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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Gamma interferon (IFN-γ) receptor restricts systemic dengue virus replication and prevents paralysis in IFN-α/β
Tyler R Prestwood1, Malika M Morar, Raphaël M Zellweger
1Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Abstract:
We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-α/βR and -γR) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-γR alone and virtually no mice lacking the IFN-α/βR alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-α/βR, signaling through the IFN-γR confers approximately 140-fold greater resistance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paralysis. Viral replication in the spleen was assessed by immunohistochemistry and flow cytometry, which revealed a reduction in the number of infected cells due to IFN-γR signaling by 2 days after infection, coincident with elevated levels of IFN-γ in the spleen and serum. By 4 days after infection, IFN-γR signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-γR, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN-γ from CD8(+) T cells. These results demonstrate the roles of IFN-γR signaling in protection from initial systemic and subsequent CNS disease following DENV infection and demonstrate the importance of CD8(+) T cells in preventing DENV-induced CNS disease.
Insights
Interferon gamma receptor (IFN-γR) signaling protects against severe dengue disease and paralysis. CD8(+) T cells are crucial for clearing dengue virus (DENV) in the central nervous system (CNS).
Area of Science:
- Immunology
- Virology
- Neuroscience
Background:
- Mice lacking both alpha/beta and gamma interferon receptors (IFN-α/βR and -γR) uniformly develop paralysis after dengue virus (DENV) infection.
- IFN-γR signaling plays a critical role in controlling DENV infection, but its specific contributions to systemic and central nervous system (CNS) disease remain incompletely understood.
Purpose of the Study:
- To investigate the protective mechanisms of IFN-γR signaling against DENV infection, particularly in the absence of IFN-α/βR signaling.
- To elucidate the role of CD8(+) T cells in DENV clearance within the CNS.
Main Methods:
- Utilized a mouse-passaged DENV variant (S221) for infection studies.
- Assessed viral replication, systemic vascular leakage, paralysis, and immune cell responses using immunohistochemistry and flow cytometry.
- Quantified IFN-γ levels in serum and spleen.
Main Results:
- In the absence of IFN-α/βR, IFN-γR signaling provided significant protection against systemic vascular leakage (140-fold resistance) and paralysis.
- IFN-γR signaling reduced DENV replication in the spleen by day 2 post-infection, correlating with elevated IFN-γ levels.
- IFN-γR signaling restricted systemic DENV replication by day 4 post-infection.
- DENV clearance occurred independently of IFN-γR, except in the CNS, where CD8(+) T cell-derived IFN-γ was essential.
Conclusions:
- IFN-γR signaling is critical for protection against systemic DENV disease and paralysis, especially when IFN-α/βR is absent.
- CD8(+) T cells are vital for eliminating DENV from the CNS, preventing neurological complications.
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