Hypermutable Haemophilus influenzae with mutations in mutS are found in cystic fibrosis sputum

Watson, Michael; Burns, Jane L.; Smith, Arnold L.

doi:10.1099/mic.0.27230-0

Cited by 76 publications

(75 citation statements)

References 66 publications

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“…Banding patterns are shown for the 26 isolates, organized into three unrelated clusters, A-C, with the majority of isolates (22/26, 85 %) in cluster A. The non-typable strain R465, analysed previously by ERIC sequencebased PCR fingerprinting in our laboratory (Watson et al, 2004), was included as a control and was confirmed to be unrelated to the other strains in the study.…”

Section: Discussionmentioning

confidence: 99%

“…Isolates with a similarity index of ¢85 % were considered identical for the purpose of this analysis. A non-typable strain, R465, was included as an unrelated control and was characterized previously by enterobacterial repetitive intergenic consensus (ERIC) sequencebased PCR fingerprinting (Watson et al, 2004).Detection of adhesins by PCR. The primers used for the detection of adhesin genes are listed in Table 2.…”

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confidence: 99%

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Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

Watson

Nelson

Nguyen

et al. 2013

Journal of Medical Microbiology

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The incidence of invasive infections due to Haemophilus influenzae has decreased significantly in developed countries with high rates of vaccination against H. influenzae serotype b (Hib). This vaccine provides no protection against H. influenzae serotype f (Hif), typically associated with invasive infections in adults with chronic disease and/or immunodeficiency, and rarely in otherwise healthy adults and children. The specific properties of Hif associated with virulence remain largely uncharacterized. A panel of 26 Hif strains consisting of both invasive disease-associated and mucosal surface non-invasive disease-associated isolates was surveyed by DNA fingerprinting, biotyping and PCR detection of hmw1, hmw2, hsf, the hif fimbrial locus and the lipooligosaccharide (LOS) biosynthetic island, and assessment of b-lactamase expression and determination of resistance to the bactericidal activity of normal adult human serum. Repetitive sequence-based PCR fingerprinting differentiated the 26 strains into three clusters, with the majority of isolates (22/26, 84.6 %) clustered into a single indistinguishable group. Most isolates (24/26, 92.3 %) were of biotype I and two isolates produced b-lactamase with detection of a conjugative plasmid, and the isolates displayed a range of resistances to the bactericidal activity of human serum. All 26 isolates carried the adhesin hsf, 21 carried a partial hif fimbrial operon and 4 had the adhesin genes hmw1/2. A LOS biosynthetic island was detected in 20 isolates consisting of the genes lic2BC. It was concluded that Hif has many recognized virulence properties and comprises a relatively homogeneous group independent of the anatomical source from which it was isolated. INTRODUCTIONHaemophilus influenzae, a human-restricted Gram-negative coccobacillus, is a commensal of the upper respiratory mucosa and a pathogen commonly causing airway mucosal disease and occasional invasive disease. Since Margaret Pittman's original description of capsular serotypes among H. influenzae isolates in 1931 (Pittman, 1931), H. influenzae serotype b (Hib) had been the most clinically significant strain causing invasive disease (e.g. meningitis, epiglottitis, septicaemia and osteomyelitis) in previously well infants and children (Aubrey & Tang, 2003). Since the early 1990s, routine administration of the Hib conjugate vaccines (which induce protective levels of anti-capsular antibody) has virtually eliminated Hib disease among infants and young children in developed countries (Agrawal & Murphy, 2011;Ladhani, 2012). However, the vaccine provides no protection from infection due to nonb serotypes, including H. influenzae serotype f (Hif), which remains a rare but significant cause of invasive infection. Given the reduction in Hib carriage among Hib conjugate vaccine recipients, concern exists as to whether invasive disease due to Hif or other non-b encapsulated strains will become more prevalent due to serotype replacement Abbreviations: BLNAR, b-lactamase-negative ampicillin-resistant; CSF, cerebrospinal ...

