Blockade of Chronic Type I Interferon Signaling to Control Persistent LCMV Infection

By Elizabeth B. Wilson, Douglas H. Yamada, Heidi J. Elsaesser, Jonathan Herskovitz, Jane C. Deng, G. Cheng, Bruce J. Aronow, C. Karp, D. Brooks. Science, 2013

747 citations recorded by the source corpus.

INTERFER(ON)ing Persistence During persistent viral infections, a dysregulated immune response fails to control the infection. Wilson et al. (p. 202) and Teijaro et al. (p. 207; see the Perspective by Odorizzi and Wherry) show this occurs because type I interferons (IFN I), critical for early responses to viral infection, contribute to the altered immunity seen during persistent infection. Antibody blockade of IFN I signaling during chronic lymphocytic choriomeningitis virus (LCMV) in mice resulted in reduced viral titers at later stages of infection, reduced expression of inhibitory immune molecules and prevented the disruptions to secondary lymphoid organs typically observed during persistent infection with LCMV. Whether type I IFNs are also detrimental to persistent viral infection humans, such as HIV and hepatitis C virus, remains to be determined. Blockade of type I interferons leads to better control of persistent lymphocytic choriomeningitis virus infection. [Also see Perspective by Odorizzi and Wherry] Type I interferons (IFN-I) are critical for antiviral immunity; however, chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent infections. We demonstrated in mice that blockade of IFN-I signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production. Thus, we demonstrated that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection.

Subfields: Epidemiology, Immunology

View Paper: https://www.semanticscholar.org/paper/71884b68044c4ef1e0d96860ac63e97769ddc408

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Citations in the corpus

Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice (2016, neutral): “Furthermore, during persistent viral infections such as those caused by lymphocytic choriomeningitis virus or SIV, IFN-I promotes chronic immune activation and upregulates the expression of inhibitory molecules such as PD-1 and LAG-3, resulting in impaired T cell responses (Sandler et al., 2014; Tei”
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, neutral): “The dose and schedule are likely critical and will need optimization, as indiscriminately blocking IFN signaling on host cells can interfere with the generation of anti-tumor (Diamond et al., 2011) and anti-viral responses (Ng et al., 2015; Sandler et al., 2014; Wilson et al., 2013).”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Administration of anti-IFNAR1 following establishment of T cell exhaustion also enhanced viral control (183, 184), highlighting the complexity of the antiviral versus proexhaustion balance for these cytokines.”
Tolerance and Exhaustion: Defining Mechanisms of T cell Dysfunction (2013, neutral): “Furthermore, suppressive cytokines such as IL-10 and transforming growth factor (TGF-β), immune cells including myeloid suppressor cells [81], Foxp3+ CD4+ regulatory T cells [7], and prolonged production of type I interferons (IFN-α/β) that paradoxically up-regulate expression and production of inhi”
Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer (2015, neutral): “Other genes include interferon stimulated genes, which may promote immune suppression through PD-L1 10,11 .”