Infection with the human immunodeficiency virus leads to a systemic immunosuppression that results in an increase in the susceptibility of the host to infection. Infection by opportunistic pathogens is responsible for the morbidity and mortality associated with AIDS. The incidence of mycobacterial diseases, including infections caused by M tuberculosis and avium, has increased significantly among HIV-infected individuals. Studies in the investigator's laboratory have correlated differences in MHC class II expression with resistance to mycobacterial growth in mice. Similar differences in MHC class II expression by human monocytes have been identified also by the investigators. Stress may be an important cofactor in susceptibility to mycobacterial disease, and this laboratory has shown that restraint stress results in a suppression of Ia expression. Differences in Ia expression indicate that there may be differences in the level of activation of the macrophages in mice that are resistant or susceptible to mycobacterial growth. The purpose of this renewal application will be to determine the role of stress in modulating the pathogenesis of mycobacterial infection and to correlate these differences to changes in Ia expression. Thus, restraint stress may alter the host parasite relationship by allowing the opportunistic pathogen to become established and grown within mononuclear phagocytes.
The specific aims are: (1) to determine the effect of restraint on the growth of Mycobacteria in vivo; (2) to determine whether restraint stress induced alteration in mycobacterial growth is mediated by the hypothalamic-pituitary-adrenal axis; (3) to determine the role of the sympathetic nervous system in restraint stress mediated alteration in mycobacterial growth; (4) to determine the effect of restraint stress on the in vitro activity of macrophages; and (5) to determine the mechanism of restraint stress mediated alteration in macrophage function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042901-13
Application #
6475505
Study Section
Special Emphasis Panel (ZMH1-BRB-T (01))
Program Officer
Sizemore, Christine F
Project Start
1989-08-01
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2003-11-30
Support Year
13
Fiscal Year
2002
Total Cost
$309,862
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
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
Wang, T; Lafuse, W P; Zwilling, B S (2000) Regulation of toll-like receptor 2 expression by macrophages following Mycobacterium avium infection. J Immunol 165:6308-13

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