RVFV virulence factor NSs triggers the mitochondrial MCL-1-BAK axis to activate pathogenic NLRP3 pyroptosis.

in PLoS pathogens by Zhenqiong Guan, Huiling Li, Chongtao Zhang, Ziyan Huang, Meidi Ye, Yulan Zhang, Shufen Li, Ke Peng

TLDR

  • The study investigates how a virus called Rift Valley fever virus (RVFV) causes inflammation in the body. The study found that the virus triggers mitochondrial damage and activates a protein called NLRP3, which leads to inflammation. The study also found that the virus uses a protein called MCL-1 to activate NLRP3 and cause inflammation. The study suggests that targeting this protein could be a potential therapeutic strategy for RVFV infection. The study also shows that the virus causes inflammation in the body by triggering a process called pyroptosis, which is a type of cell death. The study suggests that understanding this process could help us develop new treatments for RVFV infection.

Abstract

Infection of Rift Valley fever virus (RVFV), a highly pathogenic mosquito-borne zoonotic virus, triggers severe inflammatory pathogenesis but the underlying mechanism of inflammation activation is currently unclear. Here, we report that the non-structural protein NSs of RVFV triggers mitochondrial damage to activate the NLRP3 inflammasome leading to viral pathogenesis in vivo. It is found that the host transcription inhibition effect of NSs causes rapid down-regulation of myeloid cell leukemia-1(MCL-1), a pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) protein family. MCL-1 down-regulation led to BAK activation in the mitochondria, which triggered mtROS production and release of oxidized mitochondrial DNA (ox-mtDNA) into the cytosol. Cytosolic ox-mtDNA binds and activates the NLRP3 inflammasome triggering NLRP3-GSDMD pyroptosis in RVFV infected cells. A NSs mutant virus (RVFV-NSsRM) that is compromised in inducing transcription inhibition did not trigger MCL-1 down-regulation nor NLRP3-GSDMD pyroptosis. RVFV infection of the Nlrp3-/- mouse model demonstrated that the RVFV-triggered NLRP3 pyroptosis contributed to RVFV inflammatory pathogenesis and fatal infection in vivo. Infection with the RVFV-NSsRM mutant virus similarly showed alleviated inflammatory pathogenesis and reduced fatality rate. Taken together, these results revealed a mechanism by which a virulence factor activates the mitochondrial MCL-1-BAK axis through inducing host transcription inhibition to trigger NLRP3-dependent inflammatory pathogenesis.

Overview

  • The study investigates the inflammatory pathogenesis of Rift Valley fever virus (RVFV) and the underlying mechanism of inflammation activation. The study uses the non-structural protein NSs of RVFV to trigger mitochondrial damage and activate the NLRP3 inflammasome leading to viral pathogenesis in vivo. The primary objective of the study is to understand the mechanism of inflammatory pathogenesis of RVFV and identify potential targets for therapeutic intervention. The study uses a mouse model to investigate the role of NLRP3 in RVFV inflammatory pathogenesis and the effect of a mutant virus on inflammatory pathogenesis and fatality rate. The study aims to provide insights into the pathogenesis of RVFV and inform the development of new therapeutic strategies for the disease.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies that the non-structural protein NSs of RVFV triggers mitochondrial damage and activates the NLRP3 inflammasome leading to viral pathogenesis in vivo. The study also identifies that the host transcription inhibition effect of NSs causes rapid down-regulation of myeloid cell leukemia-1(MCL-1), a pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) protein family. MCL-1 down-regulation led to BAK activation in the mitochondria, which triggered mtROS production and release of oxidized mitochondrial DNA (ox-mtDNA) into the cytosol. Cytosolic ox-mtDNA binds and activates the NLRP3 inflammasome triggering NLRP3-GSDMD pyroptosis in RVFV infected cells. The study also identifies that a mutant virus (RVFV-NSsRM) that is compromised in inducing transcription inhibition did not trigger MCL-1 down-regulation nor NLRP3-GSDMD pyroptosis. The study demonstrates that the RVFV-triggered NLRP3 pyroptosis contributed to RVFV inflammatory pathogenesis and fatal infection in vivo. The study also shows that infection with the RVFV-NSsRM mutant virus similarly showed alleviated inflammatory pathogenesis and reduced fatality rate. The key findings of the study are that the NLRP3 inflammasome is activated by RVFV through the mitochondrial MCL-1-BAK axis and that targeting this pathway could be a potential therapeutic strategy for RVFV infection.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study provides insights into the pathogenesis of RVFV and identifies a potential therapeutic target for the disease. The study also highlights the importance of understanding the underlying mechanism of inflammation activation in viral infections. The study identifies limitations, such as the use of a mouse model and the need for further studies to validate the findings in humans. The study suggests future research directions, such as investigating the role of NLRP3 in other viral infections and exploring the use of small molecule inhibitors to target the NLRP3 inflammasome in RVFV infection.
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