1. Microbiology and Infectious Disease

Legionella pneumophila modulates host energy metabolism by ADP-ribosylation of ADP/ATP translocases

  1. Jiaqi Fu
  2. Mowei Zhou
  3. Marina A Gritsenko
  4. Ernesto S Nakayasu
  5. Lei Song  Is a corresponding author
  6. Zhao-Qing Luo  Is a corresponding author
  1. Purdue University, United States
  2. Pacific Northwest National Laboratory, United States
  3. Jilin University, China
https://doi.org/10.7554/eLife.73611
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  1. Jiaqi Fu
  2. Mowei Zhou
  3. Marina A Gritsenko
  4. Ernesto S Nakayasu
  5. Lei Song
  6. Zhao-Qing Luo
(2022)
Legionella pneumophila modulates host energy metabolism by ADP-ribosylation of ADP/ATP translocases
eLife 11:e73611.
https://doi.org/10.7554/eLife.73611
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Abstract

The intracellular pathogen Legionella pneumophila delivers more than 330 effectors into host cells by its Dot/Icm secretion system. Those effectors direct the biogenesis of the Legionella-containing vacuole (LCV) that permits its intracellular survival and replication. It has long been documented that the LCV is associated with mitochondria and a number of Dot/Icm effectors have been shown to target to this organelle. Yet, the biochemical function and host cell target of most of these effectors remain unknown. Here, we found that the Dot/Icm substrate Ceg3 (Lpg0080) is a mono-ADP-ribosyltransferase that localizes to the mitochondria in host cells where it attacks ADP/ATP translocases by ADP-ribosylation, and blunts their ADP/ATP exchange activity. The modification occurs on the second arginine residue in the -RRRMMM- element, which is conserved among all known ADP/ATP carriers from different organisms. Our results reveal modulation of host energy metabolism as a virulence mechanism for L. pneumophila.

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We have included all data to support our conclusions in the manuscript.

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Author details

  1. Jiaqi Fu

    Department of Biological Science, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0081-6133

  2. Mowei Zhou

    Environmental and Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Marina A Gritsenko

    Biological Science Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Ernesto S Nakayasu

    Biological Science Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Lei Song

    Department of Respiratory Medicine, Jilin University, Changchun, China
    For correspondence
    lsong@jlu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4115-065X

  6. Zhao-Qing Luo

    Department of Biological Science, Purdue University, West Lafayette, United States
    For correspondence
    luoz@purdue.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8890-6621

Funding

National Institute of Health (R01AI127465)

  • Zhao-Qing Luo

Jilin Science and Technology Agency (20200403117SF)

  • Lei Song

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sophie Helaine, Harvard Medical School, United States

Version history

  1. Received: September 4, 2021
  2. Preprint posted: September 17, 2021 (view preprint)
  3. Accepted: January 26, 2022
  4. Accepted Manuscript published: January 27, 2022 (version 1)
  5. Version of Record published: February 7, 2022 (version 2)
  6. Version of Record updated: February 23, 2022 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Jiaqi Fu
  2. Mowei Zhou
  3. Marina A Gritsenko
  4. Ernesto S Nakayasu
  5. Lei Song
  6. Zhao-Qing Luo
(2022)
Legionella pneumophila modulates host energy metabolism by ADP-ribosylation of ADP/ATP translocases
eLife 11:e73611.
https://doi.org/10.7554/eLife.73611

Share this article

https://doi.org/10.7554/eLife.73611

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    End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines.

    Methods:

    The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response.

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    Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development.

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    Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD.

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    F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.