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Section: Discussionmentioning

confidence: 99%

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Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

Watson

Nelson

Nguyen

et al. 2013

Journal of Medical Microbiology

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“…Finally, 500 H. influenzae isolates were screened for increased mutation frequency by measuring resistance to rifampicin, nalidixic acid and spectinomycin. Interestingly, 12 of the 14 identified hypermutable strains were isolated from CF sputum (Watson et al, 2004).…”

Section: Cystic Fibrosis (Cf)mentioning

confidence: 99%

Bacterial hypermutation: clinical implications

Jolivet‐Gougeon

Kovács

Gall‐David

et al. 2011

Journal of Medical Microbiology

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Heritable hypermutation in bacteria is mainly due to alterations in the methyl-directed mismatch repair (MMR) system. MMR-deficient strains have been described from several bacterial species, and all of the strains exhibit increased mutation frequency and recombination, which are important mechanisms for acquired drug resistance in bacteria. Antibiotics select for drug-resistant strains and refine resistance determinants on plasmids, thus stimulating DNA recombination via the MMR system. Antibiotics can also act as indirect promoters of antibiotic resistance by inducing the SOS system and certain error-prone DNA polymerases. These alterations have clinical consequences in that efficacious treatment of bacterial infections requires high doses of antibiotics and/or a combination of different classes of antimicrobial agents. There are currently few new drugs with low endogenous resistance potential, and the development of such drugs merits further research. IntroductionEradication of infectious diseases is constantly challenged by micro-organisms that develop new survival strategies. Previous studies suggest that mutational events play a predominant role in bacterial adaptation and confer a selective advantage (Chou et al., 2009;Cooper, 2007). Early experiments aimed at detecting mutators used mutagenized laboratory strains of bacteria, sometimes coupled with different selection strategies. LeClerc et al. (1996) reported high mutation frequency among Escherichia coli and Salmonella pathogens, challenging the theory that mutators were rare among bacterial populations. Taken together, these findings demonstrated that natural populations could respond to environmental selection in two ways, i.e. by enhanced mutation frequencies and by recombination. Transient mutator status, which involves reversion or recombination within the mutator alleles or depletion of the methyl-directed mismatch repair (MMR) system proteins, allows the organism to temporarily benefit from the elevated mutation frequency for adaptation while reducing the risk of accumulating deleterious mutations. Using a mathematical model, Rosche & Foster (1999) showed that transient hypermutators play a role in adaptive mutation in E. coli. Molecular mechanisms of hypermutationProteins involved in the DNA mismatch repair pathway help replace nucleotides introduced erroneously into the replicated DNA and also hinder recombination between non-identical DNA sequences. Deficiencies in any of the DNA mismatch repair pathway mechanisms can lead to a hypermutator phenotype. DNA repairSiegel & Bryson (1967) discovered the mutS gene in an azaserine-resistant derivative of E. coli that had a mutator phenotype and carried a deletion in the mutS gene. The majority of naturally occurring strong mutators have defects in the MMR system; the mutations are mainly in mutS (Oliver et al., 2002), but deletions in genes encoding beta-clamp proteins and in mutH, mutL and mutU (uvrD) have also been described (Fig. 1). Inactivation of basal excision repair genes, e.g. mutY, mutM, ...

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“…Natural populations quite often contain a mixture of wild-type and mutator strains (LeClerc et al 1996(LeClerc et al , 2000Matic et al 1997;Oliver et al 2000;Giraud et al 2001;Richardson et al 2002;Prunier et al 2003;Bjö rkholm et al 2004;del Campo et al 2004;Watson et al 2004). Furthermore, the somatic tissues of multicellular sexual organisms comprise populations of asexually reproducing cells possessing opportunities for an increased growth rate.…”

Section: T He Most Evolutionarily Important Characteristicmentioning

confidence: 99%

The Fixation Probability of Rare Mutators in Finite Asexual Populations

et al. 2009

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A mutator is an allele that increases the mutation rate throughout the genome by disrupting some aspect of DNA replication or repair. Mutators that increase the mutation rate by the order of 100-fold have been observed to spontaneously emerge and achieve high frequencies in natural populations and in longterm laboratory evolution experiments with Escherichia coli. In principle, the fixation of mutator alleles is limited by (i) competition with mutations in wild-type backgrounds, (ii) additional deleterious mutational load, and (iii) random genetic drift. Using a multiple-locus model and employing both simulation and analytic methods, we investigate the effects of these three factors on the fixation probability P fix of an initially rare mutator as a function of population size N, beneficial and deleterious mutation rates, and the strength of mutations s. Our diffusion-based approximation for P fix successfully captures effects ii and iii when selection is fast compared to mutation (m=s > 1). This enables us to predict the conditions under which mutators will be evolutionarily favored. Surprisingly, our simulations show that effect i is typically small for strong-effect mutators. Our results agree semiquantitatively with existing laboratory evolution experiments and suggest future experimental directions.

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Hypermutable Haemophilus influenzae with mutations in mutS are found in cystic fibrosis sputum

Cited by 76 publications

References 66 publications

Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

Bacterial hypermutation: clinical implications

The Fixation Probability of Rare Mutators in Finite Asexual Populations

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