Francisella tularensis, an intracellular pathogen causing the disease tularemia, utilizes surface glycoconjugates such as lipopolysaccharide, capsule, and capsule-like complex for its protection against inhospitable conditions of the environment. Francisella species also possess a functional glycosylation apparatus by which specific proteins are O-glycosidically modified. We here created a mutant with a nonfunctional FTS_1402 gene encoding for a putative glycan flippase and studied the consequences of its disruption. The mutant strain expressed diminished glycosylation similarly to, but to a lesser extent than, that of the oligosaccharyltransferase-deficient ΔpglA mutant. In contrast to ΔpglA, inactivation of FTS_1402 had a pleiotropic effect, leading to alteration in glycosylation and, importantly, to decrease in lipopolysaccharide, capsule, and/or capsule-like complex production, which were reflected by distinct phenotypes in host-pathogen associated properties and virulence potential of the two mutant strains. Disruption of FTS_1402 resulted in enhanced sensitivity to complement-mediated lysis and reduced virulence in mice that was independent of diminished glycosylation. Importantly, the mutant strain induced a protective immune response against systemic challenge with homologous wild-type FSC200 strain. Targeted disruption of genes shared by multiple metabolic pathways may be considered a novel strategy for constructing effective live, attenuated vaccines.
- MeSH
- ABC transportéry genetika metabolismus MeSH
- bakteriální proteiny genetika metabolismus MeSH
- chromatografie kapalinová MeSH
- Francisella tularensis genetika metabolismus patogenita MeSH
- genetická pleiotropie MeSH
- glykokonjugáty biosyntéza MeSH
- glykosylace MeSH
- hexosyltransferasy genetika metabolismus MeSH
- interakce hostitele a patogenu MeSH
- lipopolysacharidy biosyntéza MeSH
- membránové proteiny genetika metabolismus MeSH
- mutace MeSH
- myši inbrední BALB C MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- regulace genové exprese u bakterií MeSH
- tandemová hmotnostní spektrometrie MeSH
- tularemie mikrobiologie MeSH
- umlčování genů MeSH
- virulence genetika MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- cytokiny imunologie sekrece MeSH
- humanizované monoklonální protilátky aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- kongresy jako téma MeSH
- lidé MeSH
- lipopolysacharidy biosyntéza MeSH
- monoklonální protilátky * dějiny terapeutické užití MeSH
- myši MeSH
- receptory TNF chemie metabolismus MeSH
- rekonciliace medikace MeSH
- revmatoidní artritida farmakoterapie MeSH
- TNF-alfa analýza dějiny imunologie MeSH
- Check Tag
- lidé MeSH
- myši MeSH
The lipid components of pathogen cell membranes have been considered as a poor pharmacological target, due to their universal distribution and apparent homogeneity throughout living organisms. Among the rare exceptions to this view one could mention polyene antibiotics such as amphotericin, or peptide antibiotics such as the polymyxins and the gramicidins. In the last two decades, however, the above notion has been challenged by two main lines of discovery; first, natural antimicrobial peptides (AMPs) that kill pathogens by interaction with phospholipids and membrane permeabilization, and secondly, cell-penetrating peptides (CPPs), capable of introducing into cells a variety of cargoes in the absence of specific receptors, again by interaction at some point with membrane phospholipids. For both AMPs and CPPs, the pharmacological proof-of-concept has been successfully demonstrated, and promising applications as nanobiotechnological tools have been envisaged though not hitherto materialized in clinical settings. In this review we briefly examine the pros and cons of these two classes of therapeutic agents, as well as strategies aimed at rationalizing and expanding their potentiality.
- MeSH
- antibiotická rezistence genetika imunologie MeSH
- financování organizované MeSH
- infekční nemoci farmakoterapie MeSH
- kationické antimikrobiální peptidy genetika účinky léků MeSH
- lidé MeSH
- lipopolysacharidy biosyntéza MeSH
- mikrochemie metody trendy MeSH
- peptidy genetika metabolismus účinky léků MeSH
- permeabilita buněčné membrány genetika imunologie účinky léků MeSH
- rostliny MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
