Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wolbachia endosymbiotic bacteria have been implicated in the inflammatory pathogenesis of filariasis. Inflammation induced by Brugia malayi female worm extract (BMFE) is dependent on Toll-like receptors 2 and 6 (TLR2/6) with only a partial requirement for TLR1. Removal of Wolbachia, lipids, or proteins eliminates all inflammatory activity. Wolbachia bacteria contain the lipoprotein biosynthesis genes Ltg and LspA but not Lnt, suggesting Wolbachia proteins cannot be triacylated, accounting for recognition by TLR2/6. Lipoprotein databases revealed 3-11 potential lipoproteins from Wolbachia. Peptidoglycan-associated lipoprotein (PAL) and Type IV secretion system-VirB6 were consistently predicted, and B. malayi Wolbachia PAL (wBmPAL) was selected for functional characterization. Diacylated 20-mer peptides of wBmPAL (Diacyl Wolbachia lipopeptide (Diacyl WoLP)) showed a near identical TLR2/6 and TLR2/1 usage compared with BMFE and bound directly to TLR2. Diacyl WoLP induced systemic tumor necrosis factor-alpha and neutrophil-mediated keratitis in mice. Diacyl WoLP activated monocytes induce up-regulation of gp38 on human lymphatic endothelial cells and induced dendritic cell maturation and activation. Dendritic cells primed with BMFE generated a non-polarized Th1/Th2 CD4+ T cell profile, whereas priming with Wolbachia depleted extracts (following tetracycline treatment; BMFEtet) polarized to a Th2 profile that could be reversed by reconstitution with Diacyl WoLP. BMFE generated IgG1 and IgG2c antibody responses, whereas BMFEtet or inoculation of TLR2 or MyD88-/- mice produced defective IgG2c responses. Thus, in addition to innate inflammatory activation, Wolbachia lipoproteins drive interferon-gamma-dependent CD4+ T cell polarization and antibody switching.
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PMID:Wolbachia lipoprotein stimulates innate and adaptive immunity through Toll-like receptors 2 and 6 to induce disease manifestations of filariasis. 1945 89

Purpose. To investigate the expression and function of toll-like receptors (TLRs) during experimental keratomycosis. Methods. Scarified corneas of BALB/c mice were topically inoculated with Candida albicans and compared with control corneas by a murine gene microarray and immunostaining. Real-time reverse transcription polymerase chain reaction (RT-PCR) determined relative TLR gene expression in murine and human donor corneas. The scarified corneas of TLR2(-/-) mice, TLR4(-/-) mice, and C57BL/6J control mice were also inoculated with C. albicans, to determine relative severity, fungal load, and cytokine transcript levels. Results. TLR1, -2, -4, -6, and -13 were significantly upregulated (5- to 10-fold; P < 0.01) by microarray, and TLR1, -2, -4, and -13 were significantly increased (4- to 11-fold; P < 0.05) by real-time RT-PCR in BALB/c murine corneas. Similarly, TLR2, -6, and -13 were significantly upregulated (5- to 16-fold; P < or = 0.001) by real-time RT-PCR in C57BL/6J murine corneas the day after inoculation, and TLR2 and -13 remained significantly (P < 0.05) increased after 1 week. TLR2 transcript was also upregulated twofold (P = 0.04) in C. albicans-inoculated explanted human corneas. Although murine keratitis severity scores were similar, significantly more fungi were recovered from TLR2(-/-) mouse corneas (P = 0.04) than from TLR4(-/-) mouse corneas (P = 0.9). Tumor necrosis factor-alpha, interleukin 23, chemokine C-C ligands 3 and 4, and dectin-1 were significantly (P < 0.05) downregulated in C. albicans-infected corneas of TLR2(-/-) mice. Conclusions. TLR2 signals proinflammatory cytokines that control fungal growth during C. albicans keratitis. TLR13 may have an additional role in the innate immune response of murine corneal candidiasis.
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PMID:Toll-like receptors involved in the pathogenesis of experimental Candida albicans keratitis. 1993 94