Mice Deficient in STAT1 but Not STAT2 or IRF9 Develop a Lethal CD4⁺T-Cell-Mediated Disease following Infection with Lymphocytic Choriomeningitis Virus

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.

IRF7-Dependent Type I Interferon Production Induces Lethal Immune-Mediated Disease in STAT1 Knockout Mice Infected with Lymphocytic Choriomeningitis Virus

“…1B). Consistent with previous findings in our lab (17), LCMV-infected STAT1 KO mice developed a lethal wasting disease and in accordance with animal welfare requirements were euthanized between days 8 and 10 (Fig. 1A).…”

“…Magnifications: ϫ50 (C to F) and ϫ200 (G to J). alized tissue pathology affecting several organs, including the liver, which is associated with leukocyte infiltration and tissue destruction (17). In these animals, there is also the gross loss of splenic architecture.…”

“…Our previous findings showed that the levels of several cytokines in serum are significantly higher in LCMV-infected STAT1 KO mice than similarly infected WT mice at day 3 postinfection (17). In order to investigate whether IRF7 was linked to the production of these cytokines, a Q-plex assay detecting 16 cytokines in parallel was used to analyze serum samples obtained from WT, STAT1 KO, IRF7 KO, or STAT1/IRF7 DKO mice at days 0 and 3 postinfection.…”

“…inoculation of LCMV-Arm in T cell-deficient RAG or SCID mice results in persistent infection without untoward physical effects (14,15). It was therefore surprising to find that LCMV infection in STAT1 knockout (KO) mice was lethal, whereas similarly infected STAT2 KO, IRF9 KO, IFNGR KO, or STAT1/IFNGR double KO (DKO) mice survived (17). The lethal disease in LCMV-infected STAT1 KO mice is associated with a generalized immune pathology affecting all organs as well as excessive serum levels of a number of proinflammatory cytokines, suggesting that death is due to a destructive antiviral immune process.…”

“…infection (18,19). Furthermore, IFNAR-deficient mice (19), mice lacking the IFN-I signaling molecule STAT2 or IRF9 (17), or mice treated with anti-IFN-␣/␤ serum (20) do not develop LCM after i.c. infection with LCMV.…”