Staphylococcus aureus infections often lead to hematogenous spread that result in inflammation and joint destruction. Although the virulence factors associated with this bacteria have been defined, the role of the host immune response in limiting the inflammatory process is still poorly understood. Using mice with a targeted disruption in IgA gene expression (IgA-/- mice), we have recently shown another yet unrecognized role for IgA. Specifically, IgA appears to serve an essential role in maintenance of overt inflammatory cytokine and nitric oxide (NO) production. We will now investigate in detail the basis for the immunoregulatory role of IgA in modulating systemic inflammatory responses upon bacterial insult. Using a strain of S. aureus that induces sepsis and joint destruction, we will initially examine the precise role of IgA in limiting inflammatory processes using IgA-/- mice. Bacteremia will be assessed in the blood, spleen and kidneys after infection. Inflammatory cytokine production will be monitored in the blood and lymphoid tissues by ELISA and ribonuclease protection analysis respectively. Inflammation in the joints of these animals will be assessed by immunohistochemistry. Since NO production may have both detrimental and beneficial effects during S. aureus infection, we will examine if the absence of IgA potentiates NO expression in the joints of infected mice by histological analyses. Given that the NF-kB pathway is essential in the regulation of iNOS and NO production, we will examine how the absence of IgA affects various components of this pathway by cellular and molecular analyses. Finally we will determine if IgA regulates an inhibitory signaling pathway in macrophages upon bacterial stimulation. Together, these studies will determine if IgA modulates inflammatory responses to systemic bacterial infection by direct interaction with the innate immune system. The results will provide insight on the role of serum IgA to regulate inflammatory processes such as bacterial sepsis and may lead to the use of use of IgA as a therapeutic anti-inflammatory agent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
1R03AR048973-01
Application #
6533434
Study Section
Special Emphasis Panel (ZAR1-RJB-A (M1))
Program Officer
Gretz, Elizabeth
Project Start
2002-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$59,533
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78249
Murthy, Ashlesh K; Chaganty, Bharat K R; Troutman, Ty et al. (2011) Mannose-containing oligosaccharides of non-specific human secretory immunoglobulin A mediate inhibition of Vibrio cholerae biofilm formation. PLoS One 6:e16847
Cong, Yu; Jupelli, Madhulika; Guentzel, M Neal et al. (2007) Intranasal immunization with chlamydial protease-like activity factor and CpG deoxynucleotides enhances protective immunity against genital Chlamydia muridarum infection. Vaccine 25:3773-80
Murthy, Ashlesh K; Chambers, James P; Meier, Patricia A et al. (2007) Intranasal vaccination with a secreted chlamydial protein enhances resolution of genital Chlamydia muridarum infection, protects against oviduct pathology, and is highly dependent upon endogenous gamma interferon production. Infect Immun 75:666-76
Murthy, Ashlesh K; Dubose, Candice N; Banas, Jeffrey A et al. (2006) Contribution of polymeric immunoglobulin receptor to regulation of intestinal inflammation in dextran sulfate sodium-induced colitis. J Gastroenterol Hepatol 21:1372-80
Pammit, Michael A; Raulie, Erin K; Lauriano, Crystal M et al. (2006) Intranasal vaccination with a defined attenuated Francisella novicida strain induces gamma interferon-dependent antibody-mediated protection against tularemia. Infect Immun 74:2063-71
Murphey, Cathi; Murthy, Ashlesh K; Meier, Patricia A et al. (2006) The protective efficacy of chlamydial protease-like activity factor vaccination is dependent upon CD4+ T cells. Cell Immunol 242:110-7
Murthy, Ashlesh K; Cong, Yu; Murphey, Cathi et al. (2006) Chlamydial protease-like activity factor induces protective immunity against genital chlamydial infection in transgenic mice that express the human HLA-DR4 allele. Infect Immun 74:6722-9
Murthy, Ashlesh K; Sharma, Jyotika; Coalson, Jacqueline J et al. (2004) Chlamydia trachomatis pulmonary infection induces greater inflammatory pathology in immunoglobulin A deficient mice. Cell Immunol 230:56-64
Pammit, Michael A; Budhavarapu, Varija N; Raulie, Erin K et al. (2004) Intranasal interleukin-12 treatment promotes antimicrobial clearance and survival in pulmonary Francisella tularensis subsp. novicida infection. Antimicrob Agents Chemother 48:4513-9