Multiple Haemophilus influenzae Strains and Strain Variants Coexist in the Respiratory Tract of Patients with Cystic Fibrosis

Möller, Lieke V. M.; Regelink, Annette G.; Grasselier, Henny; Dankert-Roelse, J.E.; Dankert, J.; Alphen, Loek van

doi:10.1093/infdis/172.5.1388

Cited by 61 publications

(94 citation statements)

References 15 publications

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“…Past studies have demonstrated that H. influenzae colonization of the pharynx is characterized by rapid bacterial turnover (9,12,50,58) and carriage of multiple strains at any one time (18,37,43,52,58). Previous studies have demonstrated a 62% week-to-week turnover rate of H. influenzae isolated from healthy children attending day care; 37 to 43% of throat cultures contained two or more genetically distinct strains (range, zero to five) (14,56).…”

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Pharyngeal Colonization Dynamics of Haemophilus influenzae and Haemophilus haemolyticus in Healthy Adult Carriers

et al. 2007

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Haemophilus influenzae is an important cause of respiratory infections, including acute otitis media, sinusitis, and chronic bronchitis, which are preceded by asymptomatic H. influenzae colonization of the human pharynx. The aim of this study was to describe the dynamics of pharyngeal colonization by H. influenzae and an intimately related species, Haemophilus haemolyticus, in healthy adults. Throat specimens from four healthy adult carriers were screened for Haemophilus species; 860 isolates were identified as H. influenzae or H. haemolyticus based on the porphyrin test and on dependence on hemin and NAD for growth. Based on tests for hemolysis, for the presence of the 7F3 epitope of the P6 protein, and for the presence of iga in 412 of the isolates, 346 (84%) were H. influenzae, 47 (11%) were H. haemolyticus, 18 (4%) were nonhemolytic H. haemolyticus, and 1 was a variant strain. Carriers A and B were predominantly colonized with nontypeable H. influenzae, carrier C predominantly with b ؊ H. influenzae mutants, and carrier D with H. haemolyticus. A total of 358 H. influenzae and H. haemolyticus isolates were genotyped by pulsed-field gel electrophoresis (PFGE) following SmaI or EagI digestion of their DNA, and the carriers displayed the following: carrier A had 11 unique PFGE genotypes, carrier B had 15, carrier C had 7, and carrier D had 10. Thus, adult H. influenzae and H. haemolyticus carriers are colonized with multiple unique genotypes, the colonizing strains exhibit genetic diversity, and we observed day-to-day and week-to-week variability of the genotypes. These results appear to reflect both evolutionary processes that occur among H. influenzae isolates during asymptomatic pharyngeal carriage and sample-to-sample collection bias from a large, variable population of colonizing bacteria.Haemophilus species constitute approximately 10% of the total bacterial flora in the human upper respiratory tract (27). Haemophilus influenzae is an opportunistic pathogen in humans that asymptomatically colonizes the pharyngeal mucosa and occasionally the genital mucosa. The rate of carriage of H. influenzae increases from infancy (about 20% in the first year of life) to early childhood (Ͼ50% in children 5 to 6 years old), and H. influenzae is recoverable from the upper airways of 20 to 80% of healthy children (2,15,22,32).Colonization of the human respiratory mucosal surface represents a dynamic process in which bacteria are acquired, replaced, and reacquired many times in a lifetime. Past studies have demonstrated that H. influenzae colonization of the pharynx is characterized by rapid bacterial turnover (9, 12, 50, 58) and carriage of multiple strains at any one time (18,37,43,52,58). Previous studies have demonstrated a 62% week-to-week turnover rate of H. influenzae isolated from healthy children attending day care; 37 to 43% of throat cultures contained two or more genetically distinct strains (range, zero to five) (14,56).In addition to living as a commensal in the respiratory tract, H. influenzae may also cause s...

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Pharyngeal Colonization Dynamics of Haemophilus influenzae and Haemophilus haemolyticus in Healthy Adult Carriers

et al. 2007

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“…An opportunistic pathogen, NTHI resides asymptomatically in the upper airways of humans but can disseminate into privileged anatomical locations, causing infections such as otitis media, sinusitis, and pneumonia (47). NTHI is also one of the most prevalent microorganisms found in the lungs of patients with exacerbations of chronic obstructive pulmonary disease (48,49,60) and cystic fibrosis (23,43,58). An effective vaccine against NTHI strains has not yet been discovered, likely due to high variability of surface antigens between strains (60).…”

