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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Viral cell death inhibitor MC159 enhances innate immunity against vaccinia virus infection
Sreerupa Challa1, Melissa Woelfel, Melissa Guildford
1Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Abstract:
Viral inhibitors of host programmed cell death (PCD) are widely believed to promote viral replication by preventing or delaying host cell death. Viral FLIPs (Fas-linked ICE-like protease [FLICE; caspase-8]-like inhibitor proteins) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. Surprisingly, transgenic expression of the viral FLIP MC159 from molluscum contagiosum virus (MCV) in mice enhanced rather than inhibited the innate immune control of vaccinia virus (VV) replication. This effect of MC159 was specifically manifested in peripheral tissues such as the visceral fat pad, but not in the spleen. VV-infected MC159 transgenic mice mounted an enhanced innate inflammatory reaction characterized by increased expression of the chemokine CCL-2/MCP-1 and infiltration of γδ T cells into peripheral tissues. Radiation chimeras revealed that MC159 expression in the parenchyma, but not in the hematopoietic compartment, is responsible for the enhanced innate inflammatory responses. The increased inflammation in peripheral tissues was not due to resistance of lymphocytes to cell death. Rather, we found that MC159 facilitated Toll-like receptor 4 (TLR4)- and tumor necrosis factor (TNF)-induced NF-κB activation. The increased NF-κB responses were mediated in part through increased binding of RIP1 to TNFRSF1A-associated via death domain (TRADD), two crucial signal adaptors for NF-κB activation. These results show that MC159 is a dual-function immune modulator that regulates host cell death as well as NF-κB responses by innate immune signaling receptors.
Insights
Viral FLIPs (Fas-linked ICE-like protease inhibitors) typically aid viral replication. However, molluscum contagiosum virus MC159 surprisingly enhanced innate immune control of vaccinia virus in mice, modulating cell death and NF-κB signaling.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Viral inhibitors of programmed cell death (PCD) are thought to enhance viral replication.
- Viral FLIPs inhibit apoptosis and programmed necrosis, key components of PCD.
- The role of viral FLIPs in innate immunity and viral control is not fully understood.
Purpose of the Study:
- To investigate the effect of transgenic expression of molluscum contagiosum virus FLIP (MC159) on vaccinia virus replication and innate immune responses in mice.
- To determine the cellular compartment responsible for MC159's effects.
- To elucidate the molecular mechanisms underlying MC159's immune modulation.
Main Methods:
- Generation of MC159 transgenic mice.
- Infection of mice with vaccinia virus (VV).
- Analysis of innate immune responses, including chemokine expression (CCL-2/MCP-1) and immune cell infiltration (γδ T cells).
- Use of radiation chimeras to assess the role of different cellular compartments.
- Investigation of NF-κB activation pathways, including Toll-like receptor 4 (TLR4) and tumor necrosis factor (TNF) signaling, and protein-protein interactions (RIP1, TRADD).
Main Results:
- Transgenic expression of MC159 enhanced innate immune control of VV replication in peripheral tissues, but not the spleen.
- MC159 expression in the tissue parenchyma, not hematopoietic cells, mediated enhanced innate inflammatory responses.
- Enhanced inflammation involved increased CCL-2/MCP-1 expression and γδ T cell infiltration.
- MC159 facilitated Toll-like receptor 4 (TLR4) and tumor necrosis factor (TNF)-induced NF-κB activation.
- Increased NF-κB activation was partly due to enhanced binding of RIP1 to TRADD.
Conclusions:
- Molluscum contagiosum virus MC159 acts as a dual-function immune modulator.
- MC159 regulates both host cell death pathways and NF-κB activation by innate immune receptors.
- This viral protein enhances innate immune control, contrary to the typical role of viral PCD inhibitors.
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