Dataset Information

Mechanism-Based Disease Progression Model Describing Host-Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia.

ABSTRACT: The emergence of highly resistant bacteria is a serious threat to global public health. The host immune response is vital for clearing bacteria from the infected host; however, the current drug development paradigm does not take host-pathogen interactions into consideration. Here, we used a systems-based approach to develop a quantitative, mechanism-based disease progression model to describe bacterial dynamics, host immune response, and lung injury in an immunocompetent rat pneumonia model. Previously, Long-Evans rats were infected with Acinetobacter baumannii (A. baumannii) strain 307-0294 at five different inocula and total lung bacteria, interleukin-1beta (IL-1?), tumor necrosis factor-? (TNF-?), cytokine-induced neutrophil chemoattractant 1 (CINC-1), neutrophil counts, and albumin were quantified. Model development was conducted in ADAPT5 version 5.0.54 using a pooled approach with maximum likelihood estimation; all data were co-modeled. The final model characterized host-pathogen interactions during the natural time course of bacterial pneumonia. Parameters were estimated with good precision. Our expandable model will integrate drug effects to aid in the design of optimized antibiotic regimens.

SUBMITTER: Diep JK

PROVIDER: S-EPMC6118322 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mechanism-Based Disease Progression Model Describing Host-Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia.

Diep John K JK Russo Thomas A TA Rao Gauri G GG

CPT: pharmacometrics & systems pharmacology 20180824 8

The emergence of highly resistant bacteria is a serious threat to global public health. The host immune response is vital for clearing bacteria from the infected host; however, the current drug development paradigm does not take host-pathogen interactions into consideration. Here, we used a systems-based approach to develop a quantitative, mechanism-based disease progression model to describe bacterial dynamics, host immune response, and lung injury in an immunocompetent rat pneumonia model. Pre ...[more]

PMID: 29761668

Similar Datasets

Project description:BackgroundAcinetobacter baumannii is a major health problem. The most common infection caused by A. baumannii is hospital acquired pneumonia, and the associated mortality rate is approximately 50%. Neither in vivo nor ex vivo expression profiling has been performed at the proteomic or transcriptomic level for pneumonia caused by A. baumannii. In this study, we characterized the proteome of A. baumannii under conditions that simulate those found in the airways, to gain some insight into how A. baumannii adapts to the host and to improve knowledge about the pathogenesis and virulence of this bacterium. A clinical strain of A. baumannii was grown under different conditions: in the presence of bronchoalveolar lavage fluid from infected rats, of RAW 264.7 cells to simulate conditions in the respiratory tract and in control conditions. We used iTRAQ labelling and LC-MALDI-TOF/TOF to investigate how A. baumannii responds on exposure to macrophages/BALF.Results179 proteins showed differential expression. In both models, proteins involved in the following processes were over-expressed: (i) pathogenesis and virulence (OmpA, YjjK); (ii) cell wall/membrane/envelope biogenesis (MurC); (iii) energy production and conversion (acetyl-CoA hydrolase); and (iv) translation (50S ribosomal protein L9). Proteins involved in the following were under-expressed: (i) lipid metabolism (short-chain dehydrogenase); (ii) amino acid metabolism and transport (aspartate aminotransferase); (iii) unknown function (DNA-binding protein); and (iv) inorganic ion transport and metabolism (hydroperoxidase).ConclusionsWe observed alterations in cell wall synthesis and identified 2 upregulated virulence-associated proteins with >15 peptides/protein in both ex vivo models (OmpA and YjjK), suggesting that these proteins are fundamental for pathogenesis and virulence in the airways. This study is the first comprehensive overview of the ex vivo proteome of A. baumannii and is an important step towards identification of diagnostic biomarkers, novel drug targets and potential vaccine candidates in the fight against pneumonia caused by A. baumannii.

Project description:Acinetobacter baumannii is an important emerging pathogen that is capable of causing many types of severe infection, especially in immunocompromised hosts. Since A. baumannii can rapidly acquire antibiotic resistance genes, many infections are on the verge of being untreatable, and novel therapies are desperately needed. To investigate the potential utility of copper-based antibacterial strategies against Acinetobacter infections, we characterized copper resistance in a panel of recent clinical A. baumannii isolates. Exposure to increasing concentrations of copper in liquid culture and on solid surfaces resulted in dose-dependent and strain-dependent effects; levels of copper resistance varied broadly across isolates, possibly resulting from identified genotypic variation among strains. Examination of the growth-phase-dependent effect of copper on A. baumannii revealed that resistance to copper increased dramatically in stationary phase. Moreover, A. baumannii biofilms were more resistant to copper than planktonic cells but were still susceptible to copper toxicity. Exposure of bacteria to subinhibitory concentrations of copper allowed them to better adapt to and grow in high concentrations of copper; this copper tolerance response is likely achieved via increased expression of copper resistance mechanisms. Indeed, genomic analysis revealed numerous putative copper resistance proteins that share amino acid homology to known proteins in Escherichia coli and Pseudomonas aeruginosa Transcriptional analysis revealed significant upregulation of these putative copper resistance genes following brief copper exposure. Future characterization of copper resistance mechanisms may aid in the search for novel antibiotics against Acinetobacter and other highly antibiotic-resistant pathogens.ImportanceAcinetobacter baumannii causes many types of severe nosocomial infections; unfortunately, some isolates have acquired resistance to almost every available antibiotic, and treatment options are incredibly limited. Copper is an essential nutrient but becomes toxic at high concentrations. The inherent antimicrobial properties of copper give it potential for use in novel therapeutics against drug-resistant pathogens. We show that A. baumannii clinical isolates are sensitive to copper in vitro, both in liquid and on solid metal surfaces. Since bacterial resistance to copper is mediated though mechanisms of efflux and detoxification, we identified genes encoding putative copper-related proteins in A. baumannii and showed that expression of some of these genes is regulated by the copper concentration. We propose that the antimicrobial effects of copper may be beneficial in the development of future therapeutics that target multidrug-resistant bacteria.

Dataset Information

Mechanism-Based Disease Progression Model Describing Host-Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia.

Publications

Mechanism-Based Disease Progression Model Describing Host-Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets