Relationship of the Middle Ear Effusion Microbiome to Secretory Mucin Production in Pediatric Patients With Chronic Otitis Media

Krueger, Anna; Val, Stéphanie; Pérez‐Losada, Marcos; Panchapakesan, Karuna; Devaney, Joe; Duah, Vanessa; DeMason, Christine E.; Poley, Marian; Rose, Mary C.; Preciado, Diego

doi:10.1097/inf.0000000000001493

Cited by 28 publications

(42 citation statements)

References 34 publications

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“…There may be several contributory factors. Lim et al (Lim et al, 1979) found that neutrophils predominated in COME effusions that had culturable pathogenic bacteria whereas lymphocytes were prominent in culture negative effusions and furthermore, variation in effusion microbiome had an impact on mucin content (Krueger et al, 2017). We did not collect sample microbiome data that would allow us to evaluate this possibility.…”

Section: Differences In Immune Cell Profiles In Mucoid and Serous Comementioning

confidence: 93%

“…A previous genetic association study found that polymorphism in the TLR4 receptor is a risk factor for childhood COME (although this finding was not replicated) (Hafren et al, 2015), and a Tlr deficient mouse exhibits altered immune response to bacterial challenge of the middle ear (Tyrer et al, 2013). Microbiome analysis of human COME samples (Liu et al, 2011;Jervis-Bardy et al, 2015;Chan et al, 2016;Krueger et al, 2017) shows the presence of diverse bacterial communities that are a potential stimulus for TLR activation along with ongoing host tissue damage. Targeting induction of TLR pathways, for example through administration of anti-microbials, specific antibodies or proteases (Piccinini and Midwood, 2010), are logical strategies to counteract this effect.…”

Section: Upregulation Of Other Inflammatory Network In Comementioning

confidence: 99%

“…We also acknowledge the general problems with the analysis of mRNA transcriptome, in that this may not directly correlate to protein expression. The microbiota was not assayed in COME effusions and this may be a determinant of glue ear MUC5B content (Krueger et al, 2017).…”

Section: Strengths and Limitations Of This Studymentioning

confidence: 99%

“…The effusion in younger patients with COME is predominantly mucoid rather than serous (Duah et al, 2016). There are microbiome difference between mucoid and serous effusions (Krueger et al, 2017), and proteomic analysis reveals a higher content of MUC5B in mucoid effusions, as well as DNA (Val et al, 2018). Mucoid effusions also have a global tendency to increased pro-inflammatory mediators, but serous effusions have greater acute phase proteins IL-1b and IL-10, suggestive of a differing immunological response (Val et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Transcript Analysis Reveals a Hypoxic Inflammatory Environment in Human Chronic Otitis Media With Effusion

et al. 2020

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Chronic otitis media with effusion (COME) is the most common cause of childhood hearing loss in the developed world. Underlying pathophysiology is not well understood, and in particular the factors that lead to the transition from acute to chronic inflammation. Here we present the first genome-wide transcript analysis of white blood cells in the effusion of children with COME. Analysis of microarray data for enriched pathways reveals upregulation of hypoxia pathways, which is confirmed using real-time PCR and determining VEGF protein titres. Other pathways upregulated in both mucoid and serous effusions include Toll-like receptor signaling, complement, and RANK-RANKL. Cytology reveals neutrophils and macrophages predominated in both serous and mucoid effusions, however, serous samples had higher lymphocyte and eosinophil differential counts, while mucoid samples had higher neutrophil differential counts. Transcript analysis indicates serous fluids have CD4+ and CD8+ T-lymphocyte, and NK cell signatures. Overall, our findings suggest that inflammation and hypoxia pathways are important in the pathology of COME, and targets for potential therapeutic intervention, and that mucoid and serous COME may represent different immunological responses.

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Section: Differences In Immune Cell Profiles In Mucoid and Serous Comementioning

confidence: 93%

Section: Upregulation Of Other Inflammatory Network In Comementioning

confidence: 99%

Section: Strengths and Limitations Of This Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcript Analysis Reveals a Hypoxic Inflammatory Environment in Human Chronic Otitis Media With Effusion

et al. 2020

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“…In the microbiota of MEF, Alloiococcus appears to be one of the dominant genera (Jervis- Bardy et al, 2015;Chan et al, 2016Chan et al, , 2017bBoers et al, 2018;Lappan et al, 2018;Val et al, 2018;Johnston et al, 2019). Turicella is less often reported, but has been identified as a member of the MEF microbiota in 8 of the 12 MEF microbiota studies reported in Table 3 (Jervis- Bardy et al, 2015;Krueger et al, 2017;Minami et al, 2017;Sillanpää et al, 2017;Boers et al, 2018;Lappan et al, 2018;Val et al, 2018;Johnston et al, 2019). However, due to the compositional nature of microbiome data it remains difficult to interpret which organisms are more abundant than others.…”

