The Hepatitis B e antigen (HBeAg) targets and suppresses activation of the Toll-like receptor signaling pathway

Lang, Tali; Lo, Camden; Skinner, Narelle; Locarnini, Stephen; Visvanathan, Kumar; Mansell, Ashley

doi:10.1016/j.jhep.2010.12.042

Cited by 185 publications

(152 citation statements)

References 41 publications

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…30 Several mechanisms could underlie the ineffective PI3K-PKBmTOR signaling in HBe pos patient pDCs. Immunomodulatory qualities of HBeAg have been suggested previously, 36 but addition of HBeAg did not reduce S6 phosphorylation in pDCs from healthy subjects (Woltman et al 26 and data not shown). In contrast, HBsAg does have a direct effect on PI3K-PKB-mTOR activity, 26 and increased HBsAg serum levels have been reported in HBe pos patients compared with HBe neg patients.…”

Section: Org Fromsupporting

confidence: 53%

PI3K-PKB hyperactivation augments human plasmacytoid dendritic cell development and function

Laar¹,

Bosch²,

Boonstra³

et al. 2012

Blood

View full text Add to dashboard Cite

Plasmacytoid dendritic cells (pDCs) are considered potential tools or targets for immunotherapy. However, current knowledge concerning methodologies to manipulate their development or function remains limited. Here, we investigated the role of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mammalian target of rapamycin (mTOR) axis in human pDC development, survival, and function. In vitro pDC generation from human cord blood-derived CD34 ؉ hematopoietic progenitors was reduced by pharmacologic inhibition of PI3K, PKB, or mTOR activity, and peripheral blood pDCs required PI3K-PKB-mTOR signaling to survive. Accordingly, activity of this pathway in circulating pDCs correlated with their abundance in peripheral blood. Importantly, introduction of constitutively active PKB or pharmacologic inhibition of negative regulator phosphatase and tensin homolog (PTEN) resulted in increased pDC numbers in vitro and in vivo. Furthermore, MHC class II and costimulatory molecule expression, and production of IFN-␣ and TNF-␣, were augmented, which could be explained by enhanced IRF7 and NF-B activation. Finally, the numerically and functionally impaired pDCs of chronic hepatitis B patients demonstrated reduced PI3K-PKB-mTOR activity. In conclusion, intact PI3K-PKB-mTOR signaling regulates development, survival, and function of human pDCs, and pDC development and functionality can be promoted by PI3K-PKB hyperactivation. Manipulation of this pathway or its downstream targets could be used to improve the generation and function of pDCs to augment immunity. (Blood. 2012; 120(25):4982-4991) IntroductionPlasmacytoid dendritic cells (pDCs) represent a specialized DC subset that is recognized for its unique ability to rapidly produce large amounts of type 1 interferons (IFN-␣␤) on the interaction with viruses or nucleic acids of self or nonself origin. 1 Besides direct antiviral activity through the production of IFN-␣␤, pDCs have been implicated in playing a broader role in immunity. pDC activation results in the production of additional proinflammatory cytokines such as TNF-␣ and IL-6, and it stimulates the expression of MHC class I, MHC class II, and costimulatory molecules. These combined functions enable pDCs to activate T helper cells, cytotoxic T lymphocytes, natural killer cells, and plasma cell differentiation. Moreover, pDC-derived cytokines can act as adjuvants for other DC subsets such as myeloid or conventional DC. In contrast, tolerogenic functions of pDC, including the generation of regulatory T cells, have also been described. Similar to other DC subsets, pDC thus show the dual capability of being able to initiate as well as regulate immunity. [1][2][3] In accordance with their broad role in the regulation of immunity, the possibilities to use pDC as either tools or targets for immunotherapy are being increasingly explored. Activation of dysfunctional tumor-resident pDCs may be achieved by administration of TLR agonists, 4,5 and methods to induce antitumor responses by either targeting antigen to endogeno...

show abstract

Section: Org Fromsupporting

confidence: 53%

PI3K-PKB hyperactivation augments human plasmacytoid dendritic cell development and function

Laar¹,

Bosch²,

Boonstra³

et al. 2012

Blood

View full text Add to dashboard Cite

show abstract

“…HBe, which is not required for viral replication, is considered to have a role in the establishment of chronic infection (Milich and Liang, 2003). It has been shown that HBe modulates innate immune signal transduction pathways through interaction with and targeting of the signaling pathways mediated by Toll-like receptors (Lang et al, 2011). As a result of attenuated immune responses, the viral load increases greatly in the early phase of chronic infection (Liang, 2009).…”

Section: Discussionmentioning

confidence: 99%

HBV secretion is regulated through the activation of endocytic and autophagic compartments via Rab7 stimulation

Inoue

Krueger

Chen

et al. 2015

Journal of Cell Science

View full text Add to dashboard Cite

The cellular mechanisms by which hepatitis B virus (HBV) is assembled and exported are largely undefined. Recently, it has been suggested that these steps require the multivesicular body (MVB) and the autophagic machinery. However, the mechanisms by which HBV might regulate these compartments are unclear. In this study, we have found that by activating Rab7a, HBV alters its own secretion by inducing dramatic changes in the morphology of MVB and autophagic compartments. These changes are characterized by the formation of numerous tubules that are dependent upon the increase in Rab7 activity observed in the HBV-expressing HepG2.2.15 cells compared to HepG2 cells. Interestingly, transfection-based expression of the five individual viral proteins indicated that the precore protein, which is a precursor of HBeAg, was largely responsible for the increased Rab7 activity. Finally, small interfering RNA (siRNA)-mediated depletion of Rab7 significantly increased the secretion of virions, suggesting that reduced delivery of the virus to the lysosome facilitates viral secretion. These findings provide novel evidence indicating that HBV can regulate its own secretion through an activation of the endo-lysosomal and autophagic pathway mediated by Rab7 activation.

show abstract

“…HBeAg, when expressed by transduction through a recombinant baculoviral vector, was able to inhibit the induction of TNF-a in hepatic cell lines. 6 Subsequently, HBeAg was shown to suppress TIR-mediated activation of NF-kB-dependent and IFN-b promoters through disruption of homotypic TIR-TIR interaction, which is critical for TLR-mediated signaling, 25 and also through inhibition of IL-1b-mediated NFkB activation in hepatocytes. 26 Consistently, Chen et al 7 also reported that TLR2 mRNA and protein levels were significantly decreased in PBMCs from CHB patients based on real-time PCR and flow cytometric analysis.…”

Section: Interaction Between Tlrs and Hbvmentioning

confidence: 99%

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Zhang

Yang

et al. 2014

Cell Mol Immunol

View full text Add to dashboard Cite

It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T-and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

show abstract

The Hepatitis B e antigen (HBeAg) targets and suppresses activation of the Toll-like receptor signaling pathway

Cited by 185 publications

References 41 publications

PI3K-PKB hyperactivation augments human plasmacytoid dendritic cell development and function

PI3K-PKB hyperactivation augments human plasmacytoid dendritic cell development and function

HBV secretion is regulated through the activation of endocytic and autophagic compartments via Rab7 stimulation

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Contact Info

Product

Resources

About