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In Vitro Analysis of Myd88-mediated Cellular Immune Response to West Nile Virus Mutant Strain Infection
Published on: November 27, 2014
Dendritic cell-associated MAVS is required to control West Nile virus replication and ensuing humoral immune
Kelsey Roe1, Daniela Giordano1, Lucy B Young1
1Department of Immunology, University of Washington, Seattle, Washington, United States of America.
Abstract:
Mitochondrial antiviral signaling protein (MAVS) is a critical innate immune signaling protein that directs the actions of the RIG-I-like receptor (RLR) signaling pathway of RNA virus recognition and initiation of anti-viral immunity against West Nile virus (WNV). In the absence of MAVS, mice die more rapidly after infection with the pathogenic WNV-Texas (TX) strain, but also produce elevated WNV-specific IgG concomitant with increased viral burden. Here we investigated whether there was a B cell intrinsic role for MAVS during the development of protective humoral immunity following WNV infection. MAVS-/- mice survived infection from the non-pathogenic WNV-Madagascar (MAD) strain, with limited signs of disease. Compared to wildtype (WT) controls, WNV-MAD-infected MAVS-/- mice had elevated serum neutralizing antibodies, splenic germinal center B cells, plasma cells and effector T cells. We found that when rechallenged with the normally lethal WNV-TX, MAVS-/- mice previously infected with WNV-MAD were protected from disease. Thus, protective humoral and cellular immune responses can be generated in absence of MAVS. Mice with a conditional deletion of MAVS only in CD11c+ dendritic cells phenocopied MAVS whole body knockout mice in their humoral responses to WNV-MAD, displaying elevated virus titers and neutralizing antibodies. Conversely, a B cell-specific deletion of MAVS had no effect on immune responses to WNV-MAD compared to WT controls. Thus, MAVS in dendritic cells is required to control WNV replication and thereby regulate downstream humoral immune responses.
Insights
Mitochondrial antiviral signaling protein (MAVS) is crucial for controlling West Nile virus (WNV). Its absence in dendritic cells, not B cells, impairs WNV control and alters immune responses.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Mitochondrial antiviral signaling protein (MAVS) is essential for RIG-I-like receptor (RLR) signaling in antiviral immunity.
- MAVS deficiency leads to increased mortality and viral burden in West Nile virus (WNV)-infected mice.
- The role of MAVS in B cell intrinsic immunity against WNV remains unclear.
Purpose of the Study:
- To investigate the intrinsic role of MAVS in B cells during the development of protective humoral immunity against WNV.
- To determine the cell-specific function of MAVS in controlling WNV infection and immune responses.
Main Methods:
- Comparative analysis of MAVS knockout (MAVS-/-) mice and wildtype (WT) controls following infection with pathogenic (WNV-TX) and non-pathogenic (WNV-MAD) strains of WNV.
- Assessment of humoral and cellular immune responses, including antibody titers, germinal center B cells, plasma cells, and effector T cells.
- Generation and analysis of mice with conditional deletion of MAVS in CD11c+ dendritic cells and B cells.
Main Results:
- MAVS-/- mice survived WNV-MAD infection, exhibiting elevated neutralizing antibodies and enhanced splenic B and T cell responses.
- MAVS-/- mice previously infected with WNV-MAD were protected against lethal WNV-TX challenge.
- Conditional deletion of MAVS in dendritic cells mimicked whole-body knockout phenotypes, while B cell-specific deletion had no effect.
Conclusions:
- Protective humoral and cellular immune responses against WNV can be generated independently of MAVS.
- MAVS expression in dendritic cells is critical for controlling WNV replication and regulating downstream humoral immunity.
- MAVS does not play a B cell intrinsic role in WNV immune responses.
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