Down regulation of TRIF, TLR3, and MAVS in HCV infected liver correlates with the outcome of infection

Kar, Premashis; Kumar, Deepak; Gumma, Phani Kumar; Chowdhury, Soumya Jyoti; Karra, Vijay Kumar

doi:10.1002/jmv.24849

Cited by 11 publications

(11 citation statements)

References 36 publications

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“…In human hepatocyte cultures [34,35] HCV infection triggered cleavage of MAVS and TRIF host proteins by HCV NS3/4A protease, disrupting TLR3-antiviral signaling. Reduction of protein levels of MAVS and TRIF was also observed previously in chronic HCV-infected livers [36,37]. Nevertheless, we observed a robust response to TLR3 signaling in the HCV-infected liver, which supports the idea that ISG induction is weak in HCV infected cells, but strong in HCV infected liver due to paracrine activation of NPC.…”

Section: Discussionsupporting

confidence: 91%

Response of human liver tissue to innate immune stimuli

Wu¹,

Roberto²,

Knupp³

et al. 2020

Preprint

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Direct-Acting Antiviral (DAA) drugs are highly effective in eliminating HCV in most chronically infected subjects, but it is unclear whether the multiple mechanisms employed by HCV to disable both innate and adaptive immunity cease to function as soon as HCV is eliminated. To test this, we evaluated the capacity of human liver tissue to respond to TLR3 and TLR4 ligands using non-infected liver tissue, tissue with active HCV infection, and tissue from which HCV had been eliminated by DAA. We found that DAA-treated, formerly HCV-infected liver tissue manifested ongoing abnormalities of innate immunity that mapped to liver non-parenchymal cells (NPC). Hepatic innate immunity was not suppressed but enhanced in HCV-infected tissue, and these abnormalities were not corrected in the successfully DAA-treated liver tissue. In conclusion, ongoing immune activation persists in formerly HCV-infected but now DAA-cured liver.

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Section: Discussionsupporting

confidence: 91%

Response of human liver tissue to innate immune stimuli

Wu¹,

Roberto²,

Knupp³

et al. 2020

Preprint

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“…Hepatitis C virus (HCV) inhibits activation of NF-κB and IRF3 by proteolysis of TRIF (the adaptor protein, which links TLR3 and kinase). HCV utilizes the viral NS3/4A to cleave TRIF, which is an intermediate in TLR3, mitochondrial antiviral-signaling protein (MAVS), and RIG-I signaling pathways, therefore, dsRNA cannot induce the IFN production through these pathways [ 84 , 85 , 86 ]. Recently, an Orf virus (ORFV) virion-associated protein, ORFV119, was identified that inhibits the NF-κB signaling very early in infection [ 87 ].…”

Section: Intracellular Immune Ecosystem Of Virus-infected Cellsmentioning

confidence: 99%

Immune Ecosystem of Virus-Infected Host Tissues

Maarouf

Raj

Goraya

et al. 2018

IJMS

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Virus infected host cells serve as a central immune ecological niche during viral infection and replication and stimulate the host immune response via molecular signaling. The viral infection and multiplication process involves complex intracellular molecular interactions between viral components and the host factors. Various types of host cells are also involved to modulate immune factors in delicate and dynamic equilibrium to maintain a balanced immune ecosystem in an infected host tissue. Antiviral host arsenals are equipped to combat or eliminate viral invasion. However, viruses have evolved with strategies to counter against antiviral immunity or hijack cellular machinery to survive inside host tissue for their multiplication. However, host immune systems have also evolved to neutralize the infection; which, in turn, either clears the virus from the infected host or causes immune-mediated host tissue injury. A complex relationship between viral pathogenesis and host antiviral defense could define the immune ecosystem of virus-infected host tissues. Understanding of the molecular mechanism underlying this ecosystem would uncover strategies to modulate host immune function for antiviral therapeutics. This review presents past and present updates of immune-ecological components of virus infected host tissue and explains how viruses subvert the host immune surveillances.

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“…Of note, TLR3 exhibits lower levels of expression in HCC when compared with adjacent tissues, and is positively associated with TRIF, nuclear factor-κB and IFN regulatory factor 3, which may inhibit HCC proliferation and promote HCC cell apoptosis (36). The expression levels of TLR3, TRIF and mitochondrial antiviral-signaling proteins were consistently decreased in chronic HCV-infected liver tissue, compared to that of than non-diseased liver tissue (37). Additionally, endogenous miR-155 can negatively regulate TLR3 expression and inhibit IFN-β production (38).…”

Section: Discussionmentioning

confidence: 99%

ACTG1 and TLR3 are biomarkers for alcohol‑associated hepatocellular carcinoma

Gao

Tan

et al. 2018

Oncol Lett

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Alcohol consumption is a risk factor for the development of hepatocellular carcinoma (HCC); however, the association between alcohol and HCC remains unknown. The present study aimed to identify key genes related to alcohol-associated HCC to improve the current understanding of the pathology of this disease. Alcohol-associated and non-alcohol-associated HCC samples in the GSE50579 dataset of the Gene Omnibus Database were analyzed to investigate altered gene expression. Integrated bioinformatics methods were employed to clarify the biological functions of the differentially expressed genes (DEGs), including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interactions (PPIs). The present study reported that candidate biomarker micro (mi)RNAs via TargetScan Human 7.1. DEGs and their associated miRNAs (according to bioinformatics analysis) were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Additionally, 284 EGs from the GSE50579 dataset were revealed. In GO term analysis, DEGs were closely associated with the ‘regulation of nucleic acid metabolism’. KEGG pathway analysis indicated that the DEGs were tightly engaged in the ‘VEGF and VEGF receptor signaling network’, ‘proteoglycan syndecan-mediated signaling events’, ‘erbB receptor signaling’ and ‘β1 integrin cell surface interactions’. According to the results of PPI and heat map analysis, the main hub genes were centrin 3 (CETN3), Toll-like receptor 3 (TLR3), receptor tyrosine-protein kinase (ERBB4), heat shock protein family member 8, actin γ1 (ACTG1) and α-smooth muscle actin. it was demonstrated that the ACTG1, TLR3, miR-6819-3p and miRΝΑ (miR)-6877-3P had undefined associations. Furthermore, RT-qPCR analysis revealed that miR-6819-3p and miR-6877-3P may enhance the expression levels of ACTG1 and inhibit the expression levels of TLR3 in alcohol-associated HCC tissues. TLR3 and ACTG1 were proposed as potential biomarkers of alcohol-associated HCC. Investigation into the regulatory functions of miR-6819-3p and miR-6877-3P may provide novel insights into the treatment of alcohol-associated HCC.

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Down regulation of TRIF, TLR3, and MAVS in HCV infected liver correlates with the outcome of infection

Cited by 11 publications

References 36 publications

Response of human liver tissue to innate immune stimuli

Response of human liver tissue to innate immune stimuli

Immune Ecosystem of Virus-Infected Host Tissues

ACTG1 and TLR3 are biomarkers for alcohol‑associated hepatocellular carcinoma

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