(3 oxododecanoyl)–HSL, respectively. These signal to all the other bacteria so as to co-ordinate expression of virulence factors, alginate production and formation of a biofilm. This process is called quorum sensing, and enables a pathogen to reach a critical mass and then release its virulence factors to produce a massive attack on the host. It is estimated that 4% of the ~6000 Ps. aeruginosa genes are controlled by quorum sensing. Following attachment to mucosal cells, the bacteria multiply and move together by twitching motility (mediated by type IV pili), to form microcolonies64Go. At this stage, quorum sensing induces alginate synthesis and biofilm formation occurs61Go,62Go. Within the biofilm, the bacteria are relatively well protected from the external environment including both host-produced microbicides and antimicrobial drugs. The latter explains why it is so difficult, if not impossible, to clear Ps. aeruginosa infection once it is established. Once the alginate-producing mucoid phenotype has been induced, it persists and, in addition to quorum sensing-mediated conversion, it has been shown that hydrogen peroxide (an oxidant released by activated neutrophils), can induce mucoid Ps. aeruginosa in a biofilm in vitro65Go.

Aggression

Infection by Ps. aeruginosa in the CF lung does not usually lead to immediate morbidity or mortality. Rather, it is a process of chronic infection with frequent exacerbations leading to a gradual decline in lung function. How much is a result of bacterial aggression or of the chronic inflammatory response to the bacterium is unclear. However, Ps. aeruginosa does have an impressive array of virulence determinants. It releases a variety of hydrolytic enzymes including proteases, elastase, lipase, phospholipase, alkaline phosphatase and mucin sulphatase. For some, release is apparently within vesicles formed from the bacterial outer membrane and release can be increased 3–5-fold by exposure to, for example, gentamicin66Go. Ps. aeruginosa is able to catalyze the breakdown of pulmonary surfactant, perhaps by phospholipase C activity although non-mucoid strains were more active than mucoid67Go. Most strains of Ps. aeruginosa produce a range of proteolytic enzymes active against a variety of substrates. Elastase degrades elastin and immunoglobulins. The mucin in the CF airways has sulphated terminal sugars and this prevents digestion by bacterial saccharidases. However, both Ps. aeruginosa and B. cepacia have mucin sulphatase activity68Go which allows further degradation of mucin and exposure of new receptors for pathogens. In addition, Ps. aeruginosa produces a number of other factors including pyocyanin55Go, haemolysins, cytotoxins and siderophores all of which may contribute to aggression.

Two categories of Ps. aeruginosa isolates have been described that are invasive or cytolytic, but non-invasive for epithelial cells. Many pathogenic bacteria have type III secretion systems (TTS) that are assembled when the bacteria are in contact with epithelial cells69Go. TTS systems are used to transport effector molecules across the Gram-negative bacterial cell wall and have an apparatus for injecting them into host cells, by which they alter host cell activity. In Ps. aeruginosa, two of the TTS secreted effectors are exoenzyme S (ExoS) and ExoT, both of which are ADP-ribosyltransferases70Go. ExoS induces transcriptional expression of a number of pro-inflammatory cytokines and chemokines, thus contributing to pulmonary inflammation71Go. It appears that the invasion into epithelial cells is associated with defects in the TTS72Go. Recently, a genomic island, Ps. aeruginosa genomic island-1 (PAGI-1) which represents a 6729 bp region deleted from PAO1, has been found in 85% of clinical isolates including from CF patients73Go. As yet, it is unclear what roles the TTS system or PAGI-1 play in the pathogenesis of infection in the CF lung.


   Burkholderia
Top
 Footnotes
 Abstract
 Introduction
 Pseudomonas aeruginosa
 Burkholderia
References
 
Burkholderia spp. are in rRNA group II (Table 2), along with other CF lung pathogens such as Ralstonia picketii and Pandoraea spp74Go. However, Burkholderia spp., and in particular B. cepacia, are the most important pathogens in this group. They are Gram-negative, rod-shaped bacteria, motile by polar flagella (Fig. 2). They are unusual in that they do not have one circular chromosome but 2–4 circular replicons75Go,76Go. In addition, there are a number of insertion elements in the genome77Go. All of the above indicate that Burkholderia spp. have tremendous genomic plasticity.



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  		Fig. 2 Negative stain electron micrograph of Burkholderia cepacia showing pili. Bar = 500 nm.

 
There are a number of Burkholderia species, and B. cepacia has been sub-divided into a number of genomovars by DNA–DNA and DNA–ribosomal RNA hybridization studies57Go,78Go. The term genomovar is used since, by taxonomic convention, bacteria cannot be given a species name unless identifiable by phenotypic characteristics. However, some of the genomovars have now been given species names (see Table 2) and rapid methods devised for their differentiation79Go,80Go. To date, only genomovars I, III and VI remain in the B. cepacia complex.

Epidemiology

B. cepacia is named after Burkholder who, in 1950, discovered it was the cause of onion soft rot (cepia is Latin for onion), and it is known that Burkholderia spp. are also widely distributed as saprophytes in the environment78Go. Prior to the 1980s, B. cepacia was regarded as a rare opportunist causing nosocomial respiratory, urinary tract or soft tissue infections, which was able to survive in disinfectant solutions78Go. Then, it became clear, that it was associated with infection in the CF lung81Go and widely distributed in the environment57Go,78Go.

