Abstract
Hepatitis B, a viral infection that affects the liver, is thought to affect over 257 million people worldwide, and long-term infection can lead to life-threatening issues such as cirrhosis or liver cancer. Chronic hepatitis B develops by the interaction between hepatitis B virus (HBV) and host immune response. However, questions of how HBV-infected cells thwart immune system defenses remain unanswered. Extracellular vesicles (EVs) are used for cellular communication, carrying cargoes such as RNAs, proteins, and lipids and delivering them intracellularly after being endocytosed by target cells. HBV-infected liver cells secrete several types of EVs into body fluids such as complete and incomplete virions, and exosomes. We previously demonstrated that monocytes that incorporated EVs moved to immunoregulatory phenotypes via up-regulation of PD-L1, an immunocheckpoint molecule, and down-regulation of CD69, a leukocyte activation molecule. In this study, we transfected mice with HBV using hydrodynamic injection and studied the effects of EVs secreted by HBV-infected liver cells. EVs secreted from cells with HBV replication strongly suppressed the immune response, inhibiting the eradication of HBV-replicating cells in the mice transfected with HBV. EVs were systemically incorporated in multiple organs, including liver, bone marrow (BM), and intestine. Intriguingly, the BM cells that incorporated EVs acquired intestinal tropism and the dendritic cell populations in the intestine increased. These findings suggest that the EVs secreted by HBV-infected liver cells exert immunosuppressive functions, and that an association between the liver, bone marrow, and intestinal tract exists through EVs secreted from HBV-infected cells.
Highlights
Hepatitis B virus (HBV) infection is a major global health burden
Chronic hepatitis B is a risk for cirrhosis and hepatocellular carcinoma, and more than 700,000 people die from HBV-related diseases each year [3]
The results suggested that HBV-replicating cells escaped from immune cells in the liver of the mice treated with extracellular vesicles (EVs), especially after HBV induction, indicating that EVs derived from HepAD38 cells had immunosuppressive functions and that more activity was obtained by HBV replication
Summary
Characterization of EVs secreted from HBV-replicating cells and -nonreplicating cells. HBcAg was not detected in the liver of mice treated with EVs derived from HBV patients alone without HDI (Fig. S2). These results suggested that HBV infection potentiated the EV immunosuppressive ability. CD11c1 CD1031 or CD11b1 CD1031 BM-EVs cells, which indicated the regulatory DC-like cells, were detected in the small intestine 24 h after transplanting BM-EVs (Fig. 6D) These results suggested existence of the association between the liver, bone marrow, and intestinal tract through EVs secreted from HBV-replicating cells and that bone marrow cells. Incorporating EVs secreted from HBV-replicating cells may be involved in intestinal immunity
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