STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System.
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.



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.
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Infectious Disease Control, Faculty of Medicine, Oita University, Yufu, Oita, Japan.
Shinya
S
Hidano
Department of Medicine, University of Melbourne, Peter Doherty Institute, Parkville, Victoria, Australia.
Louise M
LM
Randall
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Lucas
L
Dawson
Department of Neurology, Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson, Arizona, USA.
Hans K
HK
Dietrich
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Christoph
C
Konradt
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Peter J
PJ
Klover
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Beena
B
John
Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, Virginia, USA.
Tajie H
TH
Harris
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Qun
Q
Fang
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Bradley
B
Turek
Department of Infectious Disease Control, Faculty of Medicine, Oita University, Yufu, Oita, Japan.
Takashi
T
Kobayashi
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Lothar
L
Hennighausen
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Daniel P
DP
Beiting
Department of Neurology, Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson, Arizona, USA.
Anita A
AA
Koshy
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA chunter@vet.upenn.edu.
Christopher A
0000-0003-3092-1428
CA
Hunter
D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D001921:Brain / Q000276:immunology / Q000469:parasitology; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology* / Q000469:parasitology*
D050794:STAT1 Transcription Factor; D007371:Interferon-gamma