Evaluation of the mouse model for acute otitis media

MacArthur, Carol J.; Hefeneider, Steven H.; Kempton, J. Beth; Parrish, Sarah K.; McCoy, Sharon L.; Trune, Dennis R.

doi:10.1016/j.heares.2006.05.012

Cited by 40 publications

(47 citation statements)

References 47 publications

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“…The results were consistent with our histological observation. It is now accepted that ABR offers a valid and simple physiologic test of mouse middle ear inflammation (23). All mice with AOM in our study exhibited an elevation in ABR thresholds; however, the magnitude of elevation was significantly higher in TLR2 Ϫ/Ϫ mice than in WT mice at relatively low stimulus frequencies (Fig.…”

Section: Discussionmentioning

confidence: 55%

Role for Toll-Like Receptor 2 in the Immune Response toStreptococcus pneumoniaeInfection in Mouse Otitis Media

Han

Tian

et al. 2009

Infect Immun

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Streptococcus pneumoniae is the most common pathogen associated with otitis media. To examine the role of Toll-like receptor 2 (TLR2) in host defense against Streptococcus pneumoniae infection in the middle ear, wild-type (WT; C57BL/6) and TLR2-deficient (TLR2 ؊/؊ ) mice were inoculated with Streptococcus pneumoniae (1 ؋ 10 6 CFU) through the tympanic membrane. Nineteen of 37 TLR2 ؊/؊ mice showed bacteremia and died within 3 days after the challenge, compared to only 4 of 32 WT mice that died. Of those that survived, more severe hearing loss in the TLR2 ؊/؊ mice than in the WT mice was indicated by an elevation in auditory-evoked brain stem response thresholds at 3 or 7 days postinoculation. The histological pathology was characterized by effusion and tissue damage in the middle ear, and in the TLR2 ؊/؊ mice, the outcome of infection became more severe at 7 days. At both 3 and 7 days postchallenge, the TLR2 ؊/؊ mice had higher blood bacterial titers than the WT mice (P < 0.05), and typical bacteria were identified in the effusion from both ears of both mouse groups by acridine orange staining. Moreover, by 3 days postchallenge, the mRNA accumulation levels of NF-B, tumor necrosis factor alpha, interleukin 1␤, MIP1␣, Muc5ac, and Muc5b were significantly lower in the ears of TLR2 ؊/؊ mice than in WT mice. In summary, TLR2 ؊/؊ mice may produce relatively low levels of proinflammatory cytokines following pneumococcal challenge, thus hindering the clearance of bacteria from the middle ear and leading to sepsis and a high mortality rate. This study provides evidence that TLR2 is important in the molecular pathogenesis and host response to otitis media.Streptococcus pneumoniae, a gram-positive bacterium, is one of the two most common pathogens involved in acute middle ear infection, which frequently leads to acquired hearing loss and communication disorders in children (20). The first line of host defense against bacterial infection by the innate immune system is essentially initiated by Toll-like receptors (TLRs), family-pattern-recognition receptors that detect and respond to microbial ligands (3). TLR2 mediates host responses to gram-positive bacterial cell wall components such as peptidoglycan (PGN), lipoteichoic acids (LTA), and lipoproteins (1, 37). TLR2 may function as a regulator of inflammation, and abnormal immune inflammatory responses develop in the absence of TLR2. In humans, one mutation in the TLR2 gene results in an Arg753Gln polymorphism that predisposes individuals to life-threatening bacterial infections (22). TLR2-deficient (TLR2 Ϫ/Ϫ ) mice succumb to Mycobacterium tuberculosis infection (6) and are highly susceptible to Staphylococcus aureus infection (32). TLR2 Ϫ/Ϫ mice show delayed pneumococcal phagocytosis and impaired oxidative killing by granulocytes (17). Studies have also demonstrated that TLR2 participates in the mediation of the immune response in experimental pneumococcal meningitis (16,18) and that mice with a targeted disruption of the TLR2 gene are more susceptible to meningitis-induce...

