Invasivität und intrazelluläres Wachstum von Listeria monocytogenes

Berche, Patrick; Gaillard, Jean‐Louis; Richard, S.

doi:10.1007/bf01639738

Cited by 42 publications

(22 citation statements)

References 24 publications

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“…While the MICs of L. pneumophila could not be determined at this low value because of the lack of bacterial . This is actually anticipated, since the MIC-pH relationships for the four macrolides against this organism in broth are essentially parallel, and L. monocytogenes is known to sojourn and multiply in the cytosol of many cell types (6,31), including THP-1 macrophages (30), where pH is close to neutral and where the bulk of CEM-101 is not likely to accumulate.…”

Section: Vol 53 2009 Intracellular Accumulation and Activity Of Cemmentioning

confidence: 99%

Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, againstStaphylococcus aureus,Listeria monocytogenes, andLegionella pneumophilain Human THP-1 Macrophages

Lemaire

Bambeke

Tulkens

2009

Antimicrob Agents Chemother

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CEM-101 is a novel fluoroketolide with lower MICs than those of telithromycin and macrolides. Our aim was to assess the cellular accumulation and intracellular activity of CEM-101 using models developed for analyzing the pharmacokinetics and pharmacological properties of antibiotics against phagocytized bacteria. We used THP-1 macrophages and Staphylococcus aureus (ATCC 25923 [methicillin (meticillin) sensitive]), Listeria monocytogenes (strain EGD), and Legionella pneumophila (ATCC 33153). CEM-101 reached cellular-to-extracellular-concentration ratios of about 350 within 24 h (versus approximately 20, 30, and 160 for telithromycin, clarithromycin, and azithromycin, respectively). This intracellular accumulation was suppressed by incubation at a pH of <6 and by monensin (proton ionophore) and was unaffected by verapamil (P-glycoprotein inhibitor; twofold accumulation increase for azithromycin) or gemfibrozil. While keeping with the general properties of the macrolide antibiotics in terms of maximal efficacy (E max ; approximately 1-log 10 -CFU decrease compared to the postphagocytosis inoculum after a 24-h incubation), CEM-101 showed significantly greater potency against phagocytized S. aureus than telithromycin, clarithromycin, and azithromycin (for which the 50% effective concentration [EC 50 ] and static concentrations were about 3-, 6-, and 15-fold lower, respectively). CEM-101 was also about 50-fold and 100-fold more potent than azithromycin against phagocytized L. monocytogenes and L. pneumophila, respectively. These differences in EC 50 s and static concentrations between drugs were minimized when data were expressed as multiples of the MIC, demonstrating the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects, whereas accumulation per se was unimportant. CEM-101 should show enhanced in vivo potency if used at doses similar to those of the comparators tested here.

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Section: Vol 53 2009 Intracellular Accumulation and Activity Of Cemmentioning

confidence: 99%

Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, againstStaphylococcus aureus,Listeria monocytogenes, andLegionella pneumophilain Human THP-1 Macrophages

Lemaire

Bambeke

Tulkens

2009

Antimicrob Agents Chemother

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“…Listeria express an array of virulence factors that enable the bacteria to survive and spread (16). However, LLO, the product of the hemolysin (hly) gene, is a pivotal virulence factor for not only the survival of the bacteria, but also for the development of protective immunity (17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Cytoplasmic Entry of Listeria monocytogenes Enhances Dendritic Cell Maturation and T Cell Differentiation and Function

Brzoza

Rockel

Hiltbold

2004

The Journal of Immunology

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Protective immunity to the intracellular bacterial pathogen, Listeria monocytogenes, is mediated by a vigorous T cell response. In particular, CD8+ cytolytic T cells provide essential effector function in the clearance of bacterial infection. The cytoplasmic entry of Listeria facilitated by listeriolysin O is an essential feature not only of the bacteria’s virulence, but of the ability of the bacteria to elicit protective immunity in the host. To determine how cytoplasmic entry of Listeria regulates the development of protective immunity, we examined the effects of this process on the maturation of murine dendritic cells (DC) and on their ability to prime naive CD8+ T cell responses. Costimulatory molecules (CD40, CD80, and CD86) were induced by listerial infection only when the bacteria invaded the cytoplasm. In addition, the production of IL-12, IL-10, IL-6, and TNF-α was most efficiently triggered by cytosolic Listeria. Naive T cells primed by peptide-loaded DC infected with either wild-type or nonhemolytic mutant Listeria proliferated equivalently, but a much larger proportion of those primed by wild-type Listeria monocytogenes produced IFN-γ. Costimulatory molecules induced by cytosolic entry regulated T cell proliferation and, as a result, the number of functional T cells generated. DC-produced cytokines (specifically IL-12 and IL-10) were the major factors determining the proportion of T cells producing IFN-γ. These data highlight the requirement for listerial cytoplasmic invasion for the optimal priming of T cell cytokine production and attest to the importance of this event to the development of protective CTL responses to this pathogen.

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“…Food-borne Listeria can infect intestinal epithelial cells and spread from cell to cell without exposure to the extracellular milieu (3). Furthermore, Listeria can infect phagocytic cells and escape the phagolysosome through the activity of secreted proteins, including listeriolysin O (LLO) 3 (4,5). In this way, Listeria can be disseminated to other organs and infect other cell types, particularly in the liver and spleen (6 -8).…”

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confidence: 99%

Organ-Specific Regulation of the CD8 T Cell Response toListeria monocytogenesInfection

Pope

Kim

Marzo

et al. 2001

The Journal of Immunology

362

357

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The intestinal mucosal CD8 T cell response to infection with Listeria monocytogenes was measured using MHC class I tetramers and was compared with the response in peripheral blood, secondary lymphoid tissue, and liver. To assess the vaccination potential of Listeria and to analyze responses in C57BL/6 mouse strains, a recombinant Listeria expressing OVA (rLM-ova) was generated. The response peaked at 9 days postinfection with a much larger fraction of the intestinal mucosa and liver CD8 T cell pool OVA specific, as compared with the spleen. However, these differences were not linked to bacterial titers in each site. The higher responses in lamina propria and liver resulted in a larger CD8 memory population in these tissues. Furthermore, the level of memory induced was dependent on infectious dose and inversely correlated with the magnitude of the recall response after oral challenge. Recall responses in the tissues were most robust in the lamina propria and liver, and reactivated Ag-specific T cells produced IFN-γ. Infection of CD40- or MHC class II-deficient mice induced poor CD8 T cell responses in the intestinal mucosa, but only partially reduced responses in the spleen and liver. Overall, the results point to novel pathways of tissue-specific regulation of primary and memory antimicrobial CD8 T cell responses.

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Invasivität und intrazelluläres Wachstum von Listeria monocytogenes

Cited by 42 publications

References 24 publications

Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, againstStaphylococcus aureus,Listeria monocytogenes, andLegionella pneumophilain Human THP-1 Macrophages

Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, againstStaphylococcus aureus,Listeria monocytogenes, andLegionella pneumophilain Human THP-1 Macrophages

Cytoplasmic Entry of Listeria monocytogenes Enhances Dendritic Cell Maturation and T Cell Differentiation and Function

Organ-Specific Regulation of the CD8 T Cell Response toListeria monocytogenesInfection

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