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A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

et al. 2011

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Nontypeable Haemophilus influenzae (NTHI) is a Gram-negative bacterial pathogen that causes upper and lower respiratory infections. Factors required for pulmonary infection by NTHI are not well understood. Previously, using high-throughput insertion tracking by deep sequencing (HITS), putative lung colonization factors were identified. Also, previous research indicates that secreted disulfide-dependent factors are important for virulence of H. influenzae. In the present study, HITS data were compared with an informatics-based list of putative substrates of the periplasmic oxidoreductase DsbA to find and characterize secreted virulence factors. This analysis resulted in identification of the "zinc binding essential for virulence" (zev) locus consisting of zevA (HI1249) and zevB (HI1248). NTHI mutants of zevA and zevB grew normally in rich medium but were defective for colonization in a mouse lung model. Mutants also exhibited severe growth defects in medium containing EDTA and were rescued by supplementation with zinc. Additionally, purified recombinant ZevA was found to bind to zinc with high affinity. Together, these data demonstrate that zevAB is a novel virulence factor important for zinc utilization of H. influenzae under conditions where zinc is limiting. Furthermore, evidence presented here suggests that zinc limitation is likely an important mechanism for host defense against pathogens during lung infection.

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“…To better study the persistence of this bacterium, several typing methods have been applied: serotyping, biotyping, outer membrane protein (OMP) electrophoresis, and genotyping methods, such as random PCR (1,17,18,24,35).…”

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Dynamics of Long-Term Colonization of Respiratory Tract byHaemophilus influenzaein Cystic Fibrosis Patients Shows a Marked Increase in Hypermutable Strains

et al. 2004

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The persistence and variability of 188 Haemophilus influenzae isolates in respiratory tract of 30 cystic fibrosis (CF) patients over the course of 7 years was studied. Antibiotic susceptibility testing, DNA fingerprinting, and analysis of outer membrane protein profiles were performed on all isolates. A total of 115 distinct pulsed-field gel electrophoresis profiles were identified. Ninety percent of patients were cocolonized with two or more clones over the studied period. A third of the patients were cross-colonized with one or two H. influenzae strains; 11% of the clones persisted for 3 or more months. Biotype, outer membrane protein profiles, and resistance profiles showed variation along the studied period, even in persisting clones. Four isolates (2.1%) recovered from 3 patients were type f capsulate, with three of them belonging to the same clone. ␤-Lactamase production was detected in 23.9% of isolates while 7% of the ␤-lactamase-negative isolates presented diminished susceptibility to ampicillin (␤-lactamase-negative ampicillin resistance phenotype). Remarkably, 21.3% of the H. influenzae isolates presented decreased susceptibility to ciprofloxacin, which was mainly observed in persisting clones. Of the H. influenzae isolates from CF patients, 18 (14.5%) were found to be hypermutable in comparison with 1 (1.4%) from non-CF patients (P < 0.0001). Ten patients (33.3%) were colonized by hypermutable strains over the study period. A multiresistance phenotype and long-term clonal persistence were significantly associated in some cases for up to 7 years. These results suggest that H. influenzae bronchial colonization in CF patients is a dynamic process, but better-adapted clones can persist for long periods of time.Cystic fibrosis (CF) is an autosomal recessive disorder resulting from mutations in a gene on the long arm of chromosome 7 (11). The gene product is the CF transmembrane conductance regulator, which regulates and facilitates transport of electrolytes across the epithelial cell membrane and other membranes (10).Haemophilus influenzae is regularly involved in chronic lung infections and acute exacerbations of CF patients (26). To better study the persistence of this bacterium, several typing methods have been applied: serotyping, biotyping, outer membrane protein (OMP) electrophoresis, and genotyping methods, such as random PCR (1,17,18,24,35).On the other hand, long-term antibiotic therapy is widely used for the treatment of lung infection in CF patients. The risk of developing antibiotic resistance in these patients is clearly higher than in other patients, and that is also applicable to H. influenzae (17). The first ciprofloxacin-resistant H. influenzae strains in Spain were recovered from CF patients and studied by our groups (4, 9).The goals of the present study were to carry out a prospective follow-up of CF patients over time to (i) determine whether these patients maintained the same H. influenzae strains or were subsequently colonized by different strains, (ii) study the antimicrobial suscep...

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Multiple Haemophilus influenzae Strains and Strain Variants Coexist in the Respiratory Tract of Patients with Cystic Fibrosis

Cited by 61 publications

References 15 publications

Pharyngeal Colonization Dynamics of Haemophilus influenzae and Haemophilus haemolyticus in Healthy Adult Carriers

Pharyngeal Colonization Dynamics of Haemophilus influenzae and Haemophilus haemolyticus in Healthy Adult Carriers

A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

Dynamics of Long-Term Colonization of Respiratory Tract byHaemophilus influenzaein Cystic Fibrosis Patients Shows a Marked Increase in Hypermutable Strains

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