Myeloid Differentiation Primary Response Gene 88 Is Required for the Resolution of Otitis Media

Abstract

Background Signaling defects in the Toll-like receptor (TLR) pathway, such as interleukin-1 receptor–associated kinase 4 deficiency, highlight the prominence of TLR signaling in the defense against bacterial disease. Because myeloid differentiation primary response gene 88 (MyD88) can transduce signals from almost all TLRs, we studied its role in otitis media (OM), the most common upper respiratory tract bacterial infectious disease in young children. Methods The middle ears (MEs) of wild-type (WT) and MyD88−/− mice were inoculated with nontypeable Haemophilus influenzae (NTHi). ME infection and inflammation were monitored for 21 days after surgery. Bone marrow–derived macrophages from WT and MyD88−/− mice were infected with NTHi in vitro to assess their interaction with bacteria. Results In WT mice, MyD88 expression was detected in the ME stroma at baseline. MyD88−/− mice displayed prolonged ME mucosal thickening and delayed recruitment of neutrophils and macrophages. Although WT mice cleared NTHi within 5 days, viable NTHi were isolated for up to 21 days in MyD88−/− mice. The interaction between macrophages and NTHi was significantly altered in MyD88−/− mice. Conclusions In this mouse model, MyD88-mediated signaling was important for clearance of infection and resolution of inflammation in acute OM due to NTHi. The role played by innate signaling in children susceptible to chronic or recurrent OM deserves further study.

Otitis Media and Nasopharyngeal Colonization inccl3−/−Mice

“…This persistence seems most likely to be due to the prolonged presence of NTHi, as has been observed with other defects in innate immunity (13)(14)(15). This could well be related to the phagocytic defect in ccl3 Ϫ/Ϫ macrophages.…”

“…Results for all CCL genes and the variability of expression levels are presented in Table S1 in the supplemental material. CCL20 data were reported previously in a different form (14). Data analysis was performed by using VAMPIRE (41).…”

“…Mice with mutations in TLR2 (15), MyD88 (14), or TNF (13) are impaired in the clearance of NTHi from the ME, with a concomitant delay in mucosal recovery. However, our present study found that CCL3 deletion produces a somewhat milder OM phenotype.…”

“…Previous gene expression studies of the ME mucosa in mice after NTHi exposure demonstrated increased expression levels of TLR signaling molecules, especially during the initial stages of the inflammatory response, during acute OM (11,12). Defects in TLR signaling are associated with an impaired immune response to NTHi-induced ME infection (13)(14)(15). In humans, polymorphisms in TLR genes are associated with increased susceptibility to ME infections (16,17).…”

Chronic Otitis Media: Microbial Environment During Viral Infection and Genetics of Host Susceptibility

“…Myeloid differentiation primary response gene 88 (MyD88) 67 and Toll like receptor 2 (Tlr2) 68 that both cause defects in the immune system, and Chibby (Cby) which lacks motile cilia and therefore is unable to clear effusion buildup 69 .…”