Extracellular vesicles derived from Hepatitis-D Virus infected cells induce a proinflammatory cytokine response in human peripheral blood mononuclear cells and macrophages

Hepatitis D Virus (HDV) is a satellite virus requiring a Hepatitis B Virus (HBV) envelope proteins for productive infection. Hepatitis D is the most severe form of viral hepatitis and is a global health threat affecting 15 to 20 million humans. In contrast to the Hep atitis B Virus mono-infection, against which only a minor innate immune response is mounted at most, HBV-HDV coinfection is characterized by strong activation of innate immune responses. To shed light on poorly understood mechanisms of HDV-triggered disease progression, we focussed on the question how immune cells may be activated by HDV. We hypothesized that extracellular vesicles (EVs) released from infected cells me diate this activation. We, therefore, purified EVs from the supernatant of HDV-infected and non-infected cells and incubated them with human peripheral blood mononuclear cells (PBMC) and macrophages. Here we show for the first time that HDV infection leads to the production of EVs which subsequently mediate a proinflammatory cytokine response in primary human immune cells. These data might help to understand how HDV can be sensed by non-infected immune cells.