RRC ID 17490
Author Hofer MJ, Li W, Manders P, Terry R, Lim SL, King NJ, Campbell IL.
Title Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell-mediated disease following infection with lymphocytic choriomeningitis virus.
Journal J Virol
Abstract Interferon (IFN) signaling is crucial for antiviral immunity. While type I IFN signaling is mediated by STAT1, STAT2, and IRF9, type II IFN signaling requires only STAT1. Here, we studied the roles of these signaling factors in the host response to systemic infection with lymphocytic choriomeningitis virus (LCMV). In wild-type (WT) mice and mice lacking either STAT2 or IRF9, LCMV infection was nonlethal, and the virus either was cleared (WT) or established persistence (STAT2 knockout [KO] and IRF9 KO). However, in the case of STAT1 KO mice, LCMV infection was lethal and accompanied by severe multiorgan immune pathology, elevated expression of various cytokine genes in tissues, and cytokines in the serum. This lethal phenotype was unaltered by the coabsence of the gamma interferon (IFN-γ) receptor and hence was not dependent on IFN-γ. Equally, the disease was not due to a combined defect in type I and type II IFN signaling, as IRF9 KO mice lacking the IFN-γ receptor survived infection with LCMV. Clearance of LCMV is mediated normally by CD8(+) T cells. However, the depletion of these cells in LCMV-infected STAT1 KO mice was delayed, but did not prevent, lethality. In contrast, depletion of CD4(+) T cells prevented lethality in LCMV-infected STAT1 KO mice and was associated with a reduction in tissue immune pathology. These studies highlight a fundamental difference in the role of STAT1 versus STAT2 and IRF9. While all three factors are required to limit viral replication and spread, only STAT1 has the unique function of preventing the emergence of a lethal antiviral CD4(+) T-cell response.
Volume 86(12)
Pages 6932-46
Published 2012-6-1
DOI 10.1128/JVI.07147-11
PII JVI.07147-11
PMID 22496215
PMC PMC3393544
MeSH Animals CD4-Positive T-Lymphocytes / immunology* CD4-Positive T-Lymphocytes / virology Female Humans Interferon-Stimulated Gene Factor 3, gamma Subunit / deficiency Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics Interferon-Stimulated Gene Factor 3, gamma Subunit / immunology* Interferons / genetics Interferons / immunology Lymphocytic Choriomeningitis / genetics Lymphocytic Choriomeningitis / immunology* Lymphocytic Choriomeningitis / virology Lymphocytic choriomeningitis virus / genetics Lymphocytic choriomeningitis virus / physiology* Male Mice Mice, Inbred C57BL Mice, Knockout STAT1 Transcription Factor / deficiency STAT1 Transcription Factor / genetics STAT1 Transcription Factor / immunology* STAT2 Transcription Factor / deficiency STAT2 Transcription Factor / genetics STAT2 Transcription Factor / immunology*
IF 4.501
Times Cited 28
Mice RBRC00916