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Single-Cell Metabolism and Stress Responses in Complex Host Tissues

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  • Author: Dirk Bumann1
  • Editors: Pascale Cossart2, Craig R. Roy3, Philippe Sansonetti4
    Affiliations: 1: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland; 2: Institut Pasteur, Paris, France; 3: Yale University School of Medicine, New Haven, Connecticut; 4: Institut Pasteur, Paris, France
  • Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0009-2019
  • Received 27 April 2018 Accepted 18 January 2019 Published 05 April 2019
  • Dirk Bumann, [email protected]
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  • Abstract:

    Systemic infections are a major cause of mortality worldwide and are becoming increasingly untreatable. Recent single-cell data from a mouse model of typhoid fever show that the host immune system actually eradicates many cells, while other organisms thrive at the same time in the same tissue, causing lethal disease progression. The surviving cells have highly heterogeneous metabolism, growth rates, and exposure to various stresses. Emerging evidence suggests that similarly heterogeneous host-pathogen encounters might be a key feature of many infectious diseases. This heterogeneity offers fascinating opportunities for research and application. If we understand the mechanisms that determine the disparate local outcomes, we might be able to develop entirely novel strategies for infection control by broadening successful host antimicrobial attacks and closing permissive niches in which pathogens can thrive. This review describes suitable technologies, a current working model of heterogeneous host- interactions, the impact of diverse subsets on antimicrobial chemotherapy, and major open questions and challenges.

  • Citation: Bumann D. 2019. Single-Cell Metabolism and Stress Responses in Complex Host Tissues. Microbiol Spectrum 7(2):BAI-0009-2019. doi:10.1128/microbiolspec.BAI-0009-2019.


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Systemic infections are a major cause of mortality worldwide and are becoming increasingly untreatable. Recent single-cell data from a mouse model of typhoid fever show that the host immune system actually eradicates many cells, while other organisms thrive at the same time in the same tissue, causing lethal disease progression. The surviving cells have highly heterogeneous metabolism, growth rates, and exposure to various stresses. Emerging evidence suggests that similarly heterogeneous host-pathogen encounters might be a key feature of many infectious diseases. This heterogeneity offers fascinating opportunities for research and application. If we understand the mechanisms that determine the disparate local outcomes, we might be able to develop entirely novel strategies for infection control by broadening successful host antimicrobial attacks and closing permissive niches in which pathogens can thrive. This review describes suitable technologies, a current working model of heterogeneous host- interactions, the impact of diverse subsets on antimicrobial chemotherapy, and major open questions and challenges.

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Image of FIGURE 1

A paradigm shift in pathogen analysis in host tissues. () Common methods relied on population-level readouts that revealed average properties. This revealed many exciting insights, including identification of important vaccine antigens and antimicrobial targets. () Single-cell technologies reveal an additional striking heterogeneity of pathogen properties and fates that range from vigorous growth to efficient killing. All these diverse host-pathogen encounters can occur in the same host tissue at the same time. Overall disease outcome is the net result of this underlying complexity. Identifying the molecular mechanisms that distinguish successful (for the host) from failing encounters could provide a basis for entirely novel strategies in infection control, by broadening successful host antimicrobial attacks and closing permissive niches in which pathogen subsets can thrive.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0009-2019
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Image of FIGURE 2

Working model for -host interactions in an infected spleen. () interactions with various phagocyte types. proliferates in macrophages (MΦ) and spreads to other cells. When entering a macrophage, a cell is exposed to a short and sublethal oxidative burst. Infiltrating NK and T cells secrete IFN-γ, which activates some macrophages, enabling them to kill intracellular salmonellae in part through guanylate-binding protein 2 (GBP2). Infection foci also attract inflammatory monocytes (iMO) and polymorphonuclear neutrophils (PMN), which kill intracellular with hypochlorite (HOCl; bleach). Inflammatory monocytes generate and release large amounts of NO, which diffuses to regional salmonellae, which in turn upregulate detoxifying and damage repair enzymes. () Lesion formation and spreading in infected tissues. Growing infection foci attract inflammatory monocytes (blue) and neutrophils (magenta) that kill many . However, some salmonellae escape in infected macrophages (cyan) and start new infection foci elsewhere. Early infection foci are detected by NK and T cells (green), which secrete IFN-γ and activate some of the local macrophages. Other macrophages move to yet other tissue regions, thereby spreading the infection and driving disease progression.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0009-2019
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