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The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease
Jin Huang1, Fred J DeGraves, Stephen D Lenz
1Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
Abstract:
Intracellular bacteria of the genus Chlamydia cause numerous typically chronic diseases, frequently with debilitating sequelae. Genetic determinants of disease susceptibility after infection with Chlamydia bacteria are unknown. C57BL/6 mice develop severe pneumonia and poor immunity against Chlamydia after moderate respiratory infection whereas BALB/c mice are protected from disease and develop vigorous Th1 immunity. Here we show that infected C57BL/6 macrophages release more NO synthesized by NO synthase 2 (NOS2) than BALB/c macrophages and have lower mRNA concentrations of arginase II, a competitor of NOS2 for the common substrate, l-arginine. Reduction, but not elimination, of NO production by incomplete inhibition of NOS2 abolishes susceptibility of C57BL/6 mice to Chlamydia-induced disease. Thus, the quantity of NO released by infected macrophages is the effector mechanism that regulates between pathogenic and protective responses to chlamydial infection, and genes controlling NO production determine susceptibility to chlamydial disease.
Insights
Nitric oxide (NO) produced by macrophages determines susceptibility to Chlamydia infections. High NO levels in C57BL/6 mice lead to severe disease, while lower levels in BALB/c mice promote protective immunity.
Area of Science:
- Immunology
- Microbiology
- Genetics
Background:
- Chlamydia infections cause chronic diseases with unknown genetic susceptibility factors.
- Mouse models show differential responses: C57BL/6 mice develop severe pneumonia, while BALB/c mice exhibit protective Th1 immunity.
Purpose of the Study:
- To investigate the genetic determinants of Chlamydia disease susceptibility.
- To elucidate the role of nitric oxide (NO) in regulating host response to Chlamydia infection.
Main Methods:
- Comparative analysis of macrophage responses in C57BL/6 and BALB/c mice.
- Measurement of nitric oxide synthase 2 (NOS2) and arginase II mRNA levels.
- Inhibition of NOS2 to assess its impact on disease susceptibility.
Main Results:
- C57BL/6 macrophages produced significantly more NO via NOS2 than BALB/c macrophages.
- C57BL/6 mice had lower arginase II mRNA levels, reducing competition for the substrate L-arginine.
- Partial inhibition of NOS2 in C57BL/6 mice abolished Chlamydia-induced disease susceptibility.
Conclusions:
- Macrophage-derived NO quantity is a critical effector mechanism determining pathogenic versus protective responses to Chlamydia.
- Genes controlling NO production dictate host susceptibility to chlamydial infections.