LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

  1. Chi G Weindel
  2. Samantha L Bell
  3. Krystal J Vail
  4. Kelsi O West
  5. Kristin L Patrick
  6. Robert O Watson  Is a corresponding author
  1. Texas A&M Health Science Center, United States
  2. Texas A&M University College of Veterinary Medicine and Biomedical Sciences, United States

Abstract

The Parkinson's Disease (PD)-associated gene leucine-rich repeat kinase (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferons (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 and 5.

Article and author information

Author details

  1. Chi G Weindel

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Samantha L Bell

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Krystal J Vail

    Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1964-7985
  4. Kelsi O West

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kristin L Patrick

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2442-4679
  6. Robert O Watson

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    For correspondence
    robert.watson@tamu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4976-0759

Funding

Michael J. Fox Foundation for Parkinson's Research (M1801235)

  • Robert O Watson

National Institute of Allergy and Infectious Diseases (R21AI40004)

  • Robert O Watson

National Institute of General Medical Sciences (R35GM133720)

  • Kristin L Patrick

Parkinson's Disease Foundation

  • Chi G Weindel

National Institutes of Health (5T32OD011083-10)

  • Krystal J Vail

Michael J. Fox Foundation for Parkinson's Research (12185)

  • Robert O Watson

National Institute of Allergy and Infectious Diseases (1R01AI12551)

  • Robert O Watson

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

Reviewing Editor

  1. Russell E Vance, University of California, Berkeley, United States

Ethics

Animal experimentation: This study followed the recommendations in the Guide for the Care and Use of Laboratory Animals by the National Research Council. All animals were housed, bred, and studied at Texas A&M Health Science Center using protocols reviewed and approved by the institutional animal care and use committee (IACUC) of Texas A&M University (protocol #2018-0125).

Version history

  1. Received: August 14, 2019
  2. Accepted: February 14, 2020
  3. Accepted Manuscript published: February 14, 2020 (version 1)
  4. Version of Record published: April 15, 2020 (version 2)

Copyright

© 2020, Weindel et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Chi G Weindel
  2. Samantha L Bell
  3. Krystal J Vail
  4. Kelsi O West
  5. Kristin L Patrick
  6. Robert O Watson
(2020)
LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis
eLife 9:e51071.
https://doi.org/10.7554/eLife.51071

Share this article

https://doi.org/10.7554/eLife.51071

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