Hepatitis B virus-replicating transgenic mice exhibit a functional but altered responsiveness to Tlr3 and Rig-I activation

Background and Aims Pathogenesis of Hepatitis B virus (HBV) is driven by the adaptive as well as the innate immune system. The present project aims to investigate how HBV surface antigen (HBsAg) affects hepatic responses to poly(I:C), utilising HBV-transgenic mouse strains.

Method Liver tissue from C57/Bl6 and HBV-transgenic mouse strains (tg(Alb1HBV)44Bri (Alb/HBs), tg1.4HBV-s-mut and tg1.4HBV-s-rec [F1 generation of Alb/HBs × tg1.4HBV-s-mut]) was analysed using transmission electron microscopy (TEM). All-in-one liver cell preparation was performed, obtaining primary murine hepatocytes (PMH), liver sinusoidal endothelial cells (LSEC) and Kupffer cells (KC) and remaining NPC (rNPC). Responsiveness to poly(I:C) was determined using quantitative RT-PCR and multiplex-based cytokine assay.

Results TEM visualised viral particles (tg1.4HBV-s-rec), nuclear circular formations (tg1.4HBV-s-mut) and pathologic changes in the endoplasmic reticulum (Alb/HBs). Response to poly(I:C) treatment (Tlr3) and transfection (Rig-I) was investigated. A distinct cell type-dependent and mouse strain-dependent gene expression pattern for interferon (Ifnb, Ifiti1), cytokine (Tnf, Il1b, Il10) and chemokine (Ccl2, Ccl5) was observed by quantitative RT-PCR and validated using a multiplex-based cytokine assay. Emphasizing that tg1.4HBV-s-rec-derived liver cells responded to poly(I:C) with massively suppressed gene expression, when compared to the other mouse strains. Contrary, rNPC of tg1.4HBV-s-rec mice showed the highest gene induction for Il10, Tnf, Il1b and Ccl5 in response to poly(I:C). In all HBV-transgenic mice, the induction of Ccl2 was significant lower in PMH but increased in rNPC.

Conclusion Our data indicates that PMH of tg1.4HBV-s-rec mice produce viral particles and all liver cell types exhibit a functional but suppressed Tlr3 and Rig-I signalling.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022