Section: Detection Of a Otitidis And T Otitidis In Mef Has Increasementioning

confidence: 99%

Reviewing the Pathogenic Potential of the Otitis-Associated Bacteria Alloiococcus otitidis and Turicella otitidis

Lappan

Jamieson

Peacock

2020

Front. Cell. Infect. Microbiol.

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Alloiococcus otitidis and Turicella otitidis are common bacteria of the human ear. They have frequently been isolated from the middle ear of children with otitis media (OM), though their potential role in this disease remains unclear and confounded due to their presence as commensal inhabitants of the external auditory canal. In this review, we summarize the current literature on these organisms with an emphasis on their role in OM. Much of the literature focuses on the presence and abundance of these organisms, and little work has been done to explore their activity in the middle ear. We find there is currently insufficient evidence available to determine whether these organisms are pathogens, commensals or contribute indirectly to the pathogenesis of OM. However, building on the knowledge currently available, we suggest future approaches aimed at providing stronger evidence to determine whether A. otitidis and T. otitidis are involved in the pathogenesis of OM. Such evidence will increase our understanding of the microbial risk factors contributing to OM and may lead to novel treatment approaches for severe and recurrent disease.

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MUC5B induces in vitro neutrophil extracellular trap formation: Implication in otitis media

Val

Krueger

Hussain

et al. 2020

Laryngoscope Investig Oto

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BackgroundChronic otitis media (COM) is characterized by middle ear fluid predominantly containing cytokines, Nontypeable haemophilus influenzae (NTHi), the mucin MUC5B, and neutrophil extracellular traps (NETs). NETs consist of extracellular DNA coated with antibacterial proteins such as myeloperoxidase (MPO) and citrullinated histone 3 (CitH3). NETs can damage tissues and sustain inflammation. Our study aimed to develop an in vitro model of NETosis, testing COM inductors.MethodsNETosis was evaluated in fresh blood human neutrophils attached to collagen‐coated plates and in suspension exposed to phorbol myristate acetate (PMA) as a control, and COM relevant mediators. Confocal microscopy, DNA fluorescence assay and flow cytometry were used to quantify NETosis.ResultsPMA exposure induced DNA, MPO, and CitH3 by immunofluorescence (IF) most significantly at 3 hours (3.8‐fold for DAPI, 7.6‐fold for MPO, and 6.9‐fold for CitH3, all P < .05). IL‐8 and TNF‐α cytokines showed milder increases of DAPI, MPO, and CitH3 positive cells. NTHi had no effect on these NETs markers. Purified salivary MUC5B (10 to 40 μg/mL) produced potent increases, comparable to PMA. A composite NET score summing the fold‐increases for DAPI, MPO, and CitH3 demonstrated PMA at 13.6 to 19 relative to control set at 1; and MUC5B at 8.6 to 16.3 (all P < .05). IL‐8 and TNF‐α showed scores of 5.4 and 3, respectively, but these were not statistically significant.ConclusionWe developed a reliable in vitro assay for NETosis which demonstrated that salivary MUC5B is a potent inductor of NETs whereas IL‐8, TNF‐α, live and lyzed NTHi demonstrated minimal to no NETosis.Level of evidenceNA.

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Relationship of the Middle Ear Effusion Microbiome to Secretory Mucin Production in Pediatric Patients With Chronic Otitis Media

Abstract: The microbiome of MEEs from children with chronic otitis media differs according to specific clinical features, such as mucin content, age and presence of hearing loss. These associations provide novel pathophysiologic insights across the spectrum of otitis media progression.

Cited by 28 publications

References 34 publications

Transcript Analysis Reveals a Hypoxic Inflammatory Environment in Human Chronic Otitis Media With Effusion

Transcript Analysis Reveals a Hypoxic Inflammatory Environment in Human Chronic Otitis Media With Effusion

Reviewing the Pathogenic Potential of the Otitis-Associated Bacteria Alloiococcus otitidis and Turicella otitidis

MUC5B induces in vitro neutrophil extracellular trap formation: Implication in otitis media

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