Characterization of innate immune response to hepatitis B virus genotype F acute infection in tree shrew (Tupaia belangeri) model

Abstract

Hepatitis B virus (HBV) infection is a global public health problem. The clinical outcomes of HBV infections are influenced by host as well as viral factors, including viral genotypes and subgenotypes. The interplay between HBV and host innate immunity remains unclear because of the lack of a suitable small animal model. Tree shrews (Tupaia belangeri) have been utilized as a useful animal model for hepatitis viruses such as hepatitis B and C viruses. In this study, we characterized acute infections by HBV genotype F (HBV-F) wild type (Wt) and mutant type (Mt) viruses in adult tree shrews. Serum alanine aminotransferase levels were measured before and post- infection 7 and 14 dpi. Both HBV-F-Wt and Mt were detected in the HBV-F-infected tree shrew serum and liver tissue at 7 and 14 dpi. We examined the intrahepatic expression patterns of Toll-like receptors (TLRs) (TLR1–9 mRNAs), cGAS, several transcription factors such as STAT1, STAT2, IRF7, HNF4, PD-L1, and cytokines, including IFN-β, IFN-γ, IL-6, and TNF-α in HBV-F Wt/Mt-infected tree shrews. When compared with uninfected animal group, significant suppression of TLR8 in HBV-F-Wt infected animals and significant suppression of PD-L1 in both HBV-F-Wt and Mt infected animals were observed. Thus, tree shrew can be a useful animal model to characterize HBV-F pathogenesis.

Recent advances in different interactions between toll-like receptors and hepatitis B infection: a review

“…These cells can either promote infection upon TLR engagement or produce proinflammatory cytokines and chemokines to aid in removing the virus. By generating antimicrobial molecules like TNF-α and IFN, PAMP/microbe-associated molecular patterns (MAMPs)-induced activation of TLR signaling reduces the replication and spread of invading pathogens/microbes ( 38 , 39 ). When HBV infection occurs, the TLR response may alter HBV-specific T and B cell responses, ending the HBV infection ( 23 , 40 ).…”

“…Tree shrews’ whole genomes have shown that they are more closely linked to humans than to rodents ( 54 ). Numerous studies have indicated that tree shrews are vulnerable to HBV infection ( 39 ). In research, Kayesh et al.…”

“…In research, Kayesh et al. ( 39 ) examined the infectivity of HBV-F infection in tree shrews, both wild-type and mutant (HBV-F Wt/Mt), and they also described the innate immune response against HBV infection in this model. found that HBV-F Wt/Mt may cause an acute infection in adult tree shrews, as evidenced by elevated alanine aminotransferase (ALT) levels in the sera and the presence of HBV DNA in the liver tissues of both 7 and 14 dpi-infected tree shrews.…”

“…TLR response characterization revealed several distinct responses between Mt and HBV-F-Wt, including downregulating TLR8 in Tupaia liver tissue infected with HBV-F-Wt. These variations may thus be related to the increased pathogenicity and replication activity of HBV-F-Mt compared to Wt; however, more research employing the tree shrew model is needed ( 39 ). Overall, these results point to a significant role that innate immunity plays in inhibiting HBV replication; further research is needed to determine the precise mechanisms ( 47 ).…”

Progress of Infection and Replication Systems of Hepatitis B Virus

“…It serves as a model for studying HBV and has been used to simulate acute and chronic HBV infection, showing similar liver histopathological changes and hepatocellular carcinoma features as seen in HBV patients. Whole genome sequencing has revealed that tupaia is genetically similar to primates and falls between humans and rodents. , Infections in adult animals are typically mild and transient, but in newborn animals, they can lead to long-term liver immunopathological alterations, such as fibrosis formation, hepatocellular cancer, and persistent infection with moderate viremia. , In particular, this model can be used to imitate immunoactive infection and have been utilized as models for viral hepatitis, providing insights into the direct impact of HBV infection on liver gene expression …”