Neutrophil Extracellular Traps and Fibrin in Otitis Media

Schachern, Patricia A.; Kwon, Geeyoun; Briles, David E.; Ferrieri, Patricia; Juhn, Steven K.; Cüreoğlu, Sebahattin; Paparella, Michael M.; Tsuprun, Vladimir

doi:10.1001/jamaoto.2017.1320

Cited by 9 publications

(12 citation statements)

References 24 publications

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“…In human temporal bones with different types of OM, a large number of bacteria or their aggregates were observed in association with host fibrous structures identified by immunohistochemical analysis as fibrin fibers or DNA-containing NETs. Presence of fibrin fibers and NETs was also reported in experimental animal models (4,7,(20)(21)(22) and human temporal bones FIG. 2.…”

Section: Discussionsupporting

confidence: 57%

Formations of Host Fibers and Bacteria in Human Temporal Bones With Otitis Media

Tsuprun

Shibata²,

Paparella³

et al. 2021

Otology &Amp; Neurotology

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Hypothesis:In temporal bones with otitis media, fibrin and neutrophil extracellular traps (NETs) form a fibrous network with bacteria, which is involved in growth of bacterial clusters/biofilms and chronicity of disease.Background:NETs and fibrin are important in host defense against pathogens; however, their role in otitis media is not well understood.Methods:Eight human temporal bones with serous otitis media, 30 with serous-purulent otitis media, 7 with mucoid otitis media, 23 with mucoid-purulent otitis media (OM), 30 with purulent OM, and 30 with chronic otitis media were selected based on histopathologic findings. Fibrous material with bacteria was detected with hematoxylin-eosin, Gram-Weigert, and propidium iodide stains; and its composition was analyzed with immunohistochemistry.Results:Extensive formations of fibrous material with bacteria were observed in 30% of temporal bones with serous-purulent otitis media, 29% with mucoid otitis media, 50% with mucoid-purulent OM, 57% with purulent OM, and 67% of temporal bones with histological evidence of chronic otitis media. Some of these formations showed large bacterial clusters or biofilms. Immunohistochemical analysis showed that fibrous structures were composed of fibrin or NETs.Conclusions:Formations of fibrous material with bacteria were detected in human temporal bones with different types of otitis media. Inflammatory cells were observed mostly in areas with low presence of fibrous structures. The network of fibrous material seems to prevent clearance of bacteria by phagocytic cells and thus influences growth of bacterial clusters or biofilms. Fibrin and NETs may be important for the recurrences and chronicity of disease, and contribute to clogging of tympanostomy tubes in children.

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Section: Discussionsupporting

confidence: 57%

Formations of Host Fibers and Bacteria in Human Temporal Bones With Otitis Media

Tsuprun

Shibata²,

Paparella³

et al. 2021

Otology &Amp; Neurotology

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“…The immobilization of pathogens by NETs also facilitates local phagocytosis 10 . In the context of pneumococcal infection, NET formation was first identified in the lungs during pneumococcal pneumonia, 11 in the middle ear during pneumococcal otitis media, 12 and in the cerebrospinal fluid (CSF) during S pneumoniae meningitis 13 . However, it is not known whether NETs form within the brain during bacterial meningitis.…”

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confidence: 99%

DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis

Pavan

Xavier

Ramos

et al. 2021

Annals of Neurology

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Objective: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis. Methods: We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis. Results: Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading NETs by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics. Interpretation: This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S pneumoniae meningitis.

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“…It is important to note that only viable cells were included in the enumeration of immune cell populations by flow cytometry and that these numbers likely underrepresent the total immune cell infiltration, due to cell death pathways (i.e., NETosis or necrosis), and this may explain discrepancies between scarce counts of early recruiting neutrophils, which did not correlate to increased expression of MPO or ELANE in the middle ear of infected animals at 2 day post infection. Neutrophil extracellular traps (NETs) are an important part of the immune response to bacterial infection and are present within the infected middle ears of chinchillas and humans (Schachern et al, 2017). Multiple stains of NTHi have been shown to activate neutrophil response and induce the release of neutrophil extracellular traps (NETs).…”

Section: Discussionmentioning

confidence: 99%

A Bacterial Epigenetic Switch in Non-typeable Haemophilus influenzae Modifies Host Immune Response During Otitis Media

Robledo‐Avila

Ruíz-Rosado

Partida-Sánchez

et al. 2020

Front. Cell. Infect. Microbiol.

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Non-typeable Haemophilus influenzae (NTHi) causes multiple diseases of the human airway and is a predominant bacterial pathogen of acute otitis media and otitis media in which treatment fails. NTHi utilizes a system of phase variable epigenetic regulation, termed the phasevarion, to facilitate adaptation and survival within multiple sites of the human host. The NTHi phasevarion influences numerous disease-relevant phenotypes such as biofilm formation, antibiotic resistance, and opsonization. We have previously identified an advantageous selection for a specific phasevarion status, which significantly affects severity and chronicity of experimental otitis media. In this study, we utilized pure cultures of NTHi variants in which modA was either locked ON or locked OFF, and thus modA was unable to phase vary. These locked variants were used to assess the progression of experimental otitis media and define the specific immune response induced by each subpopulation. Although the initial disease caused by each subpopulation was similar, the immune response elicited by each subpopulation was unique. The modA2 OFF variant induced significantly greater activation of macrophages both in vitro and within the middle ear during disease. In contrast, the modA2 ON variant induced a greater neutrophil extracellular trap response, which led to greater killing of the modA2 ON variant. These data suggest that not only does the NTHi phasevarion facilitate adaptation, but also allows the bacteria to alter immune responses during disease. Understanding these complex bacterial-host interactions and the regulation of bacterial factors responsible is critical to the development of better diagnostic, treatment, and preventative strategies for these bacterial pathogens.

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Neutrophil Extracellular Traps and Fibrin in Otitis Media

Cited by 9 publications

References 24 publications

Formations of Host Fibers and Bacteria in Human Temporal Bones With Otitis Media

Formations of Host Fibers and Bacteria in Human Temporal Bones With Otitis Media

DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis

A Bacterial Epigenetic Switch in Non-typeable Haemophilus influenzae Modifies Host Immune Response During Otitis Media

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