Nontypeable and Encapsulated<i>Haemophilus infuenzae</i>Yield Different Clinical Courses of Experimental Otitis Media

Melhus, Åsa; Hermansson, Ann; Prellner, Karin

doi:10.3109/00016489409126058

Cited by 31 publications

(38 citation statements)

References 12 publications

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“…Haemophilus influenzae strain 3655 (nontypeable, biotype II), originally isolated from the ME of an OM patient in St. Louis, Missouri, USA (kindly provided by Asa Melhus, Lund University, Sweden), was used at a concentration of 10 5 to 10 6 bacteria/ml to induce infection of the ME. Inocula were prepared as described previously (38,39).…”

Section: Methodsmentioning

confidence: 99%

Otitis Media and Nasopharyngeal Colonization inccl3^−/−Mice

et al. 2017

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We previously found CC chemokine ligand 3 (CCL3) to be a potent effector of inflammation during otitis media (OM): exogenous CCL3 rescues the OM phenotype of tumor necrosis factor-deficient mice and the function of macrophages deficient in several innate immune molecules. To further delineate the role of CCL3 in OM, we evaluated middle ear (ME) responses of ccl3 Ϫ/Ϫ mice to nontypeable Haemophilus influenzae (NTHi). CCL chemokine gene expression was evaluated in wildtype (WT) mice during the complete course of acute OM. OM was induced in ccl3 Ϫ/Ϫ and WT mice, and infection and inflammation were monitored for 21 days. Phagocytosis and killing of NTHi by macrophages were evaluated by an in vitro assay. The nasopharyngeal bacterial load was assessed in naive animals of both strains. Many CCL genes showed increased expression levels during acute OM, with CCL3 being the most upregulated, at levels 600-fold higher than the baseline. ccl3 Ϫ/Ϫ deletion compromised ME bacterial clearance and prolonged mucosal hyperplasia. ME recruitment of leukocytes was delayed but persisted far longer than in WT mice. These events were linked to a decrease in the macrophage capacity for NTHi phagocytosis and increased nasopharyngeal bacterial loads in ccl3 Ϫ/Ϫ mice. The generalized impairment in inflammatory cell recruitment was associated with compensatory changes in the expression profiles of CCL2, CCL7, and CCL12. CCL3 plays a significant role in the clearance of infection and resolution of inflammation and contributes to mucosal host defense of the nasopharyngeal niche, a reservoir for ME and upper respiratory infections. Therapies based on CCL3 could prove useful in treating or preventing persistent disease.KEYWORDS chemokines, otitis media, nontypeable Haemophilus influenzae, innate immunity, nasopharyngeal culture, mucosal flora O titis media (OM) is a primarily infectious disease that involves, in the majority of cases, pathogenic bacteria alone or in combination with a virus (1). The bacteria most frequently isolated from middle ear (ME) effusions during acute OM are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis (2). Children acquire these potential otopathogens, along with a broad variety of other microorganisms, as part of their normal nasopharyngeal flora early in infancy (3).The pathogenesis of OM is considered multifactorial. Prior viral infection of the nasopharynx, significantly increased bacterial colonization of the nasopharynx (4) and/or cocolonization by different bacterial strains (4, 5), as well as dysfunction of the Eustachian tube leading to pressure differences between the nasopharynx and Eustachian tube (6) have all been associated with an elevated risk of OM. Immature or compromised immune status, allergy, and genetic predispositions (7) also contribute to OM susceptibility.The fact that acute OM normally resolves in a few days, before cognate immunity

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Section: Methodsmentioning

confidence: 99%

Otitis Media and Nasopharyngeal Colonization inccl3^−/−Mice

et al. 2017

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“…Apart from a mouse passage of the pneumococcal strain prior to inoculation to enhance pathogenicity (23), the inocula for middle ear challenge were prepared as described previously (24). Only freshly prepared early-stationary-phase bacteria grown in either Todd-Hewitt broth (Difco Laboratories, Detroit, Mich.) or brain heart infusion broth (Difco) supplemented with NAD and hemin (Sigma, St. Louis, Mo.…”

