The pathogenesis of enteric fever
Active Project Grant Awarded Last action
- Award ID
- R01AI160130
- Recipient
-
University Of Washington UEI HD1WMN6945W6
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $5,689,704
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 96% complete
- Originally
- Funding
-
- $5,177,595.00 Federal
- $512,109.00 Non-federal
- Place of performance
- Seattle, WA 98195, USA
Award details come from USAspending.gov.
Description
- Abstract
- Enteric fever, caused by the salmonella serovars S. Typhi and S. Paratyphi, accounts for nearly 15 million infections and 136,000 deaths each year. We have developed a novel lethal small animal model for enteric fever using humanized mice engrafted with a functional human hematopoietic system. The ability of S. Typhi and S. Paratyphi a to cause lethal infections in humanized mice engrafted with human hematopoietic cells suggests that human macrophages are required for the pathogenesis of enteric fever and may provide a reservoir for persistent infection. A genome-wide analysis of S. Typhi in humanized mice confirms some suspected essential virulence determinants but also reveals unexpected differences between S. Typhi and non-typhoidal salmonella serovars. Moreover, we have discovered that S. Typhi persists in cultured human macrophages by preventing apoptotic cell death, due to the absence of multiple SPI-2 type III secretion system effectors that play a central role in non-typhoidal salmonella pathogenesis. NF-B inhibition selectively kill S. Typhi-infected macrophages, suggesting a novel strategy for the treatment of chronic enteric fever. Recently we have also found significant differences in the responses of enteric fever and non-typhoidal salmonella to iron deprivation, observed that the GUT microbiota antagonizes S. Typhi intestinal colonization, and demonstrated important parallels between S. Paratyphi a and S. Typhi in their interactions with human macrophages and humanized mice. Our central hypothesis is that the virulence of enteric fever salmonella serovars depends on the evasion of innate immunity and persistence in macrophages. The research plan will examine three specific aims: 1. Avoidance of macrophage cell death by enteric fever salmonella serovars. Genetic and biochemical approaches will elucidate the molecular mechanisms by which S. Typhi promotes macrophage survival and assess the relevance of macrophage survival to S. Typhi virulence in humanized mice. 2. Interactions of salmonella typhi with the GUT microbiota. The contributions of extracytoplasmic stress responses, microbiota antagonism and avoidance of macrophage cytotoxicity to the ability of S. Typhi to persistently colonize the intestinal tract will be investigated. 3. Salmonella paratyphi a virulence. A systematic analysis of S. Paratyphi a virulence determinants and its mechanisms of serum resistance, iron acquisition and macrophage persistence will be performed. The proposed studies will advance our understanding of enteric fever pathogenesis and lead to novel strategies for its prevention and treatment.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $695,708 | $0 | |
| Amendment | $674,837 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $695,708 | $0 | |
| Amendment | $695,708 | $0 | |
| Amendment | $695,708 | $0 | |
| Amendment | $695,708 | $0 | |
| Amendment | $512,109 | $0 | |
| Original award | $512,109 | $512,109 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| University Of Massachusetts | $67,000 | |
| University Of Massachusetts | $67,000 | |
| University Of Massachusetts | $67,000 |
Quick answers
Who received award R01AI160130?
R01AI160130 was awarded to University Of Washington by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on February 24, 2021.
How much is award R01AI160130 worth?
$5,689,704 has been obligated on R01AI160130: $5,177,595 in federal funding and $512,109 in non-federal funding.
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