Activation of the RLR/MAVS Signaling Pathway by the L Protein of Mopeia Virus

Zhang, Leike; Xin, Qilin; Zhu, Sheng-Lin; Wan, Weiwei; Wang, Wei; Xiao, Gengfu

doi:10.1128/jvi.01292-16

Cited by 16 publications

(12 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In agreement with our studies, several studies have recently reported that expression of a viral RdRP can activate the innate immune system in mammalian cells (81)(82)(83)(84). For instance, transient expression of HCV RdRP NS5B resulted in the induction of PRRs specific for dsRNA, including RIG-I and MDA5 that activate the innate immune signaling pathways in mouse and human hepatocytes (85,86).…”

Section: Discussionsupporting

confidence: 91%

Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity

Zheng

Yang

Jiang

et al. 2018

The Journal of Immunology

View full text Add to dashboard Cite

Tick-borne encephalitis virus (TBEV) is one of the flaviviruses that targets the CNS and causes encephalitis in humans. The mechanism of TBEV that causes CNS destruction remains unclear. It has been reported that RANTES-mediated migration of human blood monocytes and T lymphocytes is specifically induced in the brain of mice infected with TBEV, which causes ensuing neuroinflammation and may contribute to brain destruction. However, the viral components responsible for RANTES induction and the underlying mechanisms remain to be fully addressed. In this study, we demonstrate that the NS5, but not other viral proteins of TBEV, induces RANTES production in human glioblastoma cell lines and primary astrocytes. TBEV NS5 appears to activate the IFN regulatory factor 3 (IRF-3) signaling pathway in a manner dependent on RIG-I/MDA5, which leads to the nuclear translocation of IRF-3 to bind with RANTES promoter. Further studies reveal that the activity of RNA-dependent RNA polymerase (RdRP) but not the RNA cap methyltransferase is critical for TBEV NS5-induced RANTES expression, and this is likely due to RdRP-mediated synthesis of dsRNA. Additional data indicate that the residues at K359, D361, and D664 of TBEV NS5 are critical for RdRP activity and RANTES induction. Of note, NS5s from other flaviviruses, including Japanese encephalitis virus, West Nile virus, Zika virus, and dengue virus, can also induce RANTES expression, suggesting the significance of NS5-induced RANTES expression in flavivirus pathogenesis. Our findings provide a foundation for further understanding how flaviviruses cause neuroinflammation and a potential viral target for intervention.

show abstract

Section: Discussionsupporting

confidence: 91%

Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity

Zheng

Yang

Jiang

et al. 2018

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Although the significance of these findings during natural infections remains to be evaluated, these results indicate that positive selection at mammarenavirus L proteins might result from interaction with the host immune system. In line with this view, a recent work also indicated that the L protein of Mopeia virus can activate the RLR/MAVS signaling pathway, possibly via the production of small RNAs ( Zhang et al. 2016 ).…”

Section: Discussionmentioning

confidence: 76%

Ancient Evolution of Mammarenaviruses: Adaptation via Changes in the L Protein and No Evidence for Host–Virus Codivergence

Forni

Pontremoli

Clerici

et al. 2018

Genome Biology and Evolution

View full text Add to dashboard Cite

The Mammarenavirus genus includes several pathogenic species of rodent-borne viruses. Old World (OW) mammarenaviruses infect rodents in the Murinae subfamily and are mainly transmitted in Africa and Asia; New World (NW) mammarenaviruses are found in rodents of the Cricetidae subfamily in the Americas. We applied a selection-informed method to estimate that OW and NW mammarenaviruses diverged less than ∼45,000 years ago (ya). By incorporating phylogeographic inference, we show that NW mammarenaviruses emerged in the Latin America-Caribbean region ∼41,400–3,300 ya, whereas OW mammarenaviruses originated ∼23,100–1,880 ya, most likely in Southern Africa. Cophylogenetic analysis indicated that cospeciation did not contribute significantly to mammarenavirus–host associations. Finally, we show that extremely strong selective pressure on the viral polymerase accompanied the speciation of NW viruses. These data suggest that the evolutionary history of mammarenaviruses was not driven by codivergence with their hosts. The viral polymerase should be regarded as a major determinant of mammarenavirus adaptation.

