Innate host resistance to infectious agents plays an important role in determining whether infection by pathogenic microorganisms progresses to disease or whether the microorganisms are eliminated. Resistance to the growth of several intracellular pathogens, including Mycobacteria, Salmonella and Leishmania is mediated by the macrophage and is controlled by a gene, now called Nramp1, a natural resistance associated macrophage protein. The gene appears to control the functional capacity of macrophages such that macrophages that express the functional protein appear to be at a more heightened state of activation than are macrophages that do not express a functional protein. The function of the gene product in controlling resistance is not known. Based on nucleotide sequence analysis the deduced protein appears to be a transport protein.
The specific aims are to: 1) correlate mycobacterial resistance, using lung and splenic macrophages, with stable expression of mRNA and the intracellular iron with Nramp1 using both congenic and transgenic mice; 2) determine the role of Nramp1Gly169 in transition metal transport; 3) determine the role of intracellular iron and Nramp1 in mRNA stability and protein synthesis using cell lines transfected with Nramp1Gly169 and Nramp1Asp169; and 4) determine the mechanism of mRNA stability induced by iron.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059795-04
Application #
6184352
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$255,500
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Lafuse, William P; Alvarez, Gail R; Curry, Heather M et al. (2006) Mycobacterium tuberculosis and Mycobacterium avium inhibit IFN- gamma -induced gene expression by TLR2-dependent and independent pathways. J Interferon Cytokine Res 26:548-61
Curry, Heather; Alvarez, Gail R; Zwilling, Bruces S et al. (2004) Toll-like receptor 2 stimulation decreases IFN-gamma receptor expression in mouse RAW264.7 macrophages. J Interferon Cytokine Res 24:699-710
Weatherby, Kelly E; Zwilling, Bruce S; Lafuse, William P (2003) Resistance of macrophages to Mycobacterium avium is induced by alpha2-adrenergic stimulation. Infect Immun 71:22-9
Alvarez, Gail R; Zwilling, Bruce S; Lafuse, William P (2003) Mycobacterium avium inhibition of IFN-gamma signaling in mouse macrophages: Toll-like receptor 2 stimulation increases expression of dominant-negative STAT1 beta by mRNA stabilization. J Immunol 171:6766-73
Wang, Tianyi; Lafuse, William P; Takeda, Kiyoshi et al. (2002) Rapid chromatin remodeling of Toll-like receptor 2 promoter during infection of macrophages with Mycobacterium avium. J Immunol 169:795-801
Lafuse, William P; Alvarez, Gail R; Zwilling, Bruce S (2002) Role of MAP kinase activation in Nramp1 mRNA stability in RAW264.7 macrophages expressing Nramp1(Gly169). Cell Immunol 215:195-206
Zhong, W; Lafuse, W P; Zwilling, B S (2001) Infection with Mycobacterium avium differentially regulates the expression of iron transport protein mRNA in murine peritoneal macrophages. Infect Immun 69:6618-24
Kuhn, D E; Lafuse, W P; Zwilling, B S (2001) Iron transport into mycobacterium avium-containing phagosomes from an Nramp1(Gly169)-transfected RAW264.7 macrophage cell line. J Leukoc Biol 69:43-9
Wang, T; Lafuse, W P; Zwilling, B S (2001) NFkappaB and Sp1 elements are necessary for maximal transcription of toll-like receptor 2 induced by Mycobacterium avium. J Immunol 167:6924-32
Lafuse, W P; Alvarez, G R; Zwilling, B S (2000) Regulation of Nramp1 mRNA stability by oxidants and protein kinase C in RAW264.7 macrophages expressing Nramp1(Gly169). Biochem J 351 Pt 3:687-96

Showing the most recent 10 out of 16 publications