Subsequently, it emerged that certain strains of B. cepacia were highly transmissible and some could cause lethal infection in CF patients78Go,82GoGo–84Go. A variety of methods are available for typing B. cepacia. These include phenotypic methods such as pyrolysis mass spectroscopy85Go and lipopolysaccharide chemotyping86Go, but genotypic methods such as PFGE, flagellin RFLP typing and ribotyping remain the gold-standard57Go,78Go,82Go,83Go,87Go,88Go. There is one highly transmissible lineage called ET-12 (Edinburgh-Toronto) which is in B. cepacia genomovar III. This possesses two markers of transmissibility cable pili (cbl)89Go and BCESM (B. cepacia epidemic strain marker)90Go. The presence of cbl genes seems to be limited to epidemic genomovar III strains, but BCESM is present in epidemic and non-epidemic strains of B. cepacia genomovars I and III as well as in B. multivorans and B. stabilis91Go.

Certain strains of B. cepacia especially, but not only ET-12, are easily spread, person-to-person, directly presumably via respiratory secretions, (counts can exceed 108 cfu/ml) by, for example, kissing, or hands, or indirectly via spirometers or other medical equipment. Spread can occur both in hospital82Go and in a social setting57Go,78Go,83Go. One B. cepacia strain (not ET-12) has caused a nosocomial outbreak of infection in CF and non-CF patients88Go. The results of infection can vary from prolonged carriage with a gradual decline in lung function to fatal ‘cepacia syndrome’ with necrotizing pneumonia and bacteraemia82Go. Why such differences should occur is not clear, but might be related to other deficiencies unrelated to CFTR mutations, for example in mannose-binding lectin92Go.

As with ‘epidemic’ strains of Ps. aeruginosa34Go, it appears that B. cepacia ET-12 can super-infect CF patients already colonized with non-epidemic strains, displace them and result in fatal ‘cepacia syndrome’93Go. This adds an extra layer of complexity for prevention of spread of B. cepacia94Go. Finally, although B. cepacia is described as a pathogen of onions and humans, there has been a recent outbreak of mastitis in dairy sheep predominantly due to genomovar III95Go. In addition, B. cepacia is being developed for use as a biopesticide to protect crops against fungi and for bioremediation to break down herbicides that are not easily biodegradable96Go. This could pose a further threat to CF patients and its use should be approached with extreme caution.

Persistence

Following transmission, the initial interaction between B. cepacia and the airways mucosa involves attachment. At least 5 morphologically different pili have been detected on epidemic and non-epidemic strains including: cable, filamentous, spikes and mesh forms97Go. Of these, the cable pili which are associated with B. cepacia ET-12 are best characterized89Go. The receptor for cable pili is cytokeratin 1398Go which is enriched on the hyperplastic epithelia of CF airways99Go. Some cable pilus-negative B. cepacia appear to bind to asialo GM1100Go. B. cepacia is also able to bind respiratory mucin from CF patients101Go. Once established in colonization, B. cepacia must resist the bronchial killing and elimination mechanisms. Unlike Ps. aeruginosa, B. cepacia is resistant to epithelial derived antimicrobial peptides no matter what the salt concentration102Go. The ability to scavenge iron using a siderophore, ornibactin, is also important for the persistence of B. cepacia103Go. The CF airway also contains a number of reactive oxidants such as superoxide, hydrogen peroxide, hypochlorite and singlet oxygen released from activated neutrophils and macrophages. These are extremely toxic for bacteria, but virulent B. cepacia have evolved mechanisms for resisting attack. Such mechanisms include production of a melanin pigment104Go and expression of haem dimer binding proteins on the bacterial surface105Go which imparts catalase activity. Finally, B. cepacia does appear to have the ability to exist in a biofilm both in the CF lung and on plastic catheters106Go,107Go, and there is recent evidence of a quorum sensing system mediated by N-octanoylhomoserine lactone108Go. This raises the intriguing possibility of cross-talk between Ps. aeruginosa and B. cepacia in the CF lung.

Aggression

It is not clear how B. cepacia produces such devastating infection nor why some patients have prolonged infection with gradual decline in lung function and others develop ‘cepacia syndrome’ with identical bacteria. B. cepacia produces an impressive array of potential virulence determinants including protease, lipase, haemolysins, mucin sulphatase and cytotoxins57Go,68Go,78Go,109Go,110Go. Of note, the haemolysin has also been shown to induce degranulation and programmed cell death of neutrophils109Go leading to both protection of bacteria and lung damage. Clinical isolates of B. cepacia also secrete greater amounts of cytotoxins than environmental strains. In the presence of ATP these cytotoxins induce macrophage and mast cell death110Go. B. cepacia is also able to penetrate into, and survive within, cultured macrophages and lung epithelial cells111Go,112Go. Isolates of B. vietnamiensis and B. cepacia genomovar VI were able to survive for at least 5 days in activated macrophages and bacterial entry stimulated the macrophages to release TNF and reactive oxidants111Go. Thus it is proposed that repeated cycles of phagocytosis and macrophage activation could promote chronic inflammation. It is noteworthy that B. cepacia can also survive and grow within free-living amoebae113Go, a situation that parallels that of another lung pathogen Legionella pneumophila. How these phenomena are orchestrated is unclear, but the recent discovery of genes encoding a putative type III secretion system in B. cepacia ET-12114Go might help to provide an explanation. The recent description of a model of B. cepacia infection in Cftr–/– mice will also help to advance our understanding of the pathogenesis of infection115Go.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Pseudomonas aeruginosa
 Burkholderia
 References
 
Correspondence to: Professor C A Hart, Department of Medical Microbiology and Genitourinary Medicine, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK


   References
Top
 Footnotes
 Abstract
 Introduction
 Pseudomonas aeruginosa
 Burkholderia
 References
 

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