The recent emergence and spread of new bacterial pathogens has generated great interest into how infectious diseases can persist and spread within host populations. Although it is clear that antibiotic resistance can contribute to the expansion of a new pathogenic clone (e.g. multi-drug resistant Salmonella serovars), information on other factors that enhance persistence and spread of emerging pathogens remains sparse. The question of which molecular mechanisms are responsible for the emergence and transmission of a new pathogenic S. Typhimurium clone represents a high-impact topic that will be addressed in this application. Our central hypothesis is that the horizontally acquired type III secretion system effector SopE induces production of host-derived nitrate, an energetically highly valuable electron acceptor, thus fueling a bloom of Salmonella in the gut lumen through anaerobic nitrate respiration. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) Determine the role of SopE on transmission success and 2.) Determine the role of SopE in modulating expression of genes involved in anaerobic nitrate and tetrathionate respiration in the inflamed gut. Successful completion has a strong potential to have a high impact on gastroenteritis research by providing a novel concept, i.e. that the evolution of Salmonella may be driven by making new nutrients such as anaerobic respiratory electron acceptors available in the inflamed gut, thus boosting transmission success.

Public Health Relevance

Salmonella serotypes are the most common cause of death and hospitalization from diarrheal disease and the leading cause of food-borne disease outbreaks in the United States, generating between $0.5 billion to $2.3 billion in costs for medical care and lost productivity annually in the US. Research proposed in this application will support pioneering studies on molecular mechanisms that control bacterial colonization and host transmission. The proposed studies will drive knowledge about Salmonella gastroenteritis to a higher level by providing new mechanistic insights into pathogenesis and by facilitating the development of new intervention strategies through science.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI103248-01A1
Application #
8583260
Study Section
Special Emphasis Panel (ZRG1-IDM-A (80))
Program Officer
Alexander, William A
Project Start
2013-05-17
Project End
2015-04-30
Budget Start
2013-05-17
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$180,461
Indirect Cost
$62,961
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Gillis, Caroline C; Hughes, Elizabeth R; Spiga, Luisella et al. (2018) Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth. Cell Host Microbe 23:54-64.e6
Gillis, Caroline C; Hughes, Elizabeth R; Spiga, Luisella et al. (2018) Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth. Cell Host Microbe 23:570
Spiga, Luisella; Winter, Maria G; Furtado de Carvalho, Tatiane et al. (2017) An Oxidative Central Metabolism Enables Salmonella to Utilize Microbiota-Derived Succinate. Cell Host Microbe 22:291-301.e6
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Rivera-Chávez, Fabian; Lopez, Christopher A; Zhang, Lillian F et al. (2016) Energy Taxis toward Host-Derived Nitrate Supports a Salmonella Pathogenicity Island 1-Independent Mechanism of Invasion. MBio 7:
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Rivera-Chávez, Fabian; Zhang, Lillian F; Faber, Franziska et al. (2016) Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella. Cell Host Microbe 19:443-54
Winter, Sebastian E; Winter, Maria G; Poon, Victor et al. (2014) Salmonella enterica Serovar Typhi conceals the invasion-associated type three secretion system from the innate immune system by gene regulation. PLoS Pathog 10:e1004207
Winter, Sebastian E; Bäumler, Andreas J (2014) Dysbiosis in the inflamed intestine: chance favors the prepared microbe. Gut Microbes 5:71-3
Winter, Sebastian E; Bäumler, Andreas J (2014) Why related bacterial species bloom simultaneously in the gut: principles underlying the 'Like will to like' concept. Cell Microbiol 16:179-84

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