Essential role of toll-like receptor 4 in Acinetobacter baumannii-induced immune responses in immune cells

Kim, Chang-Hwan; Jeong, Yu‐Jin; Lee, Junglim; Jeon, Soo-Jin; Park, Se-Ra; Kang, Min‐Jung; Park, Jae‐Hak; Park, Jong‐Hwan

doi:10.1016/j.micpath.2012.08.008

Cited by 42 publications

(34 citation statements)

References 32 publications

(35 reference statements)

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“…These data are in agreement with those previously reported from our group showing that a susceptible A. baumannii strain induced more TNF-␣ and IL-6 release than that by MDR and pan-drugresistant A. baumannii clinical isolates (30,31). In line with these data, macrophages deficient in Toll-like receptor 4 (TLR4) or neutrophil depletion resulted in impaired bacterial killing ability against A. baumannii, possibly due at least to the alteration of production of proinflammatory cytokines (TNF-␣, IL-17, gamma interferon [IFN-␥], and IL-1␤) (32)(33)(34). In an in vivo study, Qiu et al associated the susceptibility of mice to A. baumannii infection with reduced local proinflammatory cytokine responses, including TNF-␣ responses, and with a delay in the early influx of neutrophils into the lung (35).…”

Section: Discussionsupporting

confidence: 56%

Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

Parra-Millán

Sánchez-Encinales

et al. 2016

Antimicrob Agents Chemother

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bImmune response stimulation to prevent infection progression may be an adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC) is an immunomodulator involved in immune cell recruitment and activation. In this study, we aimed to evaluate the efficacy of LPC in combination with colistin, tigecycline, or imipenem in experimental murine models of peritoneal sepsis and pneumonia. We used Acinetobacter baumannii strain Ab9, which is susceptible to colistin, tigecycline, and imipenem, and multidrug-resistant strain Ab186, which is susceptible to colistin and resistant to tigecycline and imipenem. Pharmacokinetic and pharmacodynamic parameters for colistin, tigecycline, and imipenem and the 100% minimal lethal dose (MLD 100 ) were determined for both strains. The therapeutic efficacies of LPC, colistin (60 mg/kg of body weight/day), tigecycline (10 mg/kg/day), and imipenem (180 mg/kg/day), alone or in combination, were assessed against Ab9 and Ab186 at the MLD 100 in murine peritoneal sepsis and pneumonia models. The levels of pro-and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-␣) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA) for the same experimental models after inoculating mice with the MLD of both strains. LPC in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance of Ab9 and Ab186 from the spleen and lungs and reduced bacteremia and mouse mortality rates (P < 0.05) compared with those for colistin, tigecycline, and imipenem monotherapies. Moreover, at 4 h post-bacterial infection, Ab9 induced higher TNF-␣ and lower IL-10 levels than those with Ab186 (4 g/ml versus 3 g/ml [P < 0.05] and 2 g/ml versus 3.4 g/ml [P < 0.05], respectively). LPC treatment combined with colistin, tigecycline, or imipenem modestly reduced the severity of infection by A. baumannii strains with different resistance phenotypes compared to LPC monotherapy in both experimental models.A cinetobacter baumannii is a Gram-negative coccobacillus with high clinical relevance due to the different severe nosocomial infections that it causes, mainly in intensive care units, and its capacity to develop resistance to most of the antimicrobial agents used in clinical practice (1).A multidrug resistance pattern is commonly observed for A. baumannii isolates, raising the threat of impossible-to-treat infections (2). These multidrug-resistant (MDR) isolates are generally susceptible to polymyxins (colistin and polymyxin B) and resistant to imipenem and tigecycline (3, 4). The limited antimicrobial alternatives for the treatment of severe infections by MDR A. baumannii make the search for other therapeutic options urgent. Polymyxins have been used as a last resort to treat infections by MDR A. baumannii. In humans, suboptimal and optimal doses of colistin to treat ventilator-associated pneumonia due to MDR A. baumannii prevent mortality in only 38.1% and 62.5% of cases, respectively (5, 6). Recently, in a clinical trial at our hospital, treatm...

