PMC:1069646 / 30348-35378 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/1069646","sourcedb":"PMC","sourceid":"1069646","source_url":"http://www.ncbi.nlm.nih.gov/pmc/1069646","text":"Cell Wall Structure\nA dramatic case of lineage-specific gene loss in both Wolbachia spp. includes approximately 20 genes for enzymes of cell-envelope LPS biosynthesis. It has been reported that soluble endotoxin-like products of Wolbachia endosymbionts of filarial nematodes, including B. malayi, B. pahangi, L. sigmodontis, O. volvulus, and D. immitis, contribute to the immunology and pathogenesis of filarial diseases through induction of potent inflammatory responses, including production of tumor necrosis factor alpha, interleukin-1-beta, and nitric oxide by macrophages [22,58,59,60,71,72,140,141]. Chemokine and cytokine responses to the sterile extracts of Brugia and Onchocerca were dependent on signaling through TLR4 and could be blocked by neutralizing antibodies to CD14 and by the antagonistic lipid A analogs, indicating that the inflammatory response was induced by an LPS-like molecule. Recently the major surface protein of Wolbachia spp. was implicated as the inducer of the immune response acting in a TLR2- and TLR4-dependent manner [141]. However, it is not clear whether this protein is the only Wolbachia-specific molecule eliciting a TLR4-dependent innate immune response.\nAnalysis of the wBm genome indicates that, like Ehrlichia chaffeensis and Anaplasma phagocytophilum [142], it lacks homologs of the genes responsible for biosynthesis of lipid A. Although lipid A structure can vary in different bacteria, it always consists of a polysaccharide backbone carrying fatty acid residues. The only predicted genes belonging to the glycosyltransferase family were those participating in peptidoglycan biosynthesis, and one glycosyltransferase pseudogene is present. Similarly, the only genes from the acyltransferase family are those participating in fatty acid and phospholipid biosynthesis. Thus, it is unlikely that the cell wall of wBm contains LPS-like molecules. This idea is supported by the absence of the gene products responsible for maintaining the outer membrane structure in Gram-negative bacteria, such as TolQ, TolR, TolA, and TolB.\nSeveral lines of evidence suggest that the structure of the wBm peptidoglycan is very unusual, and peptidoglycan derivatives might be responsible in part for the observed inflammatory responses. First, although all the genes necessary for biosynthesis of lipid II are present in the wBm genome, there are no homologs of alanine and glutamate racemases responsible for synthesis of pentapeptide components D-alanine and D-glutamate. While the genomes of Rickettsia spp. contain L-alanine racemase that could catalyze racemization of both alanine and glutamate, the only amino acid racemase present in the genomes of both Wolbachia is meso-DAP epimerase (Wbm0518), an enzyme catalyzing interconversions of LL- and meso-isomers of diaminopimelate. It is possible that meso-DAP epimerase is able to catalyze racemization of alanine and glutamate, although this activity has never been experimentally demonstrated. Alternatively, instead of the usual D-isomers, wBm peptidoglycan might contain L-isomers of alanine and glutamate.\nSecond, Gram-negative bacteria (including Rickettsia spp.) usually contain two monofunctional transpeptidases. One of them, FtsI (also known as PBP3), is localized to the septal ring and is required for peptidoglycan biosynthesis in the division septum, while the other, PBP2, is localized preferentially to the lateral cell wall [143]. FtsI and PBP2 are recruited to the sites of their action by two membrane proteins, FtsW and RodA, respectively. In the wBm genome, only functional orthologs of E. coli RodA and PBP2 were found; the orthologs of FtsW–FtsI are disrupted by multiple frameshifts.