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Posted On: 09/26/2020 9:09:30 AM
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Fulminant Hepatic Failure in Hepatitis A Infection - Is this an indication that has already been captured on the list?
Conclusion highlights significance of CCR5 antagonists.
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26557
RESEARCH ARTICLE
Prognostic, clinical and therapeutic importance of RANTES-CCR5 axis in hepatitis A infection: A multi-approach study
Vargab Baruah Diptika Tiwari Rajib Kishore Hazam Moumita Bose Dipankar Bujarbaruah Anjan Kumar Saikia Premashish Kar Sangit Dutta Sujoy Bose
First published: 25 September 2020
https://doi.org/10.1002/jmv.26557
Funding: : This research did not receive any specific grant from funding agencies in thepublic, commercial, or not-for-profit sectors.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.26557
ABSTRACT
Fulminant hepatic failure (FHF) is a lethal manifestation of hepatitis A virus (HAV) infection, whose underlying mechanisms are poorly understood. We aimed to evaluate the importance of the modulation of RANTES-CCR5 signalling axis and its immunomodulatory effects in directing hepatitis A disease pathogenesis using an in-silico, in-vitro and patient cohort based approach.In-silico interaction studies were performed using computation approaches with suitable software. Differential expression of relevant cytokines and immune cell markers were studied using qRT-PCR, ELISA and flow-cytometry-based methods. In HepG2 cell line, we studied inflammatory responses and susceptibility to HAV infection following RANTES stimulation and antibody blockade of CCR5.The HAV-VP3 region exhibited high interaction in CCR5: HAV complexes. RANTES levels were significantly increased in FHF cases. A reduced monocyte and T-cell activation was observed in FHF cases. RANTES expression inversely correlated with viremia but positively correlated with pro-inflammatory responses. Hyper Th1-biased immune responses, marked by high IL-12/IL-10 ratio were observed in FHF cases, which were also characterized by upregulated TNF-a expression and reduced IFN-? expression. In-vitro, RANTES was protective against HAV infection, but resulted in upregulated TNF-a expression. Although viral load increased upon regulation of inflammatory responses by CCR5 blocking, it was still significantly lower compared to control HAV-infected cells.
Our study suggests the importance of RANTES-CCR5 signalling and linked-immunomodulation in HAV disease pathogenesis, as well as highlights the utility of CCR5 antagonists as a risk-reduction strategy in FHF patients.
Our findings therefore have important implications for the management of high-risk HAV infections.
This article is protected by copyright. All rights reserved.
Fulminant Hepatic Failure in Hepatitis A Infection - Is this an indication that has already been captured on the list?
Conclusion highlights significance of CCR5 antagonists.
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26557
RESEARCH ARTICLE
Prognostic, clinical and therapeutic importance of RANTES-CCR5 axis in hepatitis A infection: A multi-approach study
Vargab Baruah Diptika Tiwari Rajib Kishore Hazam Moumita Bose Dipankar Bujarbaruah Anjan Kumar Saikia Premashish Kar Sangit Dutta Sujoy Bose
First published: 25 September 2020
https://doi.org/10.1002/jmv.26557
Funding: : This research did not receive any specific grant from funding agencies in thepublic, commercial, or not-for-profit sectors.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.26557
ABSTRACT
Fulminant hepatic failure (FHF) is a lethal manifestation of hepatitis A virus (HAV) infection, whose underlying mechanisms are poorly understood. We aimed to evaluate the importance of the modulation of RANTES-CCR5 signalling axis and its immunomodulatory effects in directing hepatitis A disease pathogenesis using an in-silico, in-vitro and patient cohort based approach.In-silico interaction studies were performed using computation approaches with suitable software. Differential expression of relevant cytokines and immune cell markers were studied using qRT-PCR, ELISA and flow-cytometry-based methods. In HepG2 cell line, we studied inflammatory responses and susceptibility to HAV infection following RANTES stimulation and antibody blockade of CCR5.The HAV-VP3 region exhibited high interaction in CCR5: HAV complexes. RANTES levels were significantly increased in FHF cases. A reduced monocyte and T-cell activation was observed in FHF cases. RANTES expression inversely correlated with viremia but positively correlated with pro-inflammatory responses. Hyper Th1-biased immune responses, marked by high IL-12/IL-10 ratio were observed in FHF cases, which were also characterized by upregulated TNF-a expression and reduced IFN-? expression. In-vitro, RANTES was protective against HAV infection, but resulted in upregulated TNF-a expression. Although viral load increased upon regulation of inflammatory responses by CCR5 blocking, it was still significantly lower compared to control HAV-infected cells.
Our study suggests the importance of RANTES-CCR5 signalling and linked-immunomodulation in HAV disease pathogenesis, as well as highlights the utility of CCR5 antagonists as a risk-reduction strategy in FHF patients.
Our findings therefore have important implications for the management of high-risk HAV infections.
This article is protected by copyright. All rights reserved.
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