The quantity of nitric oxide released by macrophages regulatesChlamydia-induced disease

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. C57BL͞6 mice develop severe pneumonia and poor immunity against Chlamydia after moderate respiratory infection whereas BALB͞c mice are protected from disease and develop vigorous Th1 immunity. Here we show that infected C57BL͞6 macrophages release more NO synthesized by NO synthase 2 (NOS2) than BALB͞c 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 C57BL͞6 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.

Genetic control of susceptibility to pulmonary infection with Chlamydia pneumoniae in the mouse

“…Mouse models of respiratory infection by C. pneumoniae show high variability between inbred strains in terms of chlamydial load in the lung and consequent lung pathology. 13 We investigated the chlamydial load in the lung at day 15 post infection, a time point at which mice from both parental strains are in the process of eliminating the infection. We chose a late time point to investigate the mechanisms underlying differential clearance rates, which in the A/J and B6 strains reflect major differences in lung pathology and disease.…”

“…When infected with C. pneumoniae, C57BL/6J (B6) mice show a robust inflammatory response characterized by a strong Th1-driven response, including high levels of IFNg and IL-12. 13,14 However, the consequences of this early inflammation are concomitant to greater lung disease and pathology in this strain, compared to A/J. The extent of chlamydial lung disease can be estimated by an increase in total lung weight, an indicator of cellular infiltration to the site of infection.…”

“…We have previously reported on a respiratory model of C. pneumoniae infection in mouse that reveals discrete phenotypes amenable to quantitative measures of disease susceptibility. 12,13 Using this model, response to infection with Chlamydia species varies widely in inbred strains of mice. When infected with C. pneumoniae, C57BL/6J (B6) mice show a robust inflammatory response characterized by a strong Th1-driven response, including high levels of IFNg and IL-12.…”

LECT2 association with macrophage-mediated killing of Helicobacter pylori by activating NF-κB and nitric oxide production

“…Exposure of macrophages to most pathogenic bacteria results in iNOS and NO production (Huang et al, 2002). For example, H. pylori infection leads to an increase in iNOS mRNA expression in macrophages.…”

Reduced Nitric Oxide Synthase 2 (NOS2) Promoter Activity in the Syrian Hamster Renders the Animal Functionally Deficient in NOS2 Activity and Unable to Control an Intracellular Pathogen

“…Lastly, although we have referred to hamster and human NOS2 transcription as being impaired (relative to the mouse), in fact it may be that the "hyperexpression" of the mouse (and rat) NOS2 gene is aberrant. Because high or low NOS2 expression can be pathologic (8,46), in vivo studies of other disease models will be needed to address the relative advantages and disadvantages of NOS2 "hypoexpression" in the hamster.…”