Study of group A streptococcus-induced central NF-κB activation and inflammation

Abstract

Group A streptococcus (GAS) infection in human causes a strong inflammatory response associated with cytokine storm which lead to multi-organ failure characterized as streptococcal toxic shock syndrome (STSS). Nuclear factor κB (NF-κB) is a critical regulator of innate immunity and inflammatory responses. To study the kinetics of NF-κB activation upon streptococcal infection, we established an in vivo luminescence reporting system for NF-κB activation in mice. After subcutaneous GAS infection, the site of primary infection, skin, was illuminated in a time-dependent manner. Surprisingly, NF-κB-mediated luminescence and iNOS expression were dramatically increased in the brain, but not notably in the peripheral organs such as liver and spleen, at 48 hr post infection (hpi). Moreover, activation of microglia, the specialized immune cell in CNS, as well as expression of inflammatory cytokines, reactive oxygen species (ROS) related genes, and protein oxidation were significantly induced in the brain at 48 hpi. To further dissect this effects of cytokine storm on central NF-κB mediated central inflammation after bacterial infection, we analyzed circulating levels of cytokines and chemokines after streptococcal infection. Tumor necrosis factor α (TNFα), which has been shown to play a pivotal role during the bacteria-induced brain abscesses, was rapidly increased at 24 hpi. Intraperitoneal administration of dominant negative TNF (DN-TNF) effectively decreased brain NF-κB mediated luminescence and expression of inflammatory cytokines. Our results demonstrated bacterial infection induced peripheral inflammatory cytokines, particularly TNFα, in turn contributing to central NF-κB activation and inflammation. This study provides valuable insight into the role of circulating TNFα-induced central NF-κB activation and the consequent central inflammation upon the bacterial infection in the peripheral.

Date of Award	2010
Original language	English
Supervisor	Pei-Jane Tsai (Supervisor) & Chun-Keung Yu (Supervisor)