Section: Methodsmentioning

confidence: 99%

“…Viable counts of the bacterial suspensions were performed at the time of the challenge. Bacterial samples from the middle ears and blood were cultured as previously described (24). Growth was classified semiquantitatively as sparse (1 to 10 CFU), moderate (11 to 100 CFU), and abundant (Ͼ100 CFU).…”

Section: Methodsmentioning

confidence: 99%

Expression of Cytokine Genes during Pneumococcal and NontypeableHaemophilus influenzaeAcute Otitis Media in the Rat

Melhus¹,

Ryan²

2000

Infect Immun

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Acute otitis media (AOM) elicits potent inflammatory responses from the cells of the middle ear mucosa as well as from infiltrating leukocytes. To explore host responses during experimental AOM induced by Streptococcus pneumoniae type 3 and nontypeable Haemophilus influenzae (NTHi), otomicroscopy findings and expression of cytokine genes in the middle ear were monitored up to 1 month postinoculation. The mucosa and infiltrating cells responded rapidly to the bacterial challenge. Otomicroscopically, AOM appeared 1 day after NTHi inoculation and 3 days after pneumococcus inoculation. Pneumococcal AOM was more severe than NTHi otitis, but in general, lower transcript levels were detected in pneumococcus-infected than in NTHi-infected animals. Interleukin-6 (IL-6) mRNA levels peaked at 3 to 6 h for both pneumococcus-infected and NTHiinfected animals. IL-1␣, tumor necrosis factor alpha, and IL-10 mRNA levels peaked at 6 h for NTHi otitis and 1 to 3 days for pneumococcal otitis. Comparing otomicroscopy with expression profiles, it would appear that the majority of cytokine mRNAs had passed their peak before the AOM diagnosis could be made clinically. Only transforming growth factor ␤ mRNA followed a slower time course, peaking very late and continuing expression even after the AOM was otomicroscopically resolved. IL-2 and IL-4 mRNAs were not detected in any animal at any time. Most of the investigated cytokines are very early markers for AOM and may be involved in initiation of inflammation, but they would be poor targets for pharmacological manipulation since their levels decline before clinical signs appear.

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“…The employed and well-established Sprague-Dawley rat models for acute suppurative otitis media have a clinical course and oto-microscopic findings resembling those observed in untreated acute otitis media in children [17][18][19].…”

Section: The Rat Modelmentioning

confidence: 91%

Eustachian tube gland tissue changes are related to bacterial species in acute otitis media

Cayé‐Thomasen

Tos

2004

International Journal of Pediatric Otorhinolaryngology

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Nontypeable and EncapsulatedHaemophilus infuenzaeYield Different Clinical Courses of Experimental Otitis Media

Cited by 31 publications

References 12 publications

Otitis Media and Nasopharyngeal Colonization inccl3^−/−Mice

Otitis Media and Nasopharyngeal Colonization inccl3^−/−Mice

Expression of Cytokine Genes during Pneumococcal and NontypeableHaemophilus influenzaeAcute Otitis Media in the Rat

Eustachian tube gland tissue changes are related to bacterial species in acute otitis media

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Nontypeable and EncapsulatedHaemophilus infuenzaeYield Different Clinical Courses of Experimental Otitis Media

Cited by 31 publications

References 12 publications

Otitis Media and Nasopharyngeal Colonization inccl3−/−Mice

Otitis Media and Nasopharyngeal Colonization inccl3−/−Mice

Expression of Cytokine Genes during Pneumococcal and NontypeableHaemophilus influenzaeAcute Otitis Media in the Rat

Eustachian tube gland tissue changes are related to bacterial species in acute otitis media

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Otitis Media and Nasopharyngeal Colonization inccl3^−/−Mice

Otitis Media and Nasopharyngeal Colonization inccl3^−/−Mice