Bunyavirus SFTSV nucleoprotein exploits TUFM-mediated mitophagy to impair antiviral innate immunity.

Severe fever with thrombocytopenia syndrome is an emerging viral hemorrhagic fever caused by a tick-borne bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), with a high case fatality. We previously found that SFTSV nucleoprotein (NP) induces macroautophagy/autophagy to facilitate virus replication. However, the role of NP in antagonizing host innate immunity remains unclear. Mitophagy, a selected form of autophagy, eliminates damaged mitochondria to maintain mitochondrial homeostasis. Here, we demonstrate that SFTSV NP triggers mitophagy to degrade MAVS (mitochondrial antiviral signaling protein), thereby blocking MAVS-mediated antiviral signaling to escape the host immune response. Mechanistically, SFTSV NP translocates to mitochondria by interacting with TUFM (Tu translation elongation factor, mitochondrial), and mediates mitochondrial sequestration into phagophores through interacting with LC3, thus inducing mitophagy. Notably, the N-terminal LC3-interacting region (LIR) motif of NP is essential for mitophagy induction. Collectively, our results demonstrated that SFTSV NP serves as a novel virulence factor, inducing TUFM-mediated mitophagy to degrade MAVS and evade the host immune response.Abbreviation: 3-MA: 3-methyladenