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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Ligase Pellino3 Regulates Macrophage Action and Survival in Response to VSV Infection in RIG-I-Dependent Path
Patryk Reniewicz1, Anna Kula1,2, Edyta Makuch1
1Bioengineering Research Group, Łukasiewicz Research Network-PORT Polish Center for Technology Development, Wroclaw 54-066, Poland.
Abstract:
Sensing of viral particles and elements that initiate mechanisms of immune response is an intrinsic ability of mammalian cells. Regulatory cytokines and antiviral mediators are released after triggering of complex signaling cascades in response to interaction of pathogen particles with pattern recognition receptors (PRRs) leading to the production of interferons (IFN) and proinflammatory cytokines. Viral RNA in the cytoplasm constitute a potent danger molecule that recognition is performed by RIG-I-like receptors, the most common group of receptors in mammalian cells, capable to recognize a foreign RNA. It is known that the E3 ubiquitin ligase Pellino3 plays an important role in antibacterial and antiviral response, but its involvement in the RLR pathways remains poorly understood. In this study, we investigate the molecular mechanisms of the innate immune response in BMDMs (immortalized macrophages from mouse bone marrow) during VSV infection. Here, we present evidence that the activation of the RIG-I/Pellino3/ERK1/2 pathway in BMDMs is crucial for the protection against VSV. We demonstrate that during infection, viral particles replicate in Pellino3 knockout BMDMs more effectively than in wild-type cells. Increased viral replication resulting in cell lysis and death is aid by impaired synthesis of IFN-I and inflammatory cytokines as a consequence of disturbances in the ERK1/2 pathway regulation.
Insights
The RIG-I/Pellino3/ERK1/2 pathway is vital for innate immunity against viral infections. Pellino3 deficiency impairs this pathway, leading to increased viral replication and reduced immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Mammalian cells possess intrinsic immune mechanisms to detect viral particles and initiate responses.
- Pattern recognition receptors (PRRs) trigger signaling cascades, releasing cytokines and antiviral mediators like interferons (IFN).
- RIG-I-like receptors (RLRs) recognize cytoplasmic viral RNA, a potent danger signal, but Pellino3's role in RLR pathways is unclear.
Purpose of the Study:
- To investigate the molecular mechanisms of innate immune response during vesicular stomatitis virus (VSV) infection in mouse bone marrow-derived macrophages (BMDMs).
- To elucidate the role of the E3 ubiquitin ligase Pellino3 in the RIG-I-like receptor (RLR) pathway and its contribution to antiviral defense.
Main Methods:
- Utilized immortalized macrophages from mouse bone marrow (BMDMs) for infection studies.
- Employed Pellino3 knockout (KO) and wild-type (WT) BMDMs to compare responses to VSV infection.
- Analyzed viral replication, interferon-I (IFN-I) synthesis, inflammatory cytokine production, and ERK1/2 pathway activation.
Main Results:
- Activation of the RIG-I/Pellino3/ERK1/2 pathway in BMDMs is essential for protection against VSV.
- Pellino3 KO BMDMs exhibited significantly higher VSV replication compared to WT BMDMs.
- Impaired ERK1/2 pathway regulation in Pellino3-deficient cells led to reduced IFN-I and inflammatory cytokine synthesis, contributing to increased viral replication and cell death.
Conclusions:
- Pellino3 plays a critical role in the RIG-I-mediated innate immune response against VSV infection.
- The RIG-I/Pellino3/ERK1/2 signaling axis is crucial for controlling viral replication and maintaining host defense.
- Targeting the Pellino3-dependent pathway could offer therapeutic strategies against viral infections.
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