STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System
Shinya Hidano,
Louise M. Randall,
Lucas Dawson,
Hans K. Dietrich,
Christoph Konradt,
Peter J. Klover,
Beena John,
Tajie H. Harris,
Qun Fang,
Bradley Turek,
Takashi Kobayashi,
Lothar Hennighausen,
Daniel P. Beiting,
Anita A. Koshy,
Christopher A. Hunter
Affiliations
Shinya Hidano
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Louise M. Randall
Department of Medicine, University of Melbourne, Peter Doherty Institute, Parkville, Victoria, Australia
Lucas Dawson
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Hans K. Dietrich
Department of Neurology, Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson, Arizona, USA
Christoph Konradt
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Peter J. Klover
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
Beena John
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Tajie H. Harris
Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, Virginia, USA
Qun Fang
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Bradley Turek
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Takashi Kobayashi
Department of Infectious Disease Control, Faculty of Medicine, Oita University, Yufu, Oita, Japan
Lothar Hennighausen
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
Daniel P. Beiting
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Anita A. Koshy
Department of Neurology, Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson, Arizona, USA
Christopher A. Hunter
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
ABSTRACT The local production of gamma interferon (IFN-γ) is important to control Toxoplasma gondii in the brain, but the basis for these protective effects is not fully understood. The studies presented here reveal that the ability of IFN-γ to inhibit parasite replication in astrocytes in vitro is dependent on signal transducer and activator of transcription 1 (STAT1) and that mice that specifically lack STAT1 in astrocytes are unable to limit parasite replication in the central nervous system (CNS). This susceptibility is associated with a loss of antimicrobial pathways and increased cyst formation in astrocytes. These results identify a critical role for astrocytes in limiting the replication of an important opportunistic pathogen. IMPORTANCE Astrocytes are the most numerous cell type in the brain, and they are activated in response to many types of neuroinflammation, but their function in the control of CNS-specific infection is unclear. The parasite Toxoplasma gondii is one of the few clinically relevant microorganisms that naturally infects astrocytes, and the studies presented here establish that the ability of astrocytes to inhibit parasite replication is essential for the local control of this opportunistic pathogen. Together, these studies establish a key role for astrocytes as effector cells and in the coordination of many aspects of the protective immune response that operates in the brain.