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Section: Discussionmentioning

confidence: 55%

Role for Toll-Like Receptor 2 in the Immune Response toStreptococcus pneumoniaeInfection in Mouse Otitis Media

Han

Tian

et al. 2009

Infect Immun

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“…Acute pneumococcal OM was induced by direct bilateral transtympanic inoculation of the middle ear, as previously described (14). Briefly, mice were anesthetized by intraperitoneal injection with ketamine hydrochloride (20 mg/kg of body weight) and xylazine (5 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

Essential Role of Factor B of the Alternative Complement Pathway in Complement Activation and Opsonophagocytosis during Acute Pneumococcal Otitis Media in Mice

Stahl

et al. 2011

Infect Immun

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We recently reported that the complement system plays a pivotal role in innate immune defense against Streptococcus pneumoniae during acute otitis media (OM) in mice. The current study was designed to determine which of the complement pathways are activated during acute pneumococcal OM and whether components of complement are expressed in the middle ear epithelium. Gene expression was determined by quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. We found that S. pneumoniae induced increased gene expression of factor B of the alternative complement pathway and C3 in mouse middle ear epithelium. Activation of factor B and C3 in the middle ear lavage fluids was significantly greater than in simultaneously obtained serum samples as determined by Western blotting. Using mice deficient in complement C1qa, factor B, and factor B/C2, we found that complement C3 activation and opsonophagocytosis of S. pneumoniae were greatly attenuated in factor B-and factor B/C2-deficient mice. These findings support the concept that local complement activation is an important host innate immune response and that activation of the alternative complement pathway represents one of the innate immune defense mechanisms against pneumococcal infection during the early stage of acute OM.

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“…The authors also found that highly virulent pneumococcal serotypes (types 3 and 6) consistently induced lethal sepsis with or without ME infection, while less virulent strains (types 9 and 19) produced otitis (164,210). Direct inoculation of bacteria into the ME can also be instrumental in assessing inflammation in the ME following the injection of heat-killed pneumococci (152,161). As acute bacterial otitis media is an inflammatory response to replicating microorganisms, the use of heat-killed bacteria does not mimic the natural disease but still allows measurements of inflammatory parameters in the ME, such as the amount and type of effusions, the thickness of the tympanic membrane, and the recruitment of polymorphonuclear cells (152).…”

Section: Rat and Mouse Modelsmentioning

confidence: 99%

“…Direct inoculation of bacteria into the ME can also be instrumental in assessing inflammation in the ME following the injection of heat-killed pneumococci (152,161). As acute bacterial otitis media is an inflammatory response to replicating microorganisms, the use of heat-killed bacteria does not mimic the natural disease but still allows measurements of inflammatory parameters in the ME, such as the amount and type of effusions, the thickness of the tympanic membrane, and the recruitment of polymorphonuclear cells (152). The mouse intratympanic/intrabullar model of pneumococcal otitis media found applications in both vaccine (211,212) and therapy (161) research fields.…”

Section: Rat and Mouse Modelsmentioning

confidence: 99%

Animal Models ofStreptococcus pneumoniaeDisease

2008

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SUMMARY Streptococcus pneumoniae is a colonizer of human nasopharynx, but it is also an important pathogen responsible for high morbidity, high mortality, numerous disabilities, and high health costs throughout the world. Major diseases caused by S. pneumoniae are otitis media, pneumonia, sepsis, and meningitis. Despite the availability of antibiotics and vaccines, pneumococcal infections still have high mortality rates, especially in risk groups. For this reason, there is an exceptionally extensive research effort worldwide to better understand the diseases caused by the pneumococcus, with the aim of developing improved therapeutics and vaccines. Animal experimentation is an essential tool to study the pathogenesis of infectious diseases and test novel drugs and vaccines. This article reviews both historical and innovative laboratory pneumococcal animal models that have vastly added to knowledge of (i) mechanisms of infection, pathogenesis, and immunity; (ii) efficacies of antimicrobials; and (iii) screening of vaccine candidates. A comprehensive description of the techniques applied to induce disease is provided, the advantages and limitations of mouse, rat, and rabbit models used to mimic pneumonia, sepsis, and meningitis are discussed, and a section on otitis media models is also included. The choice of appropriate animal models for in vivo studies is a key element for improved understanding of pneumococcal disease.

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Evaluation of the mouse model for acute otitis media

Cited by 40 publications

References 47 publications

Role for Toll-Like Receptor 2 in the Immune Response toStreptococcus pneumoniaeInfection in Mouse Otitis Media

Role for Toll-Like Receptor 2 in the Immune Response toStreptococcus pneumoniaeInfection in Mouse Otitis Media

Essential Role of Factor B of the Alternative Complement Pathway in Complement Activation and Opsonophagocytosis during Acute Pneumococcal Otitis Media in Mice

Animal Models ofStreptococcus pneumoniaeDisease

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