Microbial Quest for Food in vivo: "Nutritional virulence" as an emerging paradigm.
ABSTRACT Microbial access to host nutrients is a fundamental aspect of infectious diseases. Pathogens face complex dynamic nutritional host microenvironments that change with increasing inflammation and local hypoxia. Since the host can actively limit microbial access to nutrient supply, pathogens have evolved various metabolic adaptations to successfully exploit available host nutrients for proliferation. Recent studies have unraveled an emerging paradigm that we propose to designate as "nutritional virulence". This paradigm is based on specific virulence mechanisms that target major host biosynthetic and degradation pathways (proteasomes, autophagy, and lysosomes) or nutrient-rich sources, such as glutathione, to enhance host supply of limiting nutrients, such as Cysteine. Although Cys is the most limiting cellular amino acid, it is a metabolically favorable source of carbon and energy for various pathogens that are auxotroph for Cys but utilize idiosyncratic nutritional virulence strategies to generate a gratuitous supply of host Cys. Therefore, proliferation of some intracellular pathogens is restricted by a host nutritional rheostat regulated by certain limiting amino acids, and pathogens have evolved idiosyncratic strategies to short circuit the host nutritional rheostat. Deciphering mechanisms of microbial "nutritional virulence" and metabolism in vivo will facilitate identification of novel microbial and host targets for treatment and prevention of infectious diseases. Host-pathogen synchronization of amino acid auxotrophy indicates that this nutritional synchronization has been a major driving force in the evolution of many intracellular bacterial pathogens.
Full-textDOI: · Available from: Yousef Abu Kwaik, Sep 19, 2014
Environmental Microbiology Reports 02/2015; 7(1):2-3. DOI:10.1111/1758-2229.12236 · 3.26 Impact Factor
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ABSTRACT: Genomic data predict that, in addition to oxygen, the bacterial plant pathogen Ralstonia solanacearum can use nitrate (NO3 (-)), nitrite (NO2 (-)), nitric oxide (NO), and nitrous oxide (N2O) as terminal electron acceptors (TEAs). Genes encoding inorganic nitrogen reduction were highly expressed during tomato bacterial wilt disease, when the pathogen grows in xylem vessels. Direct measurements found that tomato xylem fluid was low in oxygen, especially in plants infected by R. solanacearum. Xylem fluid contained ~25 mM NO3 (-), corresponding to R. solanacearum's optimal NO3 (-) concentration for anaerobic growth in vitro. We tested the hypothesis that R. solanacearum uses inorganic nitrogen species to respire and grow during pathogenesis by making deletion mutants that each lacked a step in nitrate respiration (ΔnarG), denitrification (ΔaniA, ΔnorB, and ΔnosZ), or NO detoxification (ΔhmpX). The ΔnarG, ΔaniA, and ΔnorB mutants grew poorly on NO3 (-) compared to the wild type, and they had reduced adenylate energy charge levels under anaerobiosis. While NarG-dependent NO3 (-) respiration directly enhanced growth, AniA-dependent NO2 (-) reduction did not. NO2 (-) and NO inhibited growth in culture, and their removal depended on denitrification and NO detoxification. Thus, NO3 (-) acts as a TEA, but the resulting NO2 (-) and NO likely do not. None of the mutants grew as well as the wild type in planta, and strains lacking AniA (NO2 (-) reductase) or HmpX (NO detoxification) had reduced virulence on tomato. Thus, R. solanacearum exploits host NO3 (-) to respire, grow, and cause disease. Degradation of NO2 (-) and NO is also important for successful infection and depends on denitrification and NO detoxification systems. The plant-pathogenic bacterium Ralstonia solanacearum causes bacterial wilt, one of the world's most destructive crop diseases. This pathogen's explosive growth in plant vascular xylem is poorly understood. We used biochemical and genetic approaches to show that R. solanacearum rapidly depletes oxygen in host xylem but can then respire using host nitrate as a terminal electron acceptor. The microbe uses its denitrification pathway to detoxify the reactive nitrogen species nitrite (a product of nitrate respiration) and nitric oxide (a plant defense signal). Detoxification may play synergistic roles in bacterial wilt virulence by converting the host's chemical weapon into an energy source. Mutant bacterial strains lacking elements of the denitrification pathway could not grow as well as the wild type in tomato plants, and some mutants were also reduced in virulence. Our results show how a pathogen's metabolic activity can alter the host environment in ways that increase pathogen success. Copyright © 2015 Dalsing et al.mBio 03/2015; 6(2):e02471-14. DOI:10.1128/mBio.02471-14 · 6.88 Impact Factor