Relevance - Chronic bacterial infections cause significant morbidity and mortality worldwide. The World Health Organization estimates that 1.7 million people per year die from Mycobacterium tuberculosis infections, which can lie dormant in a healthy host for years. Salmonella enterics serotypes can also cause chronic asymptomatic infections in which an apparently healthy host sheds the pathogen intermittently. This situation sets the stage for acute typhoid fever in approximately 17 million naTve hosts each year. Our plan is to understand how, at the molecular and cellular levels, chronic infections are established and maintained. To accomplish this goal we will use a mouse model of persistent Salmonella enterica infection. This model is an excellent one because it examines a natural infection in a genetically tractable animal. A major focus of our proposed work is the Res (Regulation of capsule synthesis) signaling pathway, which we found contributes to the establishment of persistent infection in our mouse model. Using bacterial mutants and DNA microarrays, we have identified 127 Res-activated genes, including genes that either promote or limit in vivo colonization by Salmonella. This finding is consistent with our hypothesis that the establishment of chronic disease is prevented by both too much and too little bacterial colonization; too little colonization may allow for bacterial clearance with few or no signs of acute infection, whereas too much colonization may stimulate the immune system to efficiently eliminate the bacteria. We will begin by exploring the roles of two critical Res-activated genes that we have shown oppositely affect colonization. We also have data indicating that as-yet-uncharacterized members of the Rcs-regulon enhance Salmonella survival in interferon-g stimulated macrophages, and we will identify these genes. Interferon-g stimulated macrophages are relevant to chronic infection because they, rather than resting macrophages, are likely encountered by Salmonella upon re-seeding. In addition, we will pursue our recent findings that the host interferon-g signaling pathway is important for the creation of a cellular niche in which Salmonella replicates during persistent infection but which has not been observed during acute infection. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072492-02
Application #
7425884
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$330,315
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Brown, Diane E; Nick, Heidi J; McCoy, Melissa W et al. (2015) Increased ferroportin-1 expression and rapid splenic iron loss occur with anemia caused by Salmonella enterica Serovar Typhimurium infection in mice. Infect Immun 83:2290-9
Nagy, Toni A; Moreland, Sarah M; Detweiler, Corrella S (2014) Salmonella acquires ferrous iron from haemophagocytic macrophages. Mol Microbiol 93:1314-26
Nagy, Toni A; Moreland, Sarah M; Andrews-Polymenis, Helene et al. (2013) The ferric enterobactin transporter Fep is required for persistent Salmonella enterica serovar typhimurium infection. Infect Immun 81:4063-70
Brown, D E; Libby, S J; Moreland, S M et al. (2013) Salmonella enterica causes more severe inflammatory disease in C57/BL6 Nramp1G169 mice than Sv129S6 mice. Vet Pathol 50:867-76
McCoy, Melissa W; Moreland, Sarah M; Detweiler, Corrella S (2012) Hemophagocytic macrophages in murine typhoid fever have an anti-inflammatory phenotype. Infect Immun 80:3642-9
Pilonieta, M Carolina; Nagy, Toni A; Jorgensen, Dana R et al. (2012) A glycine betaine importer limits Salmonella stress resistance and tissue colonization by reducing trehalose production. Mol Microbiol 84:296-309
Silva-Herzog, Eugenia; Detweiler, Corrella S (2010) Salmonella enterica replication in hemophagocytic macrophages requires two type three secretion systems. Infect Immun 78:3369-77
Brown, Diane E; McCoy, Melissa W; Pilonieta, M Carolina et al. (2010) Chronic murine typhoid fever is a natural model of secondary hemophagocytic lymphohistiocytosis. PLoS One 5:e9441
Pilonieta, M Carolina; Erickson, Kimberly D; Ernst, Robert K et al. (2009) A protein important for antimicrobial peptide resistance, YdeI/OmdA, is in the periplasm and interacts with OmpD/NmpC. J Bacteriol 191:7243-52
Silva-Herzog, Eugenia; Detweiler, Corrella S (2008) Intracellular microbes and haemophagocytosis. Cell Microbiol 10:2151-8

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