Intracellular pathogens account for a significant amount of morbidity and mortality world-wide. Here, the model facultative intracellular pathogen Listeria monocytogenes (Lm) will be used to investigate how bacterial pathogens recognize and adapt to the host environment. Previous studies suggested a model in which specific alterations in the redox environment are one of the biological cues detected by intracellular pathogens during infection as a mechanism to sense their localization and regulate genes accordingly. Specifically, we identified the redox-responsive transcriptional regulator SpxA1 as essential for aerobic growth in vitro and critical for Lm virulence. Preliminary data revealed that SpxA1 regulates hundreds of genes in vitro and in vivo. These results have set the stage for investigations into the specific genes that are required in each distinct growth environment. Experiments proposed in Aim 1a will identify the genes that are required for Lm aerobic growth in vitro, while Aim 1b and 1c will define the SpxA1-dependent genes required for pathogenesis. Experiments described in Aim 2 will develop reporter strains with which to monitor SpxA1 activity and will apply these to define the host signals that activate SpxA1 in vivo. Professional pathogens, such as Lm, have evolved to resist or evade host-derived antimicrobial factors that target invading pathogens. We will use SpxA1-mediated transcriptional adaptation as a sensitive readout with which to investigate these host defenses. Results from these studies will identify the host cell stressors that are encountered during infection and the corresponding Lm transcriptional response that is required for pathogenesis. A thorough understanding of the signaling cascades that are activated during infection and the host cues that stimulate these pathways may reveal fundamental features of the host cytosol that intracellular bacterial pathogens have evolved to detect.

Public Health Relevance

This project addresses a central question in bacterial pathogenesis: how do pathogens sense and adapt to the host environment in order to cause disease? Using the model intracellular pathogen Listeria monocytogenes, we will investigate the role of an essential redox-responsive transcription factor that is critical for virulence. These studies will advance our understanding of the types of host-derived signals that are sensed by L. monocytogenes during infection and the subsequent regulatory cascades that are activated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI132356-03
Application #
9761447
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Baqar, Shahida
Project Start
2017-09-25
Project End
2022-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Ruhland, Brittany R; Reniere, Michelle L (2018) Sense and sensor ability: redox-responsive regulators in Listeria monocytogenes. Curr Opin Microbiol 47:20-25
Reniere, Michelle L (2018) Reduce, Induce, Thrive: Bacterial Redox Sensing during Pathogenesis. J Bacteriol 200: