Acinetobacter baumannii Response to Host-Mediated Zinc Limitation Requires the Transcriptional Regulator Zur

Mortensen, Brittany L.; Rathi, Subodh; Chazin, Walter J.; Skaar, Eric P.

doi:10.1128/jb.01650-14

Cited by 84 publications

(117 citation statements)

References 63 publications

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“…All animal experiments were approved by the Vanderbilt University Institutional Animal Care and Use Committee. The murine model of A. baumannii pneumonia was performed as previously described (44)(45)(46)(47)(48)(49). Briefly, Ab17978 bacteria were back-diluted 1:1,000 from an overnight culture and grown for 3.5 h at 37°C with shaking, washed twice with cold phosphate-buffered saline (PBS), and resuspended in PBS at an appropriate cell density for infection.…”

Section: Methodsmentioning

confidence: 99%

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

et al. 2017

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The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor capable of recognizing multiple pathogen-associated and dangerassociated molecular patterns that contributes to the initiation and potentiation of inflammation in many disease processes. During infection, RAGE functions to either exacerbate disease severity or enhance pathogen clearance depending on the pathogen studied. Acinetobacter baumannii is an opportunistic human pathogen capable of causing severe infections, including pneumonia and sepsis, in impaired hosts. The role of RAGE signaling in response to opportunistic bacterial infections is largely unknown. In murine models of A. baumannii pneumonia, RAGE signaling alters neither inflammation nor bacterial clearance. In contrast, RAGE Ϫ/Ϫ mice systemically infected with A. baumannii exhibit increased survival and reduced bacterial burdens in the liver and spleen. The increased survival of RAGE Ϫ/Ϫ mice is associated with increased circulating levels of the anti-inflammatory cytokine interleukin-10 (IL-10). Neutralization of IL-10 in RAGE Ϫ/Ϫ mice results in decreased survival during systemic A. baumannii infection that mirrors that of wild-type (WT) mice, and exogenous IL-10 administration to WT mice enhances survival in this model. These findings demonstrate the role for RAGE-dependent IL-10 suppression as a key modulator of mortality from Gram-negative sepsis.KEYWORDS Acinetobacter baumannii, IL-10, innate immunity, pneumonia, RAGE, receptor for advanced glycation end products, sepsis A n effective immune response to an invading pathogen depends upon host recognition of the infecting organism and resultant initiation of an immune response. This process is accomplished through the recognition of pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs) (1). Signaling downstream of PRRs, including Toll-like receptors (TLRs), activates transcription factors such as nuclear factor kappa B (NF-B), inducing expression of proinflammatory genes and thereby altering cytokine and chemokine production, resulting in inflammation and effector cell recruitment to the site of infection (1, 2). In addition to PAMPs, many PRRs have also evolved to detect altered host proteins, referred to as danger-associated molecular patterns (DAMPs) (3). The signaling mechanisms required to initiate an appropriate response to an invading pathogen may also potentiate inflammation during the course of infection, and this inflammatory response may enhance tissue damage and exacerbate disease (4). The maladaptive potentiation of inflammation in response to infection is responsible for many of the severe manifestations of infectious

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Section: Methodsmentioning

confidence: 99%

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

et al. 2017

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“…All animal experiments were approved by the Vanderbilt University Institutional Animal Care and Use Committee. The murine model of A. baumannii pneumonia was performed as previously described (31)(32)(33)(34)(35)(36). Briefly, A. baumannii ATCC 17978 bacteria were back diluted 1:1,000 from overnight culture and grown for 3.5 h at 37°C with shaking, washed twice with cold PBS, and resuspended in PBS at an appropriate cell density for infection.…”

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 9 Contributes to Defense against Acinetobacter baumannii Infection

et al. 2015

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dAcinetobacter baumannii is a common nosocomial pathogen capable of causing severe diseases associated with significant morbidity and mortality in impaired hosts. Pattern recognition receptors, such as the Toll-like receptors (TLRs), play a key role in pathogen detection and function to alert the immune system to infection. Here, we examine the role for TLR9 signaling in response to A. baumannii infection. In a murine model of A. baumannii pneumonia, TLR9؊/؊ mice exhibit significantly increased bacterial burdens in the lungs, increased extrapulmonary bacterial dissemination, and more severe lung pathology compared with those in wild-type mice. Following systemic A. baumannii infection, TLR9؊/؊ mice have significantly increased bacterial burdens in the lungs, as well as decreased proinflammatory cytokine and chemokine production. These results demonstrate that TLR9-mediated pathogen detection is important for host defense against the opportunistic pathogen Acinetobacter baumannii.

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“…In other bacteria, additional zinc import systems contribute to metal import under zinc deficiency and disruption of znuABC is not associated to clear-cut phenotypes. For example, in response to zinc deficiency Neisseria meningitidis 12 , Yersinia pestis 13, 14 and Acinetobacter baumannii 15, 16 produce membrane channels which specifically favor the entrance of zinc ions within cells.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, CF lung disease is characterized by a massive and persistent recruitment of polymorphonuclear neutrophils in the airway lumen, leading to the release of large amounts of calprotectin (CP) 26, 27 . Recent studies have established that CP controls microbial growth by sequestrating zinc and manganese ions at sites of infection and that the ability of several pathogens to withstand the antimicrobial activity of CP relies on their ability to produce metal transporters characterized by high affinity for zinc or manganese 15, 28-30 . The observation that CP is one of the most abundant components of the sputum proteome from CF patients, suggest that the extraordinary ability of P. aeruginosa to colonize the inflamed CF lung must be supported by effective strategies to counteract CP-induced metal starvation.…”

Section: Introductionmentioning

confidence: 99%

The capability of Pseudomonas aeruginosa to recruit zinc under conditions of limited metal availability is affected by inactivation of the ZnuABC transporter

et al. 2015

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The ability of a large number of bacterial pathogens to multiply in the infected host and cause disease is dependent on their ability to express high affinity zinc importers. In many bacteria ZnuABC, a transporter of the ABC family, plays a central role in the process of zinc uptake in zinc poor environments, including the tissues of the infected host. To initiate an investigation into the relevance of the zinc uptake apparatus for Pseudomonas aeruginosa pathogenicity, we have generated a znuA mutant in the PA14 strain. We have found that this mutant strain displays a limited growth defect in zinc depleted media. The znuA mutant strain is more sensitive than the wild type strain to calprotectin-mediated growth inhibition, but both the strains are highly resistant to this zinc sequestering antimicrobial protein. Moreover, intracellular zinc content is not evidently affected by inactivation of the ZnuABC transporter. These findings suggest that P. aeruginosa is equipped with redundant mechanisms for the acquisition of zinc that might favor P. aeruginosa colonization of environments containing low levels of this metal. Nonetheless, deletion of znuA affects alginate production, reduces the activity of extracellular zinc-containing proteases, including LasA, LasB and Protease IV, and decreases the ability of P. aeruginosa to disseminate during systemic infections. These results indicate that efficient zinc acquisition is critical for the expression of various virulence features typical of P. aeruginosa and that ZnuABC also plays an important role in zinc homeostasis in this microorganism.

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Acinetobacter baumannii Response to Host-Mediated Zinc Limitation Requires the Transcriptional Regulator Zur

Cited by 84 publications

References 63 publications

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

Toll-Like Receptor 9 Contributes to Defense against Acinetobacter baumannii Infection

The capability of Pseudomonas aeruginosa to recruit zinc under conditions of limited metal availability is affected by inactivation of the ZnuABC transporter

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