Brucella Infection Regulates Thioredoxin-Interacting Protein Expression to Facilitate Intracellular Survival by Reducing the Production of Nitric Oxide and Reactive Oxygen Species

Thioredoxin-interacting protein (TXNIP) is a multifunctional protein that functions in tumor suppression, oxidative stress, and inflammatory responses. However, how TXNIP functions during microbial infections is rarely reported. In this study, we demonstrate that Brucella infection decreased TXNIP expression to promote its intracellular growth in macrophages by decreasing the production of NO and reactive oxygen species (ROS). Following Brucella abortus infection, TXNIP knockout RAW264.7 cells produced significantly lower levels of NO and ROS, compared with wild-type RAW264.7 cells. Inducible NO synthase (iNOS) inhibitor treatment reduced NO levels, which resulted in a dose-dependent restoration of TXNIP expression, demonstrating that the expression of TXNIP is regulated by NO. In addition, the expression of iNOS and the production of NO were dependent on the type IV secretion system of Brucella. Moreover, Brucella infection reduced TXNIP expression in bone marrow–derived macrophages and mouse lung and spleen. Knocked down of the TXNIP expression in bone marrow–derived macrophages increased intracellular survival of Brucella. These findings revealed the following: 1) TXNIP is a novel molecule to promote Brucella intracellular survival by reducing the production of NO and ROS; 2) a negative feedback–regulation system of NO confers protection against iNOS-mediated antibacterial effects. The elucidation of this mechanism may reveal a novel host surveillance pathway for bacterial intracellular survival.