Histidine-rich glycoprotein promotes bacterial entrapment in clots and decreases mortality in a mouse model of sepsis.

Streptococcus pyogenes is a significant bacterial pathogen in humans. In this study, Histidine-rich glycoprotein (HRG), an abundant plasma protein, was found to kill S. pyogenes. Furthermore, S. pyogenes grew more efficiently in HRG deficient plasma, and clots formed in this plasma were significantly less effective at bacterial entrapment and killing. HRG deficient mice were strikingly more susceptible to S. pyogenes infection. These animals failed to control the infection at the local subcutaneous site, and abscess formation and inflammation was diminished as compared with control animals. As a result, bacterial dissemination occurred more rapidly in HRG deficient mice and they succumbed earlier and with a significantly higher mortality rate than control animals. HRG deficient mice supplemented with purified HRG gave the same phenotype as control animals, demonstrating that the lack of HRG was responsible for the increased susceptibility. The results demonstrate a previously unappreciated role for HRG as a regulator of inflammation and in the defence at the local site of bacterial infection.