Abstract
Liver sinusoidal endothelial cells (LSECs) are specialized scavenger cells that mediate high-capacity clearance of soluble waste macromolecules and colloid material, including blood-borne adenovirus. To explore if LSECs function as a sink for other viruses in blood, we studied the fate of virus-like particles (VLPs) of two ubiquitous human DNA viruses, BK and JC polyomavirus, in mice. Like complete virions, VLPs specifically bind to receptors and enter cells, but unlike complete virions, they cannot replicate. 125I-labeled VLPs were used to assess blood decay, organ-, and hepatocellular distribution of ligand, and non-labeled VLPs to examine cellular uptake by immunohisto- and -cytochemistry. BK- and JC-VLPs rapidly distributed to liver, with lesser uptake in kidney and spleen. Liver uptake was predominantly in LSECs. Blood half-life (∼1 min), and tissue distribution of JC-VLPs and two JC-VLP-mutants (L55F and S269F) that lack sialic acid binding affinity, were similar, indicating involvement of non-sialic acid receptors in cellular uptake. Liver uptake was not mediated by scavenger receptors. In spleen, the VLPs localized to the red pulp marginal zone reticuloendothelium, and in kidney to the endothelial lining of vasa recta segments, and the transitional epithelium of renal pelvis. Most VLP-positive vessels in renal medulla did not express PV-1/Meca 32, suggesting location to the non-fenestrated part of vasa recta. The endothelial cells of these vessels also efficiently endocytosed a scavenger receptor ligand, formaldehyde-denatured albumin, suggesting high endocytic activity compared to other renal endothelia. We conclude that LSECs very effectively cleared a large fraction of blood-borne BK- and JC-VLPs, indicating a central role of these cells in early removal of polyomavirus from the circulation. In addition, we report the novel finding that a subpopulation of endothelial cells in kidney, the main organ of polyomavirus persistence, showed selective and rapid uptake of VLPs, suggesting a role in viremic organ tropism.
Highlights
The mucosal surfaces of the respiratory, oral-pharyngeal and gastrointestinal tracts are constantly exposed to a multitude of different viruses, only some of which eventually cause infection and disease [1]
Of the various liver cells involved in host defense, liver sinusoidal endothelial cells (LSECs), which line the numerous sinusoids of this organ, are the least known
LSECS clearly play an important role as sentinel cells of the immune system due to: 1) their location exposing them to 25–30% of cardiac output; 2) their expression of several molecules involved in innate immunity such as various scavenger receptors [11,12,13]), the mannose receptor [14,15], toll-like receptors 2–4, 7 and 9 [16,17,18,19], and 3) their capacity to produce cytokines and other molecules to alert their environment [16,19]
Summary
The mucosal surfaces of the respiratory, oral-pharyngeal and gastrointestinal tracts are constantly exposed to a multitude of different viruses, only some of which eventually cause infection and disease [1]. Viruses are likely to leak from the gut to the portal vein, and many of these viruses end up in the liver [2,3,4,5,6,7,8]. Some picornaviruses such as hepatitis A virus initially replicate in the intestinal mucosal surface and cause acute hepatitis when reaching the liver. We have previously shown that this high scavenging activity of LSECs is conserved among all land-based vertebrates (amphibians, reptiles, birds, mammals) suggesting that this is a general mechanism for how soluble macromolecular waste material, and small colloidal particles, such as viruses, are cleared from blood [10,35]
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