Abstract
Hepatitis E virus (HEV) transmission through infected blood and blood products has already been described. However, little is known about the bone marrow (BM) as source of HEV infection. Our study aimed to investigate the presence of HEV antigen (Ag) and histological changes in BM of cynomolgus monkeys (Macaca fascicularis) experimentally and naturally infected with HEV. Four cynomolgus monkeys with acute, and two with chronic hepatitis E ─ after immunosuppressive therapy with tacrolimus ─ were compared with one colony-bred animal naturally infected. Both, natural and experimental infections were characterized by anti-HEV IgG seroconversion detected by ELISA, and viral RNA isolation confirmed by RT-qPCR and qualitative nested RT-PCR. BM biopsies were collected from all animals, submitted to histology and indirect immunofluorescence techniques and observed, respectively, by light and confocal microscopy. The HEV Ag-fluorescent-labeled cells were detected from BM biopsies obtained from three monkeys with acute and one with chronic hepatitis E, and also from the naturally infected monkey. In the experimentally infected animals with acute hepatitis, HEV Ag detection occurred at 160 days post-infection, even after viral clearance in serum, feces, and liver. Double-stranded RNA, a replicative marker, was detected in BM cells from both acute and chronically infected animals. Major histological findings included vacuolization in mononuclear and endosteal cells, an absence of organized inflammatory infiltrates, and also some fields suggesting displasic focal BM disease. These findings support the hypothesis of BM cells as secondary target sites of HEV persistence. Further experimental studies should be carried out to confirm the assumption of HEV transmission through BM transplantation.
Highlights
Hepatitis E virus (HEV) infection is a major cause of acute viral hepatitis worldwide [1]
Human cases of persistent HEV-3 infection evolving to chronic hepatitis were described in solid organ transplant (SOT) patients under immunosuppressive therapy with, e.g. tacrolimus, considered a potent macrolide immunosuppressant derived from Streptomyces tsukubaensis and a first-line medication employed to reduce the rate of rejection, especially in parenchymal organ transplantation [9]
The pattern of Double-stranded RNA (dsRNA) labeledcells was similar to those observed in the liver of the chronically infected monkey witch was found to be positive for negative strand HEV RNA by Reverse transcription (RT)-PCR (Fig 3C)
Summary
Hepatitis E virus (HEV) infection is a major cause of acute viral hepatitis worldwide [1]. Genotypes 3 (HEV-3) and 4 (HEV-4) are prevalent in developed countries where autochthonous cases of acute HEV infection are attributed mainly to zoonotic transmission to humans, associated with consumption of raw or undercooked meat from pigs, wild boars and other mammals [7, 8]. High doses of tacrolimus showed to promote infection of liver cells with HEV in cell culture models [10]. It is considered a risk factor for virus persistence in the host [11, 12]. Hepatitis-Associated Aplastic Anemia (HAAA) and Diamond-Blackfan Anemia (DBA), as well as some unspecific hematological changes, such as lymphopenia and leukopenia, were reported in patients with hepatitis E [16,17,18,19]
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