Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination.

Bruno Frederico,Brittany Chao,Janet S May,Philip G Stevenson,Clara Lawler

doi:10.1099/vir.0.000140

Abstract

Lymphocyte proliferation, mobility and longevity make them prime targets for virus infection. Myeloid cells that process and present environmental antigens to lymphocytes are consequently an important line of defence. Subcapsular sinus macrophages (SSMs) filter the afferent lymph and communicate with B-cells. How they interact with B-cell-tropic viruses is unknown. We analysed their encounter with murid herpesvirus-4 (MuHV-4), an experimentally accessible gammaherpesvirus related to Kaposi's sarcoma-associated herpesvirus. MuHV-4 disseminated via lymph nodes, and intranasally or subcutaneously inoculated virions readily infected SSMs. However, this infection was poorly productive. SSM depletion with clodronate-loaded liposomes or with diphtheria toxin in CD169–diphtheria toxin receptor transgenic mice increased B-cell infection and hastened virus spread to the spleen. Dendritic cells provided the main route to B-cells, and SSMs slowed host colonization, apparently by absorbing virions non-productively from the afferent lymph.

Highlights

Persistent virus infections pose major, unsolved health problems
To reconcile our infection studies with those of other antigens, we established a new model of intrafootpad (i.f.) murid herpesvirus-4 (MuHV-4) inoculation (Fig. 1)
Peak live imaging signals were 30fold stronger from footpads than from noses (Fig. 1b)

Summary

Introduction

Persistent virus infections pose major, unsolved health problems. The human gammaherpesviruses Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) colonize B-cells and cause cancers. How they first reach B-cells is hard to define in humans, because infection does not present clinically until it is widespread. The narrow species tropisms of these viruses offer little scope for experimental in vivo analysis. Such analysis is important : vaccination to prevent B-cell binding by cellfree EBV failed to reduce infection rates (Sokal et al, 2007), suggesting that in vivo B-cell infection follows routes other than those predominating in vitro.

Methods

Results

Conclusion