Activation of the RLR/MAVS Signaling Pathway by the L Protein of Mopeia Virus.
The family Arenaviridae includes several important human pathogens that can cause severe hemorrhagic fever and greatly threaten public health. As a major component of the innate immune system, the RLR/MAVS signaling pathway is involved in recognizing viral components and initiating antiviral activity. It has been reported that arenavirus infection can suppress the innate immune response, and NP and Z proteins of pathogenic arenaviruses can disrupt RLR/MAVS signaling, thus inhibiting production of type I interferon (IFN-I). However, recent studies have shown elevated IFN-I levels in certain arenavirus-infected cells. The mechanism by which arenavirus infection induces IFN-I responses remains unclear. In this study, we determined that the L polymerase (Lp) of Mopeia virus (MOPV), an Old World (OW) arenavirus, can activate the RLR/MAVS pathway and thus induce the production of IFN-I. This activation is associated with the RNA-dependent RNA polymerase activity of Lp. This study provides a foundation for further studies of interactions between arenaviruses and the innate immune system and for the elucidation of arenavirus pathogenesis.


OBJECTIVE
Distinct innate immune responses are observed when hosts are infected with different arenaviruses. It has been widely accepted that NP and certain Z proteins of arenaviruses inhibit the RLR/MAVS signaling pathway. The viral components responsible for the activation of the RLR/MAVS signaling pathway remain to be determined. In the current study, we demonstrate for the first time that the Lp of MOPV, an OW arenavirus, can activate the RLR/MAVS signaling pathway and thus induce the production of IFN-I. Based on our results, we proposed that dynamic interactions exist among Lp-produced RNA, NP, and the RLR/MAVS signaling pathway, and the outcome of these interactions may determine the final IFN-I response pattern: elevated or reduced. Our study provides a possible explanation for how IFN-I can become activated during arenavirus infection and may help us gain insights into the interactions that form between different arenavirus components and the innate immune system.
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Lei-Ke
LK
Zhang
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Qi-Lin
QL
Xin
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Sheng-Lin
SL
Zhu
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Wei-Wei
WW
Wan
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Wei
W
Wang
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China xiaogf@wh.iov.cn.
Gengfu
G
Xiao
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D018050:Arenavirus / Q000276:immunology / Q000378:metabolism; D018049:Arenaviruses, Old World / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000276:immunology / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007370:Interferon Type I / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; C505371:MAVS protein, human; D014764:Viral Proteins; D012321:DNA-Directed RNA Polymerases