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The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I-like receptor-dependent interferon production.

ABSTRACT: Arenavirus pathogens cause a wide spectrum of diseases in humans ranging from central nervous system disease to lethal hemorrhagic fevers with few treatment options. The reason why some arenaviruses can cause severe human diseases while others cannot is unknown. We find that the Z proteins of all known pathogenic arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Lassa, Junin, Machupo, Sabia, Guanarito, Chapare, Dandenong, and Lujo viruses, can inhibit retinoic acid-inducible gene 1 (RIG-i) and Melanoma Differentiation-Associated protein 5 (MDA5), in sharp contrast to those of 14 other nonpathogenic arenaviruses. Inhibition of the RIG-i-like receptors (RLRs) by pathogenic Z proteins is mediated by the protein-protein interactions of Z and RLRs, which lead to the disruption of the interactions between RLRs and mitochondrial antiviral signaling (MAVS). The Z-RLR interactive interfaces are located within the N-terminal domain (NTD) of the Z protein and the N-terminal CARD domains of RLRs. Swapping of the LCMV Z NTD into the nonpathogenic Pichinde virus (PICV) genome does not affect virus growth in Vero cells but significantly inhibits the type I interferon (IFN) responses and increases viral replication in human primary macrophages. In summary, our results show for the first time an innate immune-system-suppressive mechanism shared by the diverse pathogenic arenaviruses and thus shed important light on the pathogenic mechanism of human arenavirus pathogens.We show that all known human-pathogenic arenaviruses share an innate immune suppression mechanism that is based on viral Z protein-mediated RLR inhibition. Our report offers important insights into the potential mechanism of arenavirus pathogenesis, provides a convenient way to evaluate the pathogenic potential of known and/or emerging arenaviruses, and reveals a novel target for the development of broad-spectrum therapies to treat this group of diverse pathogens. More broadly, our report provides a better understanding of the mechanisms of viral immune suppression and host-pathogen interactions.

SUBMITTER: Xing J

PROVIDER: S-EPMC4325705 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I-like receptor-dependent interferon production.

Xing Junji J Ly Hinh H Liang Yuying Y

Journal of virology 20141231 5

<h4>Unlabelled</h4>Arenavirus pathogens cause a wide spectrum of diseases in humans ranging from central nervous system disease to lethal hemorrhagic fevers with few treatment options. The reason why some arenaviruses can cause severe human diseases while others cannot is unknown. We find that the Z proteins of all known pathogenic arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Lassa, Junin, Machupo, Sabia, Guanarito, Chapare, Dandenong, and Lujo viruses, can inhibit retinoic acid-i ...[more]

PMID: 25552708

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Project description:The nonstructural protein 1 (NS1) of influenza A viruses is an important virulence factor that controls host cell immune responses. In human cells, NS1 proteins inhibit the induction of type I interferon by several mechanisms, including potentially, by preventing the activation of the retinoic acid-inducible gene I (RIG-I) receptor by the ubiquitin ligase tripartite motif-containing protein 25 (TRIM25). It is unclear whether the inhibition of human TRIM25 is a universal function of all influenza A NS1 proteins or is strain dependent. It is also unclear if NS1 proteins similarly target the TRIM25 of mallard ducks, a natural reservoir host of avian influenza viruses with a long coevolutionary history and unique disease dynamics. To answer these questions, we compared the ability of five different NS1 proteins to interact with human and duck TRIM25 using coimmunoprecipitation and microscopy and assessed the consequence of this on RIG-I ubiquitination and signaling in both species. We show that NS1 proteins from low-pathogenic and highly pathogenic avian influenza viruses potently inhibit RIG-I ubiquitination and reduce interferon promoter activity and interferon-beta protein secretion in transfected human cells, while the NS1 of the mouse-adapted PR8 strain does not. However, all the NS1 proteins, when cloned into recombinant viruses, suppress interferon in infected alveolar cells. In contrast, avian NS1 proteins do not suppress duck RIG-I ubiquitination and interferon promoter activity, despite interacting with duck TRIM25. IMPORTANCE Influenza A viruses are a major cause of human and animal disease. Periodically, avian influenza viruses from wild waterfowl, such as ducks, pass through intermediate agricultural hosts and emerge into the human population as zoonotic diseases with high mortality rates and epidemic potential. Because of their coevolution with influenza A viruses, ducks are uniquely resistant to influenza disease compared to other birds, animals, and humans. Here, we investigate a mechanism of influenza A virus interference in an important antiviral signaling pathway that is orthologous in humans and ducks. We show that NS1 proteins from four avian influenza strains can block the coactivation and signaling of the human RIG-I antiviral receptor, while none block the coactivation and signaling of duck RIG-I. Understanding host-pathogen dynamics in the natural reservoir will contribute to our understanding of viral disease mechanisms, viral evolution, and the pressures that drive it, which benefits global surveillance and outbreak prevention.

Project description:UnlabelledThe live attenuated measles virus vaccine is highly immunostimulatory. Identification and characterization of its components that activate the innate immune response might provide new strategies and agents for the rational design and development of chemically defined adjuvants. In this study, we report on the activation of type I interferon (IFN) production by a defective interfering (DI) RNA isolated from the Hu-191 vaccine strain of measles virus. We found that the Hu-191 virus induced IFN-β much more potently than the Edmonston strain. In the search for IFN-inducing species in Hu-191, we identified a DI RNA specifically expressed by this strain. This DI RNA, which was of the copy-back type, was predicted to fold into a hairpin structure with a long double-stranded stem region of 206 bp, and it potently induced the expression of IFN-β. Its IFN-β-inducing activity was further enhanced when both cytoplasmic RNA sensor RIG-I and its partner, PACT, were overexpressed. On the contrary, this activity was abrogated in cells deficient in PACT or RIG-I. The DI RNA was found to be associated with PACT in infected cells. In addition, both the 5'-di/triphosphate end and the double-stranded stem region on the DI RNA were essential for its activation of PACT and RIG-I. Taken together, our findings support a model in which a viral DI RNA is sensed by PACT and RIG-I to initiate an innate antiviral response. Our work might also provide a foundation for identifying physiological PACT ligands and developing novel adjuvants or antivirals.ImportanceThe live attenuated measles virus vaccine is one of the most successful human vaccines and has largely contained the devastating impact of a highly contagious virus. Identifying the components in this vaccine that stimulate the host immune response and understanding their mechanism of action might help to design and develop better adjuvants, vaccines, antivirals, and immunotherapeutic agents. We identified and characterized a defective interfering RNA from the Hu-191 vaccine strain of measles virus which has safely been used in millions of people for many years. We further demonstrated that this RNA potently induces an antiviral immune response through cellular sensors of viral RNA known as PACT and RIG-I. Similar types of viral RNA that bind with and activate PACT and RIG-I might retain the immunostimulatory property of measles virus vaccines but would not induce adaptive immunity. They are potentially useful as chemically defined vaccine adjuvants, antivirals, and immunostimulatory agents.

Dataset Information

The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I-like receptor-dependent interferon production.

Publications

The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I-like receptor-dependent interferon production.

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