Listeria monocytogenes requires cellular respiration for NAD+ regeneration and pathogenesis
- University of California, Berkeley, United States
- Rice University, United States
- Vanderbilt University Medical Center, United States
- University of Wisconsin-Madison, United States
- University of Chicago, United States
Abstract
Cellular respiration is essential for multiple bacterial pathogens and a validated antibiotic target. In addition to driving oxidative phosphorylation, bacterial respiration has a variety of ancillary functions that obscure its contribution to pathogenesis. We find here that the intracellular pathogen Listeria monocytogenes encodes two respiratory pathways which are partially functionally redundant and indispensable for pathogenesis. Loss of respiration decreased NAD+ regeneration, but this could be specifically reversed by heterologous expression of a water-forming NADH oxidase (NOX). NOX expression fully rescued intracellular growth defects and increased L. monocytogenes loads >1,000-fold in a mouse infection model. Consistent with NAD+ regeneration maintaining L. monocytogenes viability and enabling immune evasion, a respiration-deficient strain exhibited elevated bacteriolysis within the host cytosol and NOX expression rescued this phenotype. These studies show that NAD+ regeneration represents a major role of L. monocytogenes respiration and highlight the nuanced relationship between bacterial metabolism, physiology, and pathogenesis.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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Author details
Rafael Rivera-Lugo
Funding
National Institutes of Health (T32GM007215)
- Hans B Smith
Searle Scholars Program
- Samuel H Light
National Institutes of Health (R01AI137070)
- John Demian Sauer
National Institutes of Health (R01AI073843)
- Eric P Skaar
National Institutes of Health (R01AI073843)
- Eric P Skaar
National Institutes of Health (1P01AI063302)
- Daniel A Portnoy
National Institutes of Health (1R01AI27655)
- Daniel A Portnoy
National Institutes of Health (K22AI144031)
- Samuel H Light
National Academies of Sciences, Engineering, and Medicine (Ford Foundation Fellowship)
- Rafael Rivera-Lugo
University of California (Dissertation-Year Fellowship)
- Rafael Rivera-Lugo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal work was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Protocols were reviewed and approved by the Animal Care and Use Committee at the University of California, Berkeley (AUP 2016-05-8811).
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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Listeria monocytogenes requires cellular respiration for NAD+ regeneration and pathogenesis
eLife 11:e75424.
https://doi.org/10.7554/eLife.75424
