We will use the power of complete genome sequences and forward genetics to identify novel genes that allow a bacterial pathogen to colonize systemic organs in murine models. Non-typhoidal Salmonella (NTS) are food-borne bacterial pathogens that cause hundreds of millions of cases of diarrheal disease and hundreds of thousands of deaths due to bacteremia annually worldwide. Salmonella enterica serotype Typhimurium is an appropriate model to determine the requirements for systemic infection by NTS as this serotype causes more cases of NTS bacteremia, in children under the age of 5 and in HIV infected individuals, than any other serotype. The availability of complete genome sequence information, the ease of genetic manipulation, and the availability of numerous animal models make serot. Typhimurium an excellent model system. We have generated a collection of 1030 targeted deletion strains in serot. Typhimurium (approximately 25% of the genome), developed a novel oligonucleotide microarray to assay this collection of mutants, and begun forward genetic screening of this mutant collection both in vitro and in vivo in murine models of systemic colonization. We wish to complete the development of these tools and progress to more comprehensive studies of a subset of genes involved in systemic colonization a process that occurs during NTS bacteremia caused by this organism. We will approach this goal by: 1. Completion of our deletion library in all non-essential genes in Salmonella Typhimurium, 2. Screening our complete deletion collection in murine models to identify new genes involved in systemic colonization, 3. Confirming each mutant as defective for systemic colonization, 4. Characterizing mutants that are defective for systemic colonization for their ability to associate with, invade, and replicate in cultured macrophages.

Public Health Relevance

Salmonella is a leading cause of food borne illness, causing ~1.4 million cases of diarrheal disease per year and is the single most common cause of death from food-borne illnesses associated with viruses, parasites or bacteria in the US primarily in immunocompromised persons. In young children and HIV-infected individuals, non-typhoidal Salmonellae (NTS) frequently cause systemic infection that is associated with high mortality. The rise of AIDS in many parts of the world, notably in sub- Saharan Africa, has resulted in a dramatic increase in the frequency of NTS-associated systemic infections. The work described in this project will provide novel targets for vaccines and treatments for acute systemic disease that results from Salmonella infection. This work will have a direct impact on public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI083646-04
Application #
8317678
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
2009-09-25
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$350,356
Indirect Cost
$40,132
Name
Texas A&M University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Gupta, Sushim K; McMillan, Elizabeth A; Jackson, Charlene R et al. (2016) Draft Genome Sequence of Salmonella enterica subsp. enterica Serovar Putten Strain CRJJGF_00159 (Phylum Gammaproteobacteria). Genome Announc 4:
Gupta, Sushim K; McMillan, Elizabeth A; Jackson, Charlene R et al. (2016) Draft Genome Sequence of Salmonella enterica subsp. diarizonae Serovar 61:k:1,5,(7) Strain CRJJGF_00165 (Phylum Gammaproteobacteria). Genome Announc 4:
Silva-Valenzuela, Cecilia A; Desai, Prerak T; Molina-Quiroz, Roberto C et al. (2016) Solid tumors provide niche-specific conditions that lead to preferential growth of Salmonella. Oncotarget 7:35169-80
Gupta, Sushim K; McMillan, Elizabeth A; Jackson, Charlene R et al. (2016) Draft Genome Sequence of Salmonella enterica subsp. enterica Serovar Lille Strain CRJJGF_000101 (Phylum Gammaproteobacteria). Genome Announc 4:
Elhadad, Dana; Desai, Prerak; Grassl, Guntram A et al. (2016) Differences in Host Cell Invasion and Salmonella Pathogenicity Island 1 Expression between Salmonella enterica Serovar Paratyphi A and Nontyphoidal S. Typhimurium. Infect Immun 84:1150-65
Cox, Clayton E; Wright, Anita C; McClelland, Michael et al. (2016) Influence of Salmonella enterica Serovar Typhimurium ssrB on Colonization of Eastern Oysters (Crassostrea virginica) as Revealed by a Promoter Probe Screen. Appl Environ Microbiol 82:328-39
Gupta, Sushim K; McMillan, Elizabeth A; Jackson, Charlene R et al. (2016) Draft Genome Sequence of Salmonella enterica subsp. enterica Serovar Orion Strain CRJJGF_00093 (Phylum Gammaproteobacteria). Genome Announc 4:
Gupta, Sushim K; McMillan, Elizabeth A; Jackson, Charlene R et al. (2016) Draft Genome Sequence of Salmonella enterica subsp. enterica Serovar Bardo Strain CRJJGF_00099 (Phylum Gammaproteobacteria). Genome Announc 4:
Marzel, Alex; Desai, Prerak T; Goren, Alina et al. (2016) Persistent Infections by Nontyphoidal Salmonella in Humans: Epidemiology and Genetics. Clin Infect Dis 62:879-86
Gupta, Sushim K; McMillan, Elizabeth A; Jackson, Charlene R et al. (2016) Draft Genome Sequence of Salmonella enterica subsp. enterica Serovar Blockley Strain CRJJGF_00147 (Phylum Gammaproteobacteria). Genome Announc 4:

Showing the most recent 10 out of 50 publications