show abstract

“…The ability of MOPV NP to bind this factor is not known, and no cellular partners have been identified so far. Finally, it was recently demonstrated that the polymerase of MOPV, but not that of LASV, is able to induce the activation of RIG-I and MDA5, probably through the synthesis of dsRNA (36). Altogether, these additional mechanisms may account for the differences in pathogenicity and immunogenicity between LASV and MOPV, thereby explaining the attenuation of ML29.…”

Section: Discussionmentioning

confidence: 99%

A Vaccine Platform against Arenaviruses Based on a Recombinant Hyperattenuated Mopeia Virus Expressing Heterologous Glycoproteins

Carnec

Mateo

Page

et al. 2018

J Virol

View full text Add to dashboard Cite

Several Old World and New World arenaviruses are responsible for severe endemic and epidemic hemorrhagic fevers, whereas other members of the family are nonpathogenic. To date, no approved vaccines, antivirals, or specific treatments are available, except for Junín virus. However, protection of nonhuman primates against Lassa fever virus (LASV) is possible through the inoculation of the closely related but nonpathogenic Mopeia virus (MOPV) before challenge with LASV. We reasoned that this virus, modified by using reverse genetics, would represent the basis for the generation of a vaccine platform against LASV and other pathogenic arenaviruses. After showing evidence of exoribonuclease (ExoN) activity in NP of MOPV, we found that this activity was essential for multiplication in antigen-presenting cells. The introduction of multiple mutations in the ExoN site of MOPV NP generated a hyperattenuated strain (MOPV) that is (i) genetically stable over passages, (ii) has increased immunogenic properties compared to those of MOPV, and (iii) still promotes a strong type I interferon (IFN) response. MOPV was further modified to harbor the envelope glycoproteins of heterologous pathogenic arenaviruses, such as LASV or Lujo, Machupo, Guanarito, Chapare, or Sabia virus in order to broaden specific antigenicity while preserving the hyperattenuated characteristics of the parental strain. Our MOPV-based vaccine candidate for LASV, MOPEVAC, was used in a one-shot immunization assay in nonhuman primates and fully protected them from a lethal challenge with LASV. Thus, our hyperattenuated strain of MOPV constitutes a promising new live-attenuated vaccine platform to immunize against several, if not all, pathogenic arenaviruses. Arenaviruses are emerging pathogens transmitted to humans by rodents and responsible for endemic and epidemic hemorrhagic fevers of global concern. Nonspecific symptoms associated with the onset of infection make these viruses difficult to distinguish from other endemic pathogens. Moreover, the unavailability of rapid diagnosis in the field delays the identification of the virus and early care for treatment and favors spreading. The vaccination of exposed populations would be of great help to decrease morbidity and human-to-human transmission. Using reverse genetics, we generated a vaccine platform for pathogenic arenaviruses based on a modified and hyperattenuated strain of the nonpathogenic Mopeia virus and showed that the Lassa virus candidate fully protected nonhuman primates from a lethal challenge. These results showed that a rationally designed recombinant MOPV-based vaccine is safe, immunogenic, and efficacious in nonhuman primates.

show abstract

Activation of the RLR/MAVS Signaling Pathway by the L Protein of Mopeia Virus

Cited by 16 publications

References 60 publications

Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity

Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity

Ancient Evolution of Mammarenaviruses: Adaptation via Changes in the L Protein and No Evidence for Host–Virus Codivergence

A Vaccine Platform against Arenaviruses Based on a Recombinant Hyperattenuated Mopeia Virus Expressing Heterologous Glycoproteins

Contact Info

Product

Resources

About