MyD88‐Dependent Immune Response Contributes to Hearing Loss in Experimental Pneumococcal Meningitis

Klein, Matthias; Schmidt, Caroline; Kastenbauer, Stefan; Paul, Robert; Kirschning, Carsten J.; Wagner, Hermann; Popp, Bernadette; Pfister, Hans‐Walter; Koedel, Uwe

doi:10.1086/512859

Cited by 24 publications

(15 citation statements)

References 14 publications

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“…Hearing loss was correlated with the level of CSF inflammation in a rabbit model of pneumococcal meningitis (40), and intrathecal administration of TNF-␣ alone was sufficient to induce cochlear injury similar to that observed with bacterial meningitis (15). Furthermore, TLR and MyD88 knockout mice demonstrated less hearing loss following pneumococcal meningitis (247). In a rat model, cochlear expression of iNOS and eNOS was upregulated following pneumococcal meningitis, and RNS-mediated cochlear damage could be attenuated both electrophysiologically and histopathologically by RNS scavengers (227,241,243).…”

Section: Cochlear Damage and Hearing Lossmentioning

confidence: 73%

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

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SUMMARY Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae , which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

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Section: Cochlear Damage and Hearing Lossmentioning

confidence: 73%

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

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“…On the other hand, activated microglial cells can be toxic to surrounding neurons by releasing, e.g., nitric oxide, glutamate, TNF-␣, and IL-1␤. The diminished inflammatory response decreased hearing loss in pneumococcal meningitis in MyD88-deficient mice, and neuronal injury caused by group B streptococci depended on the presence of TLR2 and MyD88 (18,22). Thus, activation of microglia during infections seems to be a double-edged sword.…”

Section: Discussionmentioning

confidence: 97%

Toll-Like Receptor Stimulation Enhances Phagocytosis and Intracellular Killing of Nonencapsulated and EncapsulatedStreptococcus pneumoniaeby Murine Microglia

Ribes¹,

Ebert²,

et al. 2010

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Toll-like receptors (TLRs) are crucial pattern recognition receptors in innate immunity that are expressed in microglia, the resident macrophages of the brain. TLR2, -4, and -9 are important in the responses against Streptococcus pneumoniae, the most common agent causing bacterial meningitis beyond the neonatal period. Murine microglial cultures were stimulated with agonists for TLR1/2 (Pam 3 CSK 4 ), TLR4 (lipopolysaccharide), and TLR9 (CpG oligodeoxynucleotide) for 24 h and then exposed to either the encapsulated D39 (serotype 2) or the nonencapsulated R6 strain of S. pneumoniae. After stimulation, the levels of interleukin-6 and CCL5 (RANTES [regulated upon activation normal T-cell expressed and secreted]) were increased, confirming microglial activation. The TLR1/2, -4, and -9 agonist-stimulated microglia ingested significantly more bacteria than unstimulated cells (P < 0.05). The presence of cytochalasin D, an inhibitor of actin polymerizaton, blocked >90% of phagocytosis. Along with an increased phagocytic activity, the intracellular bacterial killing was also increased in TLR-stimulated cells compared to unstimulated cells. Together, our data suggest that microglial stimulation by these TLRs may increase the resistance of the brain against pneumococcal infections.

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“…MyD88-deficient mice displayed a markedly diminished inflammatory host response in the CNS, as an evidenced of the reduced CSF pleocytosis and expression of cytokines, chemokines and complement factors 22 . Furthermore, MyD88-dependent immune response contributes to hearing loss in experimental pneumococcal meningitis; it is required for mounting a robust host immune response to S. pneumoniae in the CNS 23 . NF-κB comprises a closely related family to transcription factors, which play a key role on the expression of genes involved in the development of accessory cell and lymphocyte populations, expressing numerous proteins involved in inflammation and immune response 24 .…”

Section: Central Nervous System Bacterial Invasionmentioning

confidence: 99%

Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches

Barichello

Generoso

Collodel

et al. 2012

Arq. Neuro-Psiquiatr.

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Pneumococcal meningitis is a life-threatening disease characterized by an acute purulent infection affecting piamater, arachnoid and the subarachnoid space. The intense inflammatory host's response is potentially fatal and contributes to the neurological sequelae. Streptococcus pneumoniae colonizes the nasopharynx, followed by bacteremia, microbial invasion and blood-brain barrier traversal. S. pneumoniae is recognized by antigen-presenting cells through the binding of Toll-like receptors inducing the activation of factor nuclear kappa B or mitogen-activated protein kinase pathways and subsequent up-regulation of lymphocyte populations and expression of numerous proteins involved in inflammation and immune response. Many brain cells can produce cytokines, chemokines and others pro-inflammatory molecules in response to bacteria stimuli, as consequence, polymorphonuclear are attracted, activated and released in large amounts of superoxide anion and nitric oxide, leading to the peroxynitrite formation, generating oxidative stress. This cascade leads to lipid peroxidation, mitochondrial damage, blood-brain barrier breakdown contributing to cell injury during pneumococcal meningitis.

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MyD88‐Dependent Immune Response Contributes to Hearing Loss in Experimental Pneumococcal Meningitis

Cited by 24 publications

References 14 publications

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

Toll-Like Receptor Stimulation Enhances Phagocytosis and Intracellular Killing of Nonencapsulated and EncapsulatedStreptococcus pneumoniaeby Murine Microglia

Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches

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