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Journal of virology2016; 90(23); 10670-10681; doi: 10.1128/JVI.01634-16

Hepacivirus NS3/4A Proteases Interfere with MAVS Signaling in both Their Cognate Animal Hosts and Humans: Implications for Zoonotic Transmission.

Abstract: Multiple novel members of the genus Hepacivirus have recently been discovered in diverse mammalian species. However, to date, their replication mechanisms and zoonotic potential have not been explored in detail. The NS3/4A serine protease of hepatitis C virus (HCV) is critical for cleavage of the viral polyprotein. It also cleaves the cellular innate immune adaptor MAVS, thus decreasing interferon (IFN) production and contributing to HCV persistence in the human host. To investigate the conservation of fundamental aspects of the hepaciviral life cycle, we explored if MAVS cleavage and suppression of innate immune signaling represent a common mechanism employed across different clades of the genus Hepacivirus to enhance viral replication. To estimate the zoonotic potential of these nonhuman hepaciviruses, we assessed if their NS3/4A proteases were capable of cleaving human MAVS. NS3/4A proteases of viruses infecting colobus monkeys, rodents, horses, and cows cleaved the MAVS proteins of their cognate hosts and interfered with the ability of MAVS to induce the IFN-β promoter. All NS3/4A proteases from nonhuman viruses readily cleaved human MAVS. Thus, NS3/4A-dependent cleavage of MAVS is a conserved replication strategy across multiple clades within the genus Hepacivirus Human MAVS is susceptible to cleavage by these nonhuman viral proteases, indicating that it does not pose a barrier for zoonotic transmission of these viruses to humans. Objective: Virus infection is recognized by cellular sensor proteins triggering innate immune signaling and antiviral defenses. While viruses have evolved strategies to thwart these antiviral programs in their cognate host species, these evasion mechanisms are often ineffective in a novel host, thus limiting viral transmission across species. HCV, the best-characterized member of the genus Hepacivirus within the family Flaviviridae, uses its NS3/4A protease to disrupt innate immune signaling by cleaving the cellular adaptor protein MAVS. Recently, a large number of HCV-related viruses have been discovered in various animal species, including wild, livestock, and companion animals. We show that the NS3/4A proteases of these hepaciviruses from different animals and representing various clades of the genus cleave their cognate host MAVS proteins in addition to human MAVS. Therefore, cleavage of MAVS is a common strategy of hepaciviruses, and human MAVS is likely unable to limit replication of these nonhuman viruses upon zoonotic exposure.
Publication Date: 2016-11-14 PubMed ID: 27654291PubMed Central: PMC5110154DOI: 10.1128/JVI.01634-16Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research focuses on studying how various Hepaciviruses interfere with MAVS signaling, an essential part of the immune response, in both their animal hosts and humans, which in turn implicates their possible zoonotic transmission.

Study Objective and Importance

  • The ultimate goal of the research is to explore the replication mechanisms of Hepaciviruses and delve into their potential for zoonotic transmission – i.e., their ability to jump from their initial animal hosts to humans.
  • This research is essential since Hepaciviruses, specifically hepatitis C virus (HCV), interfere with the immune response of hosts, leading to persistence of the virus potentially causing long-term health issues.

Hepacivirus Mechanisms

  • HCV, utilizes a protease known as NS3/4A to disrupt immune signaling by cleaving a cellular protein called MAVS, which is critical for antiviral defenses.
  • A multitude of HCV-related viruses have recently been found in various animals, such as rodents, horses, and cows. This research focused on the application of the same MAVS cleavage by the NS3/4A proteases in these HCV-related viruses.

Key Findings

  • The NS3/4A proteases from these hepaciviruses displayed the ability to cleave MAVS proteins of both their originating animal species and humans, showing that this method of immune disruption is a common strategy among these viruses.
  • The findings suggest that human MAVS is susceptible to interference by these nonhuman viral proteases. That means it does not pose a barrier to these viruses’ zoonotic transmission, allowing for the potential infection of humans.

Implications

  • This research suggests that the nonhuman Hepaciviruses have the potential to bypass the human body’s immune defenses, allowing for their replication in a new host.
  • Understanding this mechanism brings forth new knowledge in combating viral diseases, providing a deeper insight into virus-host interactions and presenting better strategies for preventing or treating Hepacivirus infections.

Cite This Article

APA
Anggakusuma , Brown RJP, Banda DH, Todt D, Vieyres G, Steinmann E, Pietschmann T. (2016). Hepacivirus NS3/4A Proteases Interfere with MAVS Signaling in both Their Cognate Animal Hosts and Humans: Implications for Zoonotic Transmission. J Virol, 90(23), 10670-10681. https://doi.org/10.1128/JVI.01634-16

Publication

ISSN: 1098-5514
NlmUniqueID: 0113724
Country: United States
Language: English
Volume: 90
Issue: 23
Pages: 10670-10681

Researcher Affiliations

Anggakusuma,
  • Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hanover, Germany.
Brown, Richard J P
  • Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hanover, Germany.
Banda, Dominic H
  • Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hanover, Germany.
Todt, Daniel
  • Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hanover, Germany.
Vieyres, Gabrielle
  • Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hanover, Germany.
Steinmann, Eike
  • Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hanover, Germany.
Pietschmann, Thomas
  • Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hanover, Germany thomas.pietschmann@twincore.de.

MeSH Terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / physiology
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Evolution, Molecular
  • Genetic Variation
  • Hepacivirus / enzymology
  • Hepacivirus / immunology
  • Hepacivirus / pathogenicity
  • Hepatitis C / immunology
  • Hepatitis C / transmission
  • Hepatitis C / virology
  • Host Specificity
  • Humans
  • Immunity, Innate
  • Serine Proteases / genetics
  • Serine Proteases / physiology
  • Signal Transduction
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / physiology
  • Virus Replication / immunology
  • Zoonoses / immunology
  • Zoonoses / transmission
  • Zoonoses / virology

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