MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS

Abstract

Myeloid differentiation factor 88 (MyD88) is an essential intracellular signal transducer in Toll-like receptor (TLR) and interleukin (IL)-1 receptor family member-mediated cell activation. In order to characterize the role of MyD88 in pneumococcal meningitis we used gene-targeted mice lacking functional MyD88 expression. At 24 h after intracisternal infection, MyD88- deficient mice displayed a markedly diminished inflammatory host response in the CNS, as evidenced by reduced CSF pleocytosis and expression of cytokines, chemokines and complement factors. The reduced CNS inflammation was paralleled by a marked reduction in the prognostic relevant CNS complications, such as brain oedema formation. Nevertheless, MyD88 deficiency was associated with a worsening of disease which seemed to be attributable to severe bacteraemia. This notion was supported by the unexpected observation that infected MyD88-deficient mice displayed enhanced mRNA expression of inflammatory mediators [such as the proinflammatory cytokine tumour necrosis factor alpha (TNF-alpha) and the CXC chemokine macrophage inflammatory protein (MIP-2)] in the lung and consequently increased cell influx in the bronchoalveolar lavage fluid, compared with infected wild-type mice. Thus, the present study demonstrated for the first time an important role of MyD88 in immune activation to bacterial pathogens within the CNS. The role played by MyD88 in mounting an immune response to Streptococcus pneumoniae, however, seems to be dependent on the anatomical compartment involved.

Complement C1q and C3 Are Critical for the Innate Immune Response to Streptococcus pneumoniae in the Central Nervous System

“…Moreover, we recently observed that MyD88-deficient mice had a similar phenotype to that of C3-deficient mice. Infected MyD88-deficient mice displayed an attenuated immune response and less pronounced intracranial complications, but had a higher mortality rate that was associated with more severe bacteremia, more pronounced hypothermia, more frequent breathing problems, and more pronounced secondary pneumonia (19), when compared with infected wt mice. Because MyD88 deficiency was associated with a substantial suppression of the brain expression of complement factors, it is conceivable that the absence of complement factors is responsible for the clinical phenotype observed in both mouse strains.…”

“…A well-characterized mouse model of pneumococcal meningitis was used in this study (19,27). Briefly, meningitis was induced by transcutaneous injection of 15 l of a bacterial suspension containing 10 7 CFU/ml S. pneumoniae type 3 into the cisterna magna under short-term anesthesia with halothane.…”

“…Mice were weighed, put into cages, and allowed to awaken. Twenty-four hours after infection, mice were evaluated clinically as described previously (19). Thereafter, the body temperature was measured via a rectal probe, mice were reweighed, and anesthetized with ketamine/ xylazine.…”

“…To assess BBB integrity, mouse brain homogenates were examined for infiltration by albumin, an abundant serum protein that is normally excluded from the brain by the intact BBB, using ELISA as described previously (19).…”

“…Within the CSF, essential C proteins like C3 are almost totally absent under physiological conditions (17)(18)(19). During the course of bacterial meningitis, C protein concentrations can increase in the CSF, but remain below blood levels (18,20).…”