Persistent LCMV Infection Is Controlled by Blockade of Type I Interferon Signaling

Teijaro, John R.; Ng, Cherie; Lee, Andrew M.; Sullivan, Brian M.; Sheehan, Kathleen C. F.; Welch, Megan J.; Schreiber, Robert D.; Torre, Juan Carlos de la; Oldstone, Michael B. A.

doi:10.1126/science.1235214

Cited by 649 publications

(795 citation statements)

References 38 publications

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“…Indeed, early initiation of PR treatment has been suggested to improve treatment outcomes 48. Furthermore, blockade of interferon signaling during chronic LCMV infection of mice has been shown recently to clear the infection 49, 50. Whether a critical time following infection exists within which the start of PR therapy does not exacerbate CTL exhaustion remains to be ascertained.…”

Section: Discussionmentioning

confidence: 99%

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

2018

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A fraction of chronic hepatitis C patients treated with direct‐acting antivirals (DAAs) achieved sustained virological responses (SVR), or cure, despite having detectable viremia at the end of treatment (EOT). This observation, termed EOT +/SVR, remains puzzling and precludes rational optimization of treatment durations. One hypothesis to explain EOT +/SVR, the immunologic hypothesis, argues that the viral decline induced by DAAs during treatment reverses the exhaustion of cytotoxic T lymphocytes (CTLs), which then clear the infection after treatment. Whether the hypothesis is consistent with data of viral load changes in patients who experienced EOT +/SVR is unknown. Here, we constructed a mathematical model of viral kinetics incorporating the immunologic hypothesis and compared its predictions with patient data. We found the predictions to be in quantitative agreement with patient data. Using the model, we unraveled an underlying bistability that gives rise to EOT +/SVR and presents a new avenue to optimize treatment durations. Infected cells trigger both activation and exhaustion of CTLs. CTLs in turn kill infected cells. Due to these competing interactions, two stable steady states, chronic infection and viral clearance, emerge, separated by an unstable steady state with intermediate viremia. When treatment during chronic infection drives viremia sufficiently below the unstable state, spontaneous viral clearance results post‐treatment, marking EOT +/SVR. The duration to achieve this desired reduction in viremia defines the minimum treatment duration required for ensuring SVR, which our model can quantify. Estimating parameters defining the CTL response of individuals to HCV infection would enable the application of our model to personalize treatment durations.

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Section: Discussionmentioning

confidence: 99%

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

2018

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“…The persistent infection established by Cl13 in C57BL/6 or BALB/c mice is associated with induction of an immunosuppressive state, characterized by production of inhibitory cytokines, such as interleukin-10 (IL-10) and IFN-I, and up-regulation of inhibitory receptors on effector T cells, such as programmed cell death 1 (PD-1), T cell immunoglobulin and mucin domain 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3), leading to T-cell exhaustion (20)(21)(22)(23)(24)(25). Induction of T-cell exhaustion is part of a physiological program aimed at limiting immunopathology caused by excessive and protracted immune responses and high antigen/virus load (23)(24)(25)(26). Strikingly, unlike C57BL/6 (H-2 b ) or BALB/c (H-2 d ) mice, NZB mice (H-2 d ) mounted a robust cytotoxic T-cell response to Cl13 that, at day 6 pi, was almost as efficient as in ARM-challenged controls ( Fig.…”

Section: Cl13 Induces In Nzb Mice a Pathogenic Cytotoxic T-cell Responsementioning

confidence: 99%

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Baccalà¹,

Welch²,

Gonzalez-Quintial³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Lassa virus is, after dengue virus, the second most common cause of viral hemorrhagic fever. In susceptible individuals, Lassa virus infection is associated with vascular permeability, leading to tissue edema, organ failure, and death. Hemorrhagic fever viruses efficiently infect vascular endothelial cells, but are generally considered noncytopathic. Thus, the mechanism of virus-induced vascular injury remains unclear. Using the lymphocytic choriomeningitis virus variant clone 13, a prototype of Lassa virus, we show here that lethal vascular leakage in susceptible mice was completely prevented by type I IFN receptor blockade. Therefore, approaches that target type I IFNs or effector molecules induced by these cytokines may be considered for the treatment of Lassa fever and other severe hemorrhagic viral illnesses.

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“…sphingosine 1-phosphate | S1PR1 | plasmacytoid dendritic cell | interferon-α | IFNAR1 P lasmacytoid dendritic cells (pDCs) are a rare innate immune cell population in mice known for their ability to produce large quantities of type 1 IFN (IFN-I) following stimulation with viral or cellular nucleic acids. Moreover, IFN-α signaling promotes autoimmune (1), viral (2)(3)(4)(5), and bacterial disease pathogenesis (6). Suppression of IFN-α signaling has demonstrated efficacy in multiple autoimmune mouse models (7)(8)(9) and during influenza viral infection (4,10); however, the mechanism by which sphingosine 1-phosphate receptor 1 (S1PR1) signaling prevents IFN-α amplification during these disease states is currently unknown.…”

mentioning

confidence: 99%

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

Teijaro

Studer

Leaf

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal-derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and downmodulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions. sphingosine 1-phosphate | S1PR1 | plasmacytoid dendritic cell | interferon-α | IFNAR1

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Persistent LCMV Infection Is Controlled by Blockade of Type I Interferon Signaling

Cited by 649 publications

References 38 publications

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

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