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

Abstract

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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