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The Nod1, Nod2, and Rip2 axis contributes to host immune defense against intracellular Acinetobacter baumannii infection.

ABSTRACT: 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.

SUBMITTER: Bist P

PROVIDER: S-EPMC3958010 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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The Nod1, Nod2, and Rip2 axis contributes to host immune defense against intracellular Acinetobacter baumannii infection.

Bist Pradeep P Dikshit Neha N Koh Tse Hsien TH Mortellaro Alessandra A Tan Thuan Tong TT Sukumaran Bindu B

Infection and immunity 20131223 3

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 antibact ...[more]

PMID: 24366254

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Project description:The present work describes the evolution of a resistance phenotype to a multitargeting antimicrobial agent, namely, silver nanoparticles (nanosilver; NAg), in the globally prevalent bacterial pathogen Acinetobacter baumannii. The Gram-negative bacterium has recently been listed as a critical priority pathogen requiring novel treatment options by the World Health Organization. Through prolonged exposure to the important antimicrobial nanoparticle, the bacterium developed mutations in genes that encode the protein subunits of organelle structures that are involved in cell-to-surface attachment as well as in a cell envelope capsular polysaccharide synthesis-related gene. These mutations are potentially correlated with stable physiological changes in the biofilm growth behavior and with an evident protective effect against oxidative stress, most likely as a feature of toxicity defense. We further report a different adaptation response of A. baumannii to the cationic form of silver (Ag+). The bacterium developed a tolerance phenotype to Ag+, which was correlated with an indicative surge in respiratory activity and changes in cell morphology, of which these are reported characteristics of tolerant bacterial populations. The findings regarding adaptation phenomena to NAg highlight the risks of the long-term use of the nanoparticle on a priority pathogen. The findings urge the implementation of strategies to overcome bacterial NAg adaptation, to better elucidate the toxicity mechanisms of the nanoparticle, and preserve the efficacy of the potent alternative antimicrobial agent in this era of antimicrobial resistance. IMPORTANCE Several recent studies have reported on the development of bacterial resistance to broad-spectrum antimicrobial silver nanoparticles (nanosilver; NAg). NAg is currently one of the most important alternative antimicrobial agents. However, no studies have yet established whether Acinetobacter baumannii, a globally prevalent nosocomial pathogen, can develop resistance to the nanoparticle. The study herein describes how a model strain of A. baumannii with no inherent silver resistance determinants developed resistance to NAg, following prolonged exposure. The stable physiological changes are correlated with mutations detected in the bacterium genome. These mutations render the bacterium capable of proliferating at a toxic NAg concentration. It was also found that A. baumannii developed a "slower-to-kill" tolerance trait to Ag+, which highlights the unique antimicrobial activities between the nanoparticulate and the ionic forms of silver. Despite the proven efficacy of NAg, the observation of NAg resistance in A. baumannii emphasises the potential risks of the repeated overuse of this agent on a priority pathogen.

Dataset Information

The Nod1, Nod2, and Rip2 axis contributes to host immune defense against intracellular Acinetobacter baumannii infection.

Publications

The Nod1, Nod2, and Rip2 axis contributes to host immune defense against intracellular Acinetobacter baumannii infection.

Similar Datasets

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