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Section: Discussionsupporting

confidence: 56%

Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

Parra-Millán

Sánchez-Encinales

et al. 2016

Antimicrob Agents Chemother

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“…However, a recent study showed that bone marrow-derived macrophages from TLR4-deficient mice still produced significant amounts of proinflammatory cytokines (12). In addition, although A. baumannii LPS was a potent stimulator of the TLR4 pathway (9), LPS-deficient A. baumannii was still able to stimulate macrophages (13).…”

Section: Discussionmentioning

confidence: 99%

“…This observed difference in the host susceptibility between both studies was attributed to the difference in the ability of LPS shedding by the two different bacterial strains used in these studies. Yet another report showed that although deficiency of TLR4 or LPS significantly affected the innate immune response of murine macrophages/dendritic cells to A. baumannii infection, it did not abrogate it completely (12,13). The latter study hinted that there exist additional host innate bacterial systems that recognize and initiate immune responses against A. baumannii.…”

Section: Leukin-8 (Il-8) By Lung Epithelial Cells In Vitro During a mentioning

confidence: 96%

The Nod1, Nod2, and Rip2 Axis Contributes to Host Immune Defense against Intracellular Acinetobacter baumannii Infection

et al. 2014

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Acinetobacter baumannii is a major extensively drug-resistant lethal human nosocomial bacterium. However, the host innate immune mechanisms controlling A. baumannii are not well understood. Although viewed as an extracellular pathogen, A. baumannii can also invade and survive intracellularly. However, whether host innate immune pathways sensing intracellular bacteria contribute to immunity against A. baumannii is not known. Here, we provide evidence for the first time that intracellular antibacterial innate immune receptors Nod1 and Nod2, and their adaptor Rip2, play critical roles in the sensing and clearance of A. baumannii by human airway epithelial cells in vitro. A. baumannii infection upregulated Rip2 expression. Silencing of Nod1, Nod2, and Rip2 expression profoundly increased intracellular invasion and prolonged the multiplication and survival of A. baumannii in lung epithelial cells. Notably, the Nod1/2-Rip2 axis did not contribute to the control of A. baumannii infection of human macrophages, indicating that they play cell type-specific roles. The Nod1/2-Rip2 axis was needed for A. baumannii infection-induced activation of NF-B but not mitogen-activated protein kinases. Moreover, the Nod1/2-Rip2 axis was critical to induce optimal cytokine and chemokine responses to A. baumannii infection. Mechanistic studies showed that the Nod1/2 pathway contributed to the innate control of A. baumannii infection through the production of ␤-defensin 2 by airway epithelial cells. This study revealed new insights into the immune control of A. baumannii and may contribute to the development of effective immune therapeutics and vaccines against A. baumannii.

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“…The endotoxins are also considered as a potent stimulators of inflammatory signalling in human monocytic cells, dependent on both TLR2 (toll-like receptor) and TLR4 receptors. Therefore, the pathology of Acinetobacter infections may be associated with exaggerated innate immune response to the LPS [23][24][25]. Further determinants implicated in the virulence of A. baumannii are capsular polysaccharides.…”

Section: Virulence Factorsmentioning

confidence: 99%

Acinetobacter baumannii: biology and drug resistance — role of carbapenemases

Nowak

Paluchowska

2015

Folia Histochem Cytobiol.

107

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Acinetobacter baumannii is a Gram-negative, glucose-non-fermenting, oxidase-negative coccobacillus, most commonly associated with the hospital settings. The ability to survive in adverse environmental conditions as well as high level of natural and acquired antimicrobial resistance make A. baumannii one of the most important nosocomial pathogens. While carbapenems have long been considered as antimicrobials of last-resort, the rates of clinical A. baumannii strains resistant to these antibiotics are increasing worldwide. Carbapenem resistance among A. baumannii is conferred by coexisting mechanisms including: decrease in permeability of the outer membrane, efflux pumps, production of beta-lactamases, and modification of penicillin-binding proteins. The most prevalent mechanism of carbapenem resistance among A. baumannii is associated with carbapenem-hydrolysing enzymes that belong to Ambler class D and B beta-lactamases. In addition, there have also been reports of resistance mediated by selected Ambler class A carbapenemases among A. baumannii strains. Resistance determinants in A. baumannii are located on chromosome and plasmids, while acquisition of new mechanisms can be mediated by insertion sequences, integrons, transposons, and plasmids. Clinical relevance of carbapenem resistance among strains isolated from infected patients, carriers and hospital environment underlines the need for carbapenemase screening. Currently available methods vary in principle, accuracy and efficiency. The techniques that deserve particular attention belong to both easily accessible unsophisticated methods as well as advanced techniques based on mass spectrometry or molecular biology. While carbapenemases limit the therapeutic options in A. baumannii infections, studies concerning novel beta-lactamase inhibitors offer a new insight into effective therapy.

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Essential role of toll-like receptor 4 in Acinetobacter baumannii-induced immune responses in immune cells

Cited by 42 publications

References 32 publications

Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

The Nod1, Nod2, and Rip2 Axis Contributes to Host Immune Defense against Intracellular Acinetobacter baumannii Infection

Acinetobacter baumannii: biology and drug resistance — role of carbapenemases

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