\nThird, genomes of bacteria that have peptidoglycan in their cell wall usually contain at least one gene coding for a high molecular weight penicillin-binding protein responsible for cross-linking of the murein sacculus. The transpeptidase and transglycosylase domains of this protein catalyze transpeptidation and transglycosylation of the murein precursors, respectively, to form the carbohydrate backbone of murein and the interstrand peptide linkages. No homologs of bifunctional transpeptidase/transglycosylase or monofunctional biosynthetic transglycosylase were found in the genomes of Wolbachia spp., although they are present in the Rickettsial genomes. The homolog of lytic transglycosylase, which is responsible for hydrolysis of the carbohydrate backbone during bacterial growth and division, is also absent from the genomes of both Wolbachia spp. Thus, their peptidoglycan can be cross-linked by the interstrand peptide linkages, but the carbohydrate backbone is not polymerized. These observations suggest that peptidoglycan of wBm has some features in common with the peptidoglycan-derived cytotoxin produced by Neisseria gonorrhoeae and Bordetella pertussis [144,145] and that muramyl peptides derived from wBm peptidoglycan could elicit the inflammatory response contributing to the pathogenesis of filarial infection.","divisions":[{"label":"Title","span":{"begin":0,"end":19}}],"tracks":[{"project":"2_test","denotations":[{"id":"15780005-10770808-84825071","span":{"begin":579,"end":581},"obj":"10770808"},{"id":"15780005-11741630-84825072","span":{"begin":582,"end":584},"obj":"11741630"},{"id":"15780005-14738900-84825073","span":{"begin":585,"end":587},"obj":"14738900"},{"id":"15780005-14733727-84825074","span":{"begin":588,"end":590},"obj":"14733727"},{"id":"15780005-11008105-84825075","span":{"begin":597,"end":600},"obj":"11008105"},{"id":"15780005-15210803-84825076","span":{"begin":601,"end":604},"obj":"15210803"},{"id":"15780005-15210803-84825077","span":{"begin":1057,"end":1060},"obj":"15210803"},{"id":"15780005-12933880-84825078","span":{"begin":1301,"end":1304},"obj":"12933880"},{"id":"15780005-12519203-84825079","span":{"begin":3430,"end":3433},"obj":"12519203"},{"id":"15780005-12010959-84825080","span":{"begin":4870,"end":4873},"obj":"12010959"},{"id":"T46772","span":{"begin":579,"end":581},"obj":"10770808"},{"id":"T25242","span":{"begin":582,"end":584},"obj":"11741630"},{"id":"T21188","span":{"begin":585,"end":587},"obj":"14738900"},{"id":"T95872","span":{"begin":588,"end":590},"obj":"14733727"},{"id":"T24532","span":{"begin":597,"end":600},"obj":"11008105"},{"id":"T91555","span":{"begin":601,"end":604},"obj":"15210803"},{"id":"T71938","span":{"begin":1057,"end":1060},"obj":"15210803"},{"id":"T7155","span":{"begin":1301,"end":1304},"obj":"12933880"},{"id":"T44662","span":{"begin":3430,"end":3433},"obj":"12519203"},{"id":"T12354","span":{"begin":4870,"end":4873},"obj":"12010959"}],"attributes":[{"subj":"15780005-10770808-84825071","pred":"source","obj":"2_test"},{"subj":"15780005-11741630-84825072","pred":"source","obj":"2_test"},{"subj":"15780005-14738900-84825073","pred":"source","obj":"2_test"},{"subj":"15780005-14733727-84825074","pred":"source","obj":"2_test"},{"subj":"15780005-11008105-84825075","pred":"source","obj":"2_test"},{"subj":"15780005-15210803-84825076","pred":"source","obj":"2_test"},{"subj":"15780005-15210803-84825077","pred":"source","obj":"2_test"},{"subj":"15780005-12933880-84825078","pred":"source","obj":"2_test"},{"subj":"15780005-12519203-84825079","pred":"source","obj":"2_test"},{"subj":"15780005-12010959-84825080","pred":"source","obj":"2_test"},{"subj":"T46772","pred":"source","obj":"2_test"},{"subj":"T25242","pred":"source","obj":"2_test"},{"subj":"T21188","pred":"source","obj":"2_test"},{"subj":"T95872","pred":"source","obj":"2_test"},{"subj":"T24532","pred":"source","obj":"2_test"},{"subj":"T91555","pred":"source","obj":"2_test"},{"subj":"T71938","pred":"source","obj":"2_test"},{"subj":"T7155","pred":"source","obj":"2_test"},{"subj":"T44662","pred":"source","obj":"2_test"},{"subj":"T12354","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#ecb393","default":true}]}]}}