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Our studies have demonstrated previously that suppression of gp96 prevents E.?coli K1 traversal across the BBB (Mittal and Prasadarao, 2010). Since gp96 acts as a chaperone for TLR2 and TLR4, we determined whether lack of either of these molecules would affect the outcome of meningitis. The virulence of E.?coli K1 was analysed in newborn TLR2?/? or TLR4?/? mice. As https://en.wikipedia.org/wiki/Pentamorphone shown in Fig.?1A, all of the TLR2?/? mice survived until 4 days post infection similar to wild-type animals that received saline. In contrast, 50% of E.?coli K1-infected TLR4?/? newborn mice became extremely sick by 48?h and were euthanized. The remaining 50% became moribund and were subsequently euthanized at 72?h. In contrast, the wild-type newborn mice did not become moribund until 72 to 86?h post infection. These observations indicate that lack of TLR2 is protective against E.?coli meningitis whereas absence of TLR4 aggravates the disease process. Histopathologic analysis of brain sections of the infected wild-type mice revealed a significant neutrophil infiltration in the cortex and signs of gliosis (Fig.?1B). However, the brains of the TLR2?/? mice appeared normal, indicating that E.?coli K1 did not cause detectable brain injury in these animals. In contrast, the brain histopathology of the TLR4?/? mice was similar to or worse than that of the infected wild-type mice at 48 to 72?h post infection. By quantitative culture, the brain bacterial load in the TLR4?/? mice was twofold greater than in the control-infected mice at 48 and 72?h post infection, while no bacteria were cultured from TLR2?/? mice (Fig.?1C). These results indicate http://www.selleckchem.com/products/Adriamycin.html that TLR2 expression is necessary for E.?coli K1 to cause meningitis, whereas TLR4 is required for the maximal host defence against meningitis. Traversal of E.?coli K1 from the circulation across the BBB, which constitutes a single cell layer http://www.selleckchem.com/products/LBH-589.html of endothelial cells, is a critical step in the pathogenesis of meningitis (Prasadarao, 2002). Since our in vivo experiments showed that TLR2 and TLR4 play important roles in E.?coli K1-induced pathology in newborn mice, we used real-time PCR to determine the effects of OmpA+ and OmpA? E.?coli K1 infection on HBMEC ecgp96, tlr2 and tlr4 mRNA expression. Infection of HBMEC with OmpA+ E.?coli caused ecgp96 transcript levels to increase 3.0?��?0.75-fold by 60 and 90?min post infection (Fig.?2A). In contrast, infection of HBMEC with OmpA? E.?coli infection actually suppressed ecgp96 mRNA expression below that of uninfected control HBMEC at 30�C90?min (**P?