Enter the text here that is the new abstract information for your application. This section must be no vii longer than 30 lines of text. Human brucellosis, caused by Bruce/Ia spp., is one of the most widespread zoonotic diseases globally, with an estimated 500,000 new cases each year. An important aspect of B. abortus infection is its ability to persist within phagocytic cells of the reticuloendothelial system. We have shown that the virB locus, encoding a Type IV secretion system (T4SS), is essential for survival in phagocytes and virulence in mice. However, the mechanisms by which the T4SS allows B. abortus to establish its niche in the host are unknown. The objective of this application is to characterize the role of molecules secreted by the B. abortus T4SS in interaction with host cells. The central hypothesis of this application is that the T4SS functions in establishing a replicative niche in the host by can D-0 O-0 0 fl) E (fl targeting the Bruce//a-containing vacuole to the endoplasmic reticulum (ER). The rationale for the proposed research is that characterization of virulence mechanisms v,' excellent research environment that is highly conducive to its successful completion. The central hypothesis will be tested and the objectives of this application accomplished by pursuing the following specific aim: (i) Determine the contribution of T4SS-translocated effector proteins to persistent infection of the reticuloendothelial system significantly influencing concepts and methods driving the field.

Public Health Relevance

for human health: Brucella is a bacterial pathogen that causes a febrile illness in people who have consumed unpasteurized goat, sheep or cow's milk contaminated with the bacteria. Worldwide, there are over 500,000 new cases of brucellosis each year. The fevers caused by Brucella are particularly debilitating and if not treated properly, can recur for years after the initial infection. This application proposes to determine how Brucella is able to persist in infected people for an extended period of time, by determining the role of a specific virulence factor known as the Type IV secretion system that enables Brucella to survive within the body's immune cells. Information gained from this work will help understand the basis for this debilitating disease, which will in turn, aid in the development of improved human vaccines and diagnostics for brucellosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050553-11
Application #
7936213
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mukhopadhyay, Suman
Project Start
2001-07-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
11
Fiscal Year
2010
Total Cost
$338,725
Indirect Cost
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
Celli, Jean; Tsolis, Renée M (2015) Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes? Nat Rev Microbiol 13:71-82
Keestra-Gounder, A Marijke; Tsolis, Renée M; Bäumler, Andreas J (2015) Now you see me, now you don't: the interaction of Salmonella with innate immune receptors. Nat Rev Microbiol 13:206-16
Kerrinnes, Tobias; Young, Briana M; Leon, Carlos et al. (2015) Phospholipase A1 modulates the cell envelope phospholipid content of Brucella melitensis, contributing to polymyxin resistance and pathogenicity. Antimicrob Agents Chemother 59:6717-24
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Xavier, Mariana N; Winter, Maria G; Spees, Alanna M et al. (2013) PPAR?-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages. Cell Host Microbe 14:159-70
de Jong, Maarten F; Starr, Tregei; Winter, Maria G et al. (2013) Sensing of bacterial type IV secretion via the unfolded protein response. MBio 4:e00418-12
Xavier, Mariana N; Winter, Maria G; Spees, Alanna M et al. (2013) CD4+ T cell-derived IL-10 promotes Brucella abortus persistence via modulation of macrophage function. PLoS Pathog 9:e1003454
Terwagne, Matthieu; Ferooz, Jonathan; Rolán, Hortensia G et al. (2013) Innate immune recognition of flagellin limits systemic persistence of Brucella. Cell Microbiol 15:942-960
de Jong, Maarten F; Tsolis, Renee M (2012) Brucellosis and type IV secretion. Future Microbiol 7:47-58

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