Signal Transducers and Activators of Transcription 1 (STAT1), STAT2, and T Cells Mediate Interferon-Dependent Protection Against Neurobrucellosis.

Abstract

Brucellosis is a significant zoonotic disease throughout the world. Human brucellosis patients develop flu-like symptoms and focal complications including arthritis and neurobrucellosis, which is the most morbid complication of Brucella infection. In this study, we employed murine models to uncover the role of T-cell-mediated immunity, interferons, and signal transducers and activators of transcription (STAT) signaling in the development of neurobrucellosis caused by Brucella melitensis. Through adoptive transfer experiments, we discovered that T cells are recruited to the brains of Brucella-infected mice and are able to prevent central nervous system infection in an interferon-γ (IFN-γ)-dependent manner. Transferred T cells were also able to reduce established colonization of the brain by Brucella. In addition, we found that STAT1 plays a protective role against colonization of the brain by Brucella and the progression of neurobrucellosis, and that IFN-γ signaling is not entirely essential for these protective effects. While STAT2 deficiency alone did not affect Brucella burdens, a combined deficiency of STAT2 and the IFN-γ receptor led to elevated Brucella burdens in brains and blood, and a higher likelihood of developing neurologic symptoms relative to animals lacking the IFN-γ receptor alone. Our findings indicate that T cells and IFN signaling through both STAT1 and STAT2 play complex and important roles in protecting against bacterial colonization and development of neurologic symptoms following infection by Brucella.