A Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus

Pradeep D Uchil,Ruoxi Pi,Kelsey A Haugh,Mark S Ladinsky,John D Ventura,Brad S Barrett,Mario L Santiago,Pamela J Bjorkman,George Kassiotis,Xaver Sewald,Walther Mothes

doi:10.1016/j.chom.2018.11.011

Abstract

SummaryLymph- and blood-borne retroviruses exploit CD169/Siglec-1-mediated capture by subcapsular sinus and marginal zone metallophilic macrophages for trans-infection of permissive lymphocytes. However, the impact of CD169-mediated virus capture on retrovirus dissemination and pathogenesis in vivo is unknown. In a murine model of the splenomegaly-inducing retrovirus Friend virus complex (FVC) infection, we find that while CD169 promoted draining lymph node infection, it limited systemic spread to the spleen. At the spleen, CD169-expressing macrophages captured incoming blood-borne retroviruses and limited their spread to the erythroblasts in the red pulp where FVC manifests its pathogenesis. CD169-mediated retroviral capture activated conventional dendritic cells 1 (cDC1s) and promoted cytotoxic CD8+ T cell responses, resulting in efficient clearing of FVC-infected cells. Accordingly, CD169 blockade led to higher viral loads and accelerated death in susceptible mouse strains. Thus, CD169 plays a protective role during FVC pathogenesis by reducing viral dissemination to erythroblasts and eliciting an effective cytotoxic T lymphocyte response via cDC1s.

Highlights

Viruses are immotile but can disseminate within the host either by exploiting the natural flow of body fluids or by using mobile cells
Lymph- and blood-filtering lectin CD169/Siglec-1 expressed on sentinel marginal zone metallophilic macrophages (MMMs) and subcapsular sinus (SCS) macrophages plays a crucial role in capturing retroviral particles such as murine leukemia virus (MLV) and human immunodeficiency virus 1 (HIV-1), thereby promoting the transition of virus dissemination from a cell-free to cell-associated mode (Sewald et al, 2015)
We assessed the extent of retrovirus particle spread 1 hr after subcutaneous (s.c.) injection in B6 and CD169À/À mice using luciferase-encoding Friend MLV (FrMLV) (Figure 1A)

Summary

Introduction

Viruses are immotile but can disseminate within the host either by exploiting the natural flow of body fluids or by using mobile cells. Lymph- and blood-filtering lectin CD169/Siglec-1 expressed on sentinel marginal zone metallophilic macrophages (MMMs) and subcapsular sinus (SCS) macrophages plays a crucial role in capturing retroviral particles such as murine leukemia virus (MLV) and human immunodeficiency virus 1 (HIV-1), thereby promoting the transition of virus dissemination from a cell-free to cell-associated mode (Sewald et al, 2015). Retrovirus-laden SCS macrophages trans-infected susceptible lymphocytes, which further spread the retroviral infection by formation of virological synapses. Efficient MLV and HIV-1 infection in mouse models required CD169, suggesting that CD169-mediated trans-infection of permissive lymphocytes was exploited by retroviruses. The impact of CD169-mediated virus capture and promotion of infection on long-term retrovirus dissemination and pathogenesis remains to be investigated

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Conclusion