Salmonella enterica serovar Typhi causes typhoid fever, a severe infection that affects more than twenty million people every year. Much knowledge has been gained over the last twenty years concerning how Salmonella causes disease through manipulating host cellular pathways and how host cells respond. However, there is tremendous variation in who gets infected and the severity of infections. How host signaling pathways and responses are affected by human genetic variation to modulate susceptibility to Salmonella infection is poorly understood. This naturally occurring host genetic variation is an untapped resource that could reveal novel components of pathways, prediction of susceptibility, and possibly host-directed therapeutic targets. The long-term goal of this research is to understand how host genetic differences alter the responsiveness and susceptibility of cells to Salmonella infection and how this affects risk and severity of disease in people. In pursuit of this goal, genome-wide association studies (GWAS) of cellular Salmonella infection traits were carried out using a platform called Hi-HOST (High-throughput Human in vitro Susceptibility Testing). In Hi- HOST screens, precise measurements of infection readouts are conducted on cells derived from hundreds of genotyped individuals. Genome-wide association is then used to identify genetic differences that underlie variation in the cellular infection phenotypes. Using Hi HOST, three new regulators that affect Salmonella- induced cell death in cells and sepsis in human populations were identified and characterized. The objective of this application is to use Hi-HOST and subsequent studies to define and characterize host genetic differences that alter S. typhi invasion and early survival. The host genetic differences serve as the starting point for mechanistic studies to determine how host pathways involving macropinocytosis and early survival are altered. By integrating these cellular studies with animal models and genotyping of human typhoid fever cohorts, an in depth understanding will be achieved for how genetic differences contribute to who gets sick and why.
In Aim 1, common human genetic variation that modulates S. typhi invasion will be identified and validated.
In Aim 2, the impact of variation in S. typhi invasion on typhoid fever in human populations and Salmonella infections in animal models will be assessed.
In Aim 3, mechanisms for how the newly identified regulators modulate S. typhi invasion will be characterized. Carrying out these Aims will result in the elucidation of new mechanisms in host-pathogen interactions and ultimately a broad understanding for how genetic differences determine which individuals are at risk for typhoid fever and possibly other diseases caused by pathogens which utilize similar invasion mechanisms. With rising concerns over resistance to broad-spectrum antimicrobials, this study may leverage our genetic differences to reveal new therapeutic targets focused instead on host modulation.

Public Health Relevance

Salmonella typhi causes typhoid fever, a severe infection that affects more than 20 million people every year. This application uses identification and characterization of natural human genetic variation regulating S. typhi invasion, along with studies of human populations and animal models, to improve our understanding of how Salmonella gets into and survives within cells and how this affects risk of typhoid fever. This study will reveal why certain genetic differences predispose individuals to typhoid fever and other Salmonella infections and may also reveal new targets for host-directed therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI118903-03
Application #
9205481
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
2015-08-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$433,415
Indirect Cost
$152,360
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Alvarez, Monica I; Glover, Luke C; Luo, Peter et al. (2017) Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol. Proc Natl Acad Sci U S A 114:E7746-E7755
Pittman, Kelly J; Glover, Luke C; Wang, Liuyang et al. (2016) The Legacy of Past Pandemics: Common Human Mutations That Protect against Infectious Disease. PLoS Pathog 12:e1005680