Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection

Du, Yanyun; Wu, Jun; Liu, Jia; Zheng, Xin; Yang, Dongliang; Lu, Mengji

doi:10.3389/fimmu.2022.965018

Cited by 18 publications

(10 citation statements)

References 98 publications

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“…To further define the relationship between innate inflammatory signaling and PIK3R5 expression, we treated leukemia cell lines, two each with low or high PIK3R5, with resiquimod. Resiquimod is an agonist of Toll-like receptors (TLRs), pattern recognition receptors that initiate innate immune responses by sensing microbial stimuli and are also tonically activated in some hematologic malignancies 21–24 . Resiquimod treatment strikingly increased PIK3R5 mRNA and protein levels in leukemia cells with baseline low PIK3R5 expression (THP1 and DF-DCN-2; Fig.…”

Section: Resultsmentioning

confidence: 99%

Targetable leukemia dependency on noncanonical PI3Kγ signaling

Luo,

Raulston,

Prado

et al. 2023

Preprint

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Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ and stabilizes the active enzymatic complex. Mechanistically, we identify p21 (RAC1) activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of Akt kinase. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activatedPIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals a targetable dependency on PI3Kγ/PAK1 signaling that is amenable to near-term evaluation in patients with acute leukemia.

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Section: Resultsmentioning

confidence: 99%

Targetable leukemia dependency on noncanonical PI3Kγ signaling

Luo,

Raulston,

Prado

et al. 2023

Preprint

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“…Toll-like receptor (TLR) agonists are a distinct class of pattern recognition receptors that recognize both pathogen- and damage-associated molecular patterns ( Tsounis et al., 2021 ). TLRs induce antiviral defenses through intracellular signaling pathways that induce antiviral inflammatory cytokines and IFNs use to shape adaptive immunity ( Du et al., 2022 ).…”

Section: The Treatment Strategies For Modulating Host Immunitymentioning

confidence: 99%

The progress of molecules and strategies for the treatment of HBV infection

Pan

Xia

et al. 2023

Front. Cell. Infect. Microbiol.

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Hepatitis B virus infections have always been associated with high levels of mortality. In 2019, hepatitis B virus (HBV)-related diseases resulted in approximately 555,000 deaths globally. In view of its high lethality, the treatment of HBV infections has always presented a huge challenge. The World Health Organization (WHO) came up with ambitious targets for the elimination of hepatitis B as a major public health threat by 2030. To accomplish this goal, one of the WHO’s strategies is to develop curative treatments for HBV infections. Current treatments in a clinical setting included 1 year of pegylated interferon alpha (PEG-IFNα) and long-term nucleoside analogues (NAs). Although both treatments have demonstrated outstanding antiviral effects, it has been difficult to develop a cure for HBV. The reason for this is that covalently closed circular DNA (cccDNA), integrated HBV DNA, the high viral burden, and the impaired host immune responses all hinder the development of a cure for HBV. To overcome these problems, there are clinical trials on a number of antiviral molecules being carried out, all -showing promising results so far. In this review, we summarize the functions and mechanisms of action of various synthetic molecules, natural products, traditional Chinese herbal medicines, as clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR/Cas)-based systems, zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), all of which could destroy the stability of the HBV life cycle. In addition, we discuss the functions of immune modulators, which can enhance or activate the host immune system, as well some representative natural products with anti-HBV effects.

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“…Other types of interferon have a role in the suppression of HBV replication, such as IFN-α/β and IFN-γ, which are produced by different types of both parenchymal and non-parenchymal cells, such as NK and NKT [62][63][64]. Some data suggest that tool-like receptors (TLRs) play a central role in the activation of these cells [65]. In animal models, TLR7 agonist was able to activate NK, NKT, and T-cells with a consequent suppression of viral replication [66].…”

Section: Hbv and Host Immune Systemmentioning

confidence: 99%

HBV Infection and Host Interactions: The Role in Viral Persistence and Oncogenesis

Nevola

Beccia

Rosato³

et al. 2023

IJMS

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Hepatitis B virus (HBV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Despite the advent of vaccines and potent antiviral agents able to suppress viral replication, recovery from chronic HBV infection is still an extremely difficult goal to achieve. Complex interactions between virus and host are responsible for HBV persistence and the risk of oncogenesis. Through multiple pathways, HBV is able to silence both innate and adaptive immunological responses and become out of control. Furthermore, the integration of the viral genome into that of the host and the production of covalently closed circular DNA (cccDNA) represent reservoirs of viral persistence and account for the difficult eradication of the infection. An adequate knowledge of the virus–host interaction mechanisms responsible for viral persistence and the risk of hepatocarcinogenesis is necessary for the development of functional cures for chronic HBV infection. The purpose of this review is, therefore, to analyze how interactions between HBV and host concur in the mechanisms of infection, persistence, and oncogenesis and what are the implications and the therapeutic perspectives that follow.

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Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection

Cited by 18 publications

References 98 publications

Targetable leukemia dependency on noncanonical PI3Kγ signaling

Targetable leukemia dependency on noncanonical PI3Kγ signaling

The progress of molecules and strategies for the treatment of HBV infection

HBV Infection and Host Interactions: The Role in Viral Persistence and Oncogenesis

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