O-polysaccharide is both the dominant immunogen and a major virulence determinant of Brucella spp. In the absence of O-polysaccharide classical Brucella species do not cause disease, and are rapidly cleared from :he host. Data from in vitro model systems appears less decisive. Although most evidence suggests rough mutants retain resistance to macrophage microbicidal killing mechanisms, some results suggest considerable replicative ability that may be masked by increased sensitivity to early killing mechanisms. However, there are also reports of cytotoxic cell death (CCD) induced by infection with rough mutants that is specific for """"""""nacrophages. CCD is accompanied by elevated levels of tumor necrosis factor (TNFa), and nitric oxide (NO) and examination of macrophages revealed nuclear recruitment of nuclear factor kappa B (NF-kappaB) in macrophages exposed to rough organisms that remained in the cytoplasm of cells infected with smooth organisms. There is an increasing consensus that interaction between Brucella and the host cell may be in part controlled or altered by lipopolysaccharide (LPS) on the surface of Brucella. Our long-range goal is to identify the genes required for intracellular survival of Brucella. The objectives of !his application are to determine the contribution of O-polysaccharide in establishing a successful infection through its interaction with macrophages. Our central hypothesis is that O-polysaccharide is an essential element in the interaction between Brucella and host macrophages and enhances survival by evading or altering the innate immune response. The rationale for the proposed research is that understanding the interactions between smooth organisms and the host cell to elicit proper uptake and survival will enhance understanding of the mechanisms resulting in persistence and disease and provide information for the development of improved vaccines or treatments to enhance clearance of infections. We are particularly well prepared to study this interaction because we have established a Brucella mefitensis mutant bank and in vitro and in vivo models of infection and have the capacity to examine Brucella macrophage interaction at the cellular level and in animals models of infection using molecular, genomic and bioinformatic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048496-05
Application #
6998471
Study Section
Special Emphasis Panel (ZRG1-VMD (01))
Program Officer
Mukhopadhyay, Suman
Project Start
2000-09-01
Project End
2009-11-30
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
5
Fiscal Year
2006
Total Cost
$355,202
Indirect Cost
Name
Texas Agrilife Research
Department
Pathology
Type
Schools of Earth Sciences/Natur
DUNS #
847205713
City
College Station
State
TX
Country
United States
Zip Code
77843
Pandey, Aseem; Lin, Furong; Cabello, Ana L et al. (2018) Activation of Host IRE1?-Dependent Signaling Axis Contributes the Intracellular Parasitism of Brucella melitensis. Front Cell Infect Microbiol 8:103
Pandey, Aseem; Ding, Sheng Li; Qin, Qing-Ming et al. (2017) Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection. Cell Host Microbe 21:637-649.e6
Pandey, Aseem; Cabello, Ana; Akoolo, Lavoisier et al. (2016) The Case for Live Attenuated Vaccines against the Neglected Zoonotic Diseases Brucellosis and Bovine Tuberculosis. PLoS Negl Trop Dis 10:e0004572
Case, Elizabeth Di Russo; Smith, Judith A; Ficht, Thomas A et al. (2016) Space: A Final Frontier for Vacuolar Pathogens. Traffic 17:461-74
Pei, Jianwu; Kahl-McDonagh, Melissa; Ficht, Thomas A (2014) Brucella dissociation is essential for macrophage egress and bacterial dissemination. Front Cell Infect Microbiol 4:23
Meegan, Jenny; Dunn, J Lawrence; Venn-Watson, Stephanie K et al. (2012) Serologic response in bottlenose dolphins Tursiops truncatus infected with Brucella sp. using a dolphin-specific indirect ELISA. Dis Aquat Organ 102:73-85
Pei, Jianwu; Ding, Xicheng; Fan, Yaping et al. (2012) Toll-like receptors are critical for clearance of Brucella and play different roles in development of adaptive immunity following aerosol challenge in mice. Front Cell Infect Microbiol 2:115
Weeks, Jenni N; Galindo, Cristi L; Drake, Kenneth L et al. (2010) Brucella melitensis VjbR and C12-HSL regulons: contributions of the N-dodecanoyl homoserine lactone signaling molecule and LuxR homologue VjbR to gene expression. BMC Microbiol 10:167
Ficht, Thomas (2010) Brucella taxonomy and evolution. Future Microbiol 5:859-66
Jupiter, Daniel C; Ficht, Thomas A; Samuel, James et al. (2010) DNA watermarking of infectious agents: progress and prospects. PLoS Pathog 6:e1000950

Showing the most recent 10 out of 20 publications