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Updated: May 1, 2026
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
A murid gamma-herpesviruses exploits normal splenic immune communication routes for systemic spread
Bruno Frederico1, Brittany Chao1, Janet S May1
1Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK.
Abstract:
Gamma-herpesviruses (γHVs) are widespread oncogenic pathogens that chronically infect circulating lymphocytes. How they subvert the immune check-point function of the spleen to promote persistent infection is not clear. We show that Murid Herpesvirus-4 (MuHV-4) enters the spleen by infecting marginal zone (MZ) macrophages, which provided a conduit to MZ B cells. Relocation of MZ B cells to the white pulp allowed virus transfer to follicular dendritic cells. From here the virus reached germinal center B cells to establish persistent infection. Mice lacking MZ B cells, or treated with a sphingosine-1-phosphate receptor agonist to dislocate them, were protected against MuHV-4 colonization. MuHV-4 lacking ORF27, which encodes a glycoprotein necessary for efficient intercellular spread, could infect MZ macrophages but was impaired in long-term infection. Thus, MuHV-4, a γHV, exploits normal immune communication routes to spread by serial lymphoid/myeloid exchange.
Insights
Murid herpesvirus-4 (MuHV-4) exploits spleen immune cells like macrophages and B cells to establish chronic infection. Blocking these pathways protects mice, revealing a novel viral spread mechanism.
Area of Science:
- Virology
- Immunology
- Pathogen Biology
Background:
- Gamma-herpesviruses (γHVs) are oncogenic pathogens infecting lymphocytes.
- Mechanisms of spleen immune evasion by γHVs for persistent infection remain unclear.
Purpose of the Study:
- To elucidate how Murid herpesvirus-4 (MuHV-4) utilizes spleen architecture to establish persistent infection.
- To identify key cellular targets and pathways exploited by MuHV-4 in the spleen.
Main Methods:
- Tracking MuHV-4 infection in mouse spleens using cellular and molecular techniques.
- Utilizing knockout mice lacking specific immune cell populations (MZ B cells).
- Employing pharmacological agents (sphingosine-1-phosphate receptor agonist) to disrupt immune cell localization.
Main Results:
- MuHV-4 infects marginal zone (MZ) macrophages, facilitating transfer to MZ B cells.
- Virus spreads from MZ B cells to follicular dendritic cells and then to germinal center B cells for persistence.
- Mice lacking MZ B cells or treated to dislocate them showed protection against MuHV-4 colonization.
- MuHV-4 mutants lacking ORF27 exhibited impaired long-term infection despite initial macrophage entry.
Conclusions:
- MuHV-4 employs a serial lymphoid/myeloid exchange strategy, exploiting normal immune communication routes within the spleen.
- Targeting MZ macrophages and MZ B cells offers a potential therapeutic strategy against MuHV-4 infection.
- Understanding this viral dissemination pathway is crucial for controlling γHV persistence and oncogenesis.
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