Complete Genome Sequence of Haemophilus influenzae Strain 375 from the Middle Ear of a Pediatric Patient with Otitis Media

Sinha, Sunita; Balashov, Sergey; Viadas, Cristina; Grassa, Christopher J.; Ehrlich, Garth D.; Nislow, Corey; Redfield, Rosemary J.; Garmendía, Junkal

doi:10.1128/genomea.01245-14

Cited by 15 publications

(25 citation statements)

References 17 publications

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“…NTHi 375 was selected to represent the non-encapsulated H. influenzae strains; however, due to the enormous genetic variability of non-typeable strains it is difficult to generalize our findings with regards to other strains. Of importance, the complete genome sequence of strain 375 has been recently reported [27]. Nevertheless, we believe this strain is relevant because it is a clinical isolate from the middle ear of a pediatric patient with otitis media.…”

Section: Discussionmentioning

confidence: 99%

Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Choi

Nix

Gaultier

et al. 2015

Vaccine

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Section: Discussionmentioning

confidence: 99%

Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Choi

Nix

Gaultier

et al. 2015

Vaccine

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“…NTHi liquid cultures were grown in sBHI. NTHi375 is a genome-sequenced clinical isolate previously used in host-pathogen interplay studies (13,14,30).…”

Section: Methodsmentioning

confidence: 99%

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

Euba

Moleres

Segura

et al. 2015

Antimicrob Agents Chemother

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Therapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated. Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary infection. Glucocorticoids and statins lacked in vitro and/or in vivo efficacy. Conversely, the sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection.

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“…HI0529 and NF38_02430 are annotated as a tdk thymidine kinase in the RdKW20 and NTHi375 genomes, respectively (Fleischmann et al, 1995; Mell et al, 2014). Different to nupC , the tdk gene expression was shown to be similar in WT and Δ thyA strains grown in sBHI, independently of thymidine addition (Figure S2C).…”

Section: Resultsmentioning

confidence: 99%

Inactivation of the Thymidylate Synthase thyA in Non-typeable Haemophilus influenzae Modulates Antibiotic Resistance and Has a Strong Impact on Its Interplay with the Host Airways

Rodríguez-Arce

Martí

Euba

et al. 2017

Front. Cell. Infect. Microbiol.

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Antibacterial treatment with cotrimoxazol (TxS), a combination of trimethoprim and sulfamethoxazole, generates resistance by, among others, acquisition of thymidine auxotrophy associated with mutations in the thymidylate synthase gene thyA, which can modify the biology of infection. The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) is frequently encountered in the lower airways of chronic obstructive pulmonary disease (COPD) patients, and associated with acute exacerbation of COPD symptoms. Increasing resistance of NTHi to TxS limits its suitability as initial antibacterial against COPD exacerbation, although its relationship with thymidine auxotrophy is unknown. In this study, the analysis of 2,542 NTHi isolates recovered at Bellvitge University Hospital (Spain) in the period 2010–2014 revealed 119 strains forming slow-growing colonies on the thymidine low concentration medium Mueller Hinton Fastidious, including one strain isolated from a COPD patient undergoing TxS therapy that was a reversible thymidine auxotroph. To assess the impact of thymidine auxotrophy in the NTHi-host interplay during respiratory infection, thyA mutants were generated in both the clinical isolate NTHi375 and the reference strain RdKW20. Inactivation of the thyA gene increased TxS resistance, but also promoted morphological changes consistent with elongation and impaired bacterial division, which altered H. influenzae self-aggregation, phosphorylcholine level, C3b deposition, and airway epithelial infection patterns. Availability of external thymidine contributed to overcome such auxotrophy and TxS effect, potentially facilitated by the nucleoside transporter nupC. Although, thyA inactivation resulted in bacterial attenuation in a lung infection mouse model, it also rendered a lower clearance upon a TxS challenge in vivo. Thus, our results show that thymidine auxotrophy modulates both the NTHi host airway interplay and antibiotic resistance, which should be considered at the clinical setting for the consequences of TxS administration.

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Complete Genome Sequence of Haemophilus influenzae Strain 375 from the Middle Ear of a Pediatric Patient with Otitis Media

Cited by 15 publications

References 17 publications

Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

Inactivation of the Thymidylate Synthase thyA in Non-typeable Haemophilus influenzae Modulates Antibiotic Resistance and Has a Strong Impact on Its Interplay with the Host Airways

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