Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
David Deng
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Andrea Anaya-Sanchez
Graduate Group in Microbiology, University of California, Berkeley, Berkeley, United States
Sara Tejedor-Sanz
Department of Biosciences, Rice University, Houston, United States; The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, United States
Eugene Tang
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Valeria M Reyes Ruiz
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, United States; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, United States
Hans B Smith
Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States; Center for Computational Biology, University of California, Berkeley, Berkeley, United States
Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, United States
Eric P Skaar
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, United States; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, United States
Caroline M Ajo-Franklin
Department of Biosciences, Rice University, Houston, United States; The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, United States
Daniel A Portnoy
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States
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 >1000-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.
