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Lymph Node Macrophages Restrict Murine Cytomegalovirus Dissemination
Helen E Farrell1, Nick Davis-Poynter1, Kimberley Bruce1
1Sir Albert Sakzewski Virus Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland and Royal Children's Hospital, Brisbane, Queensland, Australia.
Journal of Virology
|May 1, 2015
Summary
Murine cytomegalovirus (MCMV) infection spreads through lymph nodes, where subcapsular sinus macrophages act as a bottleneck. Depleting these macrophages accelerates MCMV spread, suggesting they are a potential vaccine target.
Area of Science:
- Virology
- Immunology
- Infectious Disease
Background:
- Cytomegaloviruses (CMVs) establish chronic infections, spreading from entry sites to vascular and shedding sites.
- Human CMV (HCMV) is difficult to study due to its spread preceding symptoms, making murine CMV (MCMV) a valuable model.
- The precise route of MCMV systemic spread from peripheral sites is not fully understood.
Purpose of the Study:
- To investigate the initial spread of murine cytomegalovirus (MCMV) following peripheral inoculation.
- To identify the role of lymph nodes and specific immune cells in controlling MCMV dissemination.
- To evaluate the potential of targeting specific immune cells for therapeutic intervention against CMV infection.
Main Methods:
- Viral luciferase imaging to track MCMV spread after footpad inoculation.
- Analysis of infected cells within the popliteal lymph nodes (PLN) using markers like CD169 and CD11c.
- Depletion of subcapsular sinus macrophages (SSM) using liposomal clodronate or a CD169-diphtheria toxin receptor transgene.
- Assessment of viral replication and spread to secondary sites like the spleen post-macrophage depletion.
Main Results:
- MCMV initially spread to popliteal lymph nodes (PLN), with rapid colonization and slow subsequent spread, indicating a bottleneck.
- Acutely infected PLN cells were primarily CD169(+) subcapsular sinus macrophages (SSM), which supported viral replication poorly.
- Depletion of SSM shifted MCMV infection to stromal cells, increased viral production, and accelerated spread to the spleen.
- SSM appeared to slow MCMV spread by limiting access to permissive fibroblasts and poorly supporting lytic replication.
Conclusions:
- MCMV dissemination occurs via lymph nodes, with SSM acting as a crucial bottleneck that limits viral spread.
- SSM control MCMV spread by restricting infection of susceptible fibroblasts and poorly supporting viral replication.
- Targeting SSM represents a potential strategy for controlling MCMV and possibly HCMV systemic infection.
