Relationship between Azithromycin Susceptibility and Administration Efficacy for Nontypeable Haemophilus influenzae Respiratory Infection

Euba, Begoña; Moleres, Javier; Viadas, Cristina; Barberán, M.; Caballero, Lucía; Grilló, María Jesús; Bengoechea, José A.; de-Torres, Juan P.; Liñares, Josefina; Leiva, José; Garmendia, Junkal

doi:10.1128/aac.04447-14

Cited by 15 publications

(24 citation statements)

References 72 publications

(112 reference statements)

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“…S7B). Last, we used an in vivo mouse respiratory infection model system [79][80][81]85,86]. At 24 hpi, NTHi375ΔhxuCBA lung and BALF bacterial numbers were lower than those recovered for the WT strain ( Figure 6(c), left panels).…”

Section: Moonlighting Features Of H Influenzae Heme-binding Systemsmentioning

confidence: 99%

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Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner

et al. 2019

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Nutrient iron sequestration is the most significant form of nutritional immunity and causes bacterial pathogens to evolve strategies of host iron scavenging. Cigarette smoking contains iron particulates altering lung and systemic iron homeostasis, which may enhance colonization in the lungs of patients suffering chronic obstructive pulmonary disease (COPD) by opportunistic pathogens such as nontypeable. NTHi is a heme auxotroph, and the NTHi genome contains multiple heme acquisition systems whose role in pulmonary infection requires a global understanding. In this study, we determined the relative contribution to NTHi airway infection of the four heme-acquisition systems HxuCBA, PE, SapABCDFZ, and HbpA-DppBCDF that are located at the bacterial outer membrane or the periplasm. Our computational studies provided plausible 3D models for HbpA, SapA, PE, and HxuA interactions with heme. Generation and characterization of single mutants in the hxuCBA, hpe, sapA, and hbpA genes provided evidence for participation in heme binding-storage and inter-bacterial donation. The hxuA, sapA, hbpA, and hpe genes showed differential expression and responded to heme. Moreover, HxuCBA, PE, SapABCDFZ, and HbpA-DppBCDF presented moonlighting properties related to resistance to antimicrobial peptides or glutathione import, together likely contributing to the NTHi-host airway interplay, as observed upon cultured airway epithelia and in vivo lung infection. The observed multifunctionality was shown to be system-specific, thus limiting redundancy. Together, we provide evidence for heme uptake systems as bacterial factors that act in a coordinated and multi-functional manner to subvert nutritional-and other sources of host innate immunity during NTHi airway infection.

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Section: Moonlighting Features Of H Influenzae Heme-binding Systemsmentioning

confidence: 99%

“…A549 type II human pneumocytes (ATCC CCL-185) were maintained and seeded as described [79][80][81][82][83][84][85][86]. For infection, PBS-normalized bacterial suspensions (OD 600 = 1) were prepared by using NTHi strains grown on chocolate agar.…”

Section: Cell Culture and Bacterial Infectionmentioning

confidence: 99%

Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner

et al. 2019

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“…A549 cells were maintained, seeded, and infected for 2 h, as described previously (10,34). Cells were washed three times with PBS and incubated for 6 h in RPMI 1640 medium containing 10% FCS, 10 mM HEPES, and gentamicin (100 g/ml).…”

Section: Methodsmentioning

confidence: 99%

“…Rolipram treatment was performed at a dose of 10 mg/kg of body weight in 0.1 ml of PBS-ethanol (2:1) and administered by oroesophageal gavage (Popper & Sons, Inc.) (38). NTHi intranasal infection was performed, and the lungs were processed as previously described (7,10,34,35) at 12 or 24 hpi. Each lung homogenate was serially 10-fold diluted in PBS, and 100 l of each dilution was spread in triplicate on sBHI-agar (detection limit, Ͻ10 CFU/lung).…”

Section: Methodsmentioning

confidence: 99%

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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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Effect of Qingfei Mixture (清肺合剂) on pediatric mycoplasma pneumoniae pneumonia with phlegm heat obstructing Fei (Lung) syndrome

Yang

Yao

et al. 2017

Chin. J. Integr. Med.

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Relationship between Azithromycin Susceptibility and Administration Efficacy for Nontypeable Haemophilus influenzae Respiratory Infection

Cited by 15 publications

References 72 publications

Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner

Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner

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

Effect of Qingfei Mixture (清肺合剂) on pediatric mycoplasma pneumoniae pneumonia with phlegm heat obstructing Fei (Lung) syndrome

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