title: T-bet Is Required for the Rapid Clearance of Attenuated Rabies Virus from Central Nervous System Tissue.
abstract: Much of our understanding of CNS immunity has been gained from models involving pathological inflammation. Attenuated rabies viruses (RABV) are unique tools to study CNS immunity in the absence of conventional inflammatory mechanisms, as they spread from the site of inoculation to the CNS transaxonally, thereby bypassing the blood-brain barrier (BBB), and are cleared without neutrophil or monocyte infiltration. To better understand the role of CD4 T cell subsets in the clearance of the virus from CNS tissues, we examined the development of antiviral immunity in wild-type (WT) and T-bet knockout mice (T-bet(-/-)), which lack Th1 cells. Early control of RABV replication in the CNS tissues of WT mice is associated with the production of IFN-γ, with antiviral effects likely mediated through the enhanced expression of type I IFNs. Of interest, IFN-α and -γ are overexpressed in the infected T-bet(-/-) by comparison with WT CNS tissues, and the initial control of RABV infection is similar. Ultimately, attenuated RABV are cleared from the CNS tissues of WT mice by Ab locally produced by the activities of infiltrating T and B cells. Although T and B cell infiltration into the CNS of infected T-bet(-/-) mice is comparable, their activities are not, the consequence being delayed, low-level Ab production and prolonged RABV replication. More importantly, neither T-bet(-/-) mice immunized with an attenuated virus, nor WT mice with Th2 RABV-specific immunity induced by immunization with inactivated virus, are protected in the long term against challenge with a pathogenic RABV.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Aurore
authors.initials: A
authors.lastname: Lebrun
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Carla
authors.initials: C
authors.lastname: Portocarrero
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Rhonda B
authors.initials: RB
authors.lastname: Kean
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Darryll A
authors.initials: DA
authors.lastname: Barkhouse
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107; and.
authors.forename: Milosz
authors.initials: M
authors.lastname: Faber
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107; Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA 19107 douglas.hooper@jefferson.edu.
authors.forename: D Craig
authors.initials: DC
authors.lastname: Hooper
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D011818:Rabies / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D011819:Rabies Vaccines / Q000276:immunology / Q000378:metabolism; D011820:Rabies virus / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D013997:Time Factors; D014613:Vaccines, Attenuated / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D000914:Antibodies, Viral; D016898:Interferon-alpha; D011819:Rabies Vaccines; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014613:Vaccines, Attenuated; D016899:Interferon-beta; D007371:Interferon-gamma