Cynomolgus monkeys (Macaca fascicularis) experimentally and naturally infected with hepatitis E virus: The bone marrow as a possible new viral target

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.

Presence and persistence of hepatitis E virus RNA and proteins in human bone marrow

“…The constant detection of HEV ORF2 proteins, the capsid proteins, in bone marrow suggests that HEV may replicate in the bone marrow cells. Very recently, an animal study found that HEV antigens can be detected in the bone marrow of both HEV genotype 3 experimentally infected or naturally infected cynomolgus monkeys [8]. The present study, along with the previous study conducted in cynomolgus monkeys, reinforces the assumption of bone marrow as a new HEV target.…”

Lower Levels of Transaminases but Higher Levels of Serum Creatinine in Patients with Acute Hepatitis E in Comparison to Patients with Hepatitis A

“…In addition, there is increasing evidence to suggest that HEV also replicates in extrahepatic tissues like the kidneys. Previous studies have detected HEV RNA and antigen in the urine of patients with acute and chronic infections as well as in the kidneys of artificially infected cynomolgus monkeys [ 12 , 13 ]. Viral replication has also been demonstrated in the kidneys of infected rabbits by detection of both positive and negative strands of HEV RNA as well as by immunohistochemical analysis [ 14 ].…”

Systematic Review of Hepatitis E Virus in Brazil: A One-Health Approach of the Human-Animal-Environment Triad

“…In the past years there has been an interest in studying HEV infection in non-human primates, inclusively Macaca fascicularis were used on experimental in vivo studies performed in Brazil to evaluate HEV pathogenesis [ 91 , 92 , 93 ]. HEV seroprevalences have been reported in farmed Rhesus monkeys in China (70.8%) [ 94 ] and in captive non-human primates in Italy (4.2%) [ 95 ] but the only seroprevalence study performed in Brazil in wild non-human primates did not detect any (0%) anti-HEV antibodies [ 11 ].…”