scholarly journals Involvement of Innate Immune Receptors in the Resolution of Acute Hepatitis B in Woodchucks

2021 ◽  
Vol 12 ◽  
Author(s):  
Manasa Suresh ◽  
Bin Li ◽  
Marta G. Murreddu ◽  
Severin O. Gudima ◽  
Stephan Menne
Keyword(s):  
T Cell ◽  
Hepatitis B ◽  
Acute Hepatitis ◽  
Liver Enzyme ◽  
T Cell Responses ◽  
Receptor Expression ◽  
Viral Control ◽  
Effector Molecules ◽  
Cell Responses ◽  
Acute Hepatitis B

The antiviral property of small agonist compounds activating pattern recognition receptors (PRRs), including toll-like and RIG-I receptors, have been preclinically evaluated and are currently tested in clinical trials against chronic hepatitis B (CHB). The involvement of other PRRs in modulating hepatitis B virus infection is less known. Thus, woodchucks with resolving acute hepatitis B (AHB) after infection with woodchuck hepatitis virus (WHV) were characterized as animals with normal or delayed resolution based on their kinetics of viremia and antigenemia, and the presence and expression of various PRRs were determined in both outcomes. While PRR expression was unchanged immediately after infection, most receptors were strongly upregulated during resolution in liver but not in blood. Besides well-known PRRs, including TLR7/8/9 and RIG-I, other less-characterized receptors, such as IFI16, ZBP1/DAI, AIM2, and NLRP3, displayed comparable or even higher expression. Compared to normal resolution, a 3–4-week lag in peak receptor expression and WHV-specific B- and T-cell responses were noted during delayed resolution. This suggested that PRR upregulation in woodchuck liver occurs when the mounting WHV replication reaches a certain level, and that multiple receptors are involved in the subsequent induction of antiviral immune responses. Liver enzyme elevations occurred early during normal resolution, indicating a faster induction of cytolytic mechanisms than in delayed resolution, and correlated with an increased expression of NK-cell and CD8 markers and cytolytic effector molecules. The peak liver enzyme level, however, was lower during delayed resolution, but hepatic inflammation was more pronounced and associated with a higher expression of cytolytic markers. Further comparison of PRR expression revealed that most receptors were significantly reduced in woodchucks with established and progressing CHB, and several RNA sensors more so than DNA sensors. This correlated with a lower expression of receptor adaptor and effector molecules, suggesting that persistent, high-level WHV replication interferes with PRR activation and is associated with a diminished antiviral immunity based on the reduced expression of immune cell markers, and absent WHV-specific B- and T-cell responses. Overall, the differential expression of PRRs during resolution and persistence of WHV infection emphasizes their importance in the ultimate viral control during AHB that is impaired during CHB.

scholarly journals Dynamics of the Immune Response in Acute Hepatitis B Infection

2017 ◽  
Vol 4 (4) ◽  
Author(s):  
Femke Stelma ◽  
Sophie B Willemse ◽  
Robin Erken ◽  
Annikki de Niet ◽  
Marjan J Sinnige ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Acute Hepatitis ◽  
Nk Cells ◽  
T Cell Responses ◽  
Hbv Infection ◽  
Cell Responses ◽  
B Virus ◽  
Acute Hepatitis B

Abstract Background Acute hepatitis B virus infection in adults is generally self-limiting but may lead to chronicity in a minority of patients. Methods We included 9 patients with acute hepatitis B virus (HBV) infection and collected longitudinal follow-up samples. Natural killer (NK) cell characteristics were analyzed by flowcytometry. HBV-specific T-cell function was analyzed by in vitro stimulation with HBV peptide pools and intracellular cytokine staining. Results Median baseline HBV DNA load was 5.12 log IU/mL, and median ALT was 2652 U/mL. Of 9 patients, 8 cleared HBsAg within 6 months whereas 1 patient became chronically infected. Early time points after infection showed increased CD56bright NK cells and an increased proportion of cells expressing activation markers. Most of these had normalized at week 24, while the proportion of TRAIL-positive CD56bright NK cells remained high in the chronically infected patient. In patients who cleared HBV, functional HBV-specific CD8+ and CD4+ responses could be observed, whereas in the patient who developed chronic infection, only low HBV-specific T-cell responses were observed. Conclusions NK cells are activated early in the course of acute HBV infection. Broad and multispecific T-cell responses are observed in patients who clear acute HBV infection, but not in a patient who became chronically infected.

scholarly journals Long-lasting memory T cell responses following self-limited acute hepatitis B.

1996 ◽  
Vol 98 (5) ◽  
pp. 1185-1194 ◽  
Author(s):  
A Penna ◽  
M Artini ◽  
A Cavalli ◽  
M Levrero ◽  
A Bertoletti ◽  
...  
Keyword(s):  
T Cell ◽  
Hepatitis B ◽  
Acute Hepatitis ◽  
T Cell Responses ◽  
Memory T Cell ◽  
Cell Responses ◽  
Acute Hepatitis B

scholarly journals Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Keigo Kawashima ◽  
Masanori Isogawa ◽  
Susumu Hamada-Tsutsumi ◽  
Ian Baudi ◽  
Satoru Saito ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Type I Interferon ◽  
T Cell Responses ◽  
Antigen Expression ◽  
Type I ◽  
Interferon Signaling ◽  
Cell Responses ◽  
B Virus

ABSTRACT Robust virus-specific CD8+ T cell responses are required for the clearance of hepatitis B virus (HBV). However, the factors that determine the magnitude of HBV-specific CD8+ T cell responses are poorly understood. To examine the impact of genetic variations of HBV on HBV-specific CD8+ T cell responses, we introduced three HBV clones (Aa_IND [Aa], C_JPN22 [C22], and D_IND60 [D60]) that express various amounts of HBV antigens into the livers of C57BL/6 (B6) (H-2b) mice and B10.D2 (H-2d) mice. In B6 mice, clone C22 barely induced HBV-specific CD8+ T cell responses and persisted the longest, while clone D60 elicited strong HBV-specific CD8+ T cell responses and was rapidly cleared. These differences between HBV clones largely diminished in H-2d mice. Interestingly, the magnitude of HBV-specific CD8+ T cell responses in B6 mice was associated with the HB core antigen expression level during the early phase of HBV transduction. Surprisingly, robust HBV-specific CD8+ T cell responses to clone C22 were induced in interferon-α/β receptor-deficient (IFN-αβR–/–) (H-2b) mice. The induction of HBV-specific CD8+ T cell responses to C22 in IFN-αβR–/– mice reflects enhanced HBV antigen expression because the suppression of antigen expression by HBV-specific small interfering RNA (siRNA) attenuated HBV-specific T cell responses in IFN-αβR–/– mice and prolonged HBV expression. Collectively, these results suggest that HBV genetic variation and type I interferon signaling determine the magnitude of HBV-specific CD8+ T cell responses by regulating the initial antigen expression levels. IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8+ T cell responses are required for the clearance of HBV. However, the relative contributions of genetic variation and innate immune responses to the induction of HBV-specific CD8+ T cell responses are not fully understood. In this study, we discovered that different clearance rates between HBV clones after hydrodynamic transduction were associated with the magnitude of HBV-specific CD8+ T cell responses and initial HB core antigen expression. Surprisingly, type I interferon signaling negatively regulated HBV-specific CD8+ T cell responses by reducing early HBV antigen expression. These results show that the magnitude of the HBV-specific CD8+ T cell response is regulated primarily by the initial antigen expression level.

scholarly journals Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion

2012 ◽  
Vol 210 (1) ◽  
pp. 99-114 ◽  
Author(s):  
Dimitra Peppa ◽  
Upkar S. Gill ◽  
Gary Reynolds ◽  
Nicholas J.W. Easom ◽  
Laura J. Pallett ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hepatitis B ◽  
Nk Cells ◽  
Human Liver ◽  
Large Population ◽  
Death Receptor ◽  
T Cell Responses ◽  
Dependent Manner ◽  
Cell Responses

Antiviral T cell responses in hepatotropic viral infections such as hepatitis B virus (HBV) are profoundly diminished and prone to apoptotic deletion. In this study, we investigate whether the large population of activated NK cells in the human liver contributes to this process. We show that in vitro removal of NK cells augments circulating CD8+ T cell responses directed against HBV, but not against well-controlled viruses, in patients with chronic hepatitis B (CHB). We find that NK cells can rapidly eliminate HBV-specific T cells in a contact-dependent manner. CD8+ T cells in the liver microcirculation are visualized making intimate contact with NK cells, which are the main intrahepatic lymphocytes expressing TNF-related apoptosis-inducing ligand (TRAIL) in CHB. High-level expression of the TRAIL death receptor TRAIL-R2 is found to be a hallmark of T cells exposed to the milieu of the HBV-infected liver in patients with active disease. Up-regulation of TRAIL-R2 renders T cells susceptible to caspase-8–mediated apoptosis, from which they can be partially rescued by blockade of this death receptor pathway. Our findings demonstrate that NK cells can negatively regulate antiviral immunity in chronic HBV infection and illustrate a novel mechanism of T cell tolerance in the human liver.

Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B

2018 ◽  
Vol 69 (3) ◽  
pp. 584-593 ◽  
Author(s):  
Franziska Rinker ◽  
Christine L. Zimmer ◽  
Christoph Höner zu Siederdissen ◽  
Michael P. Manns ◽  
Anke R.M. Kraft ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
T Cell Responses ◽  
Cell Responses ◽  
B Virus ◽  
Negative Chronic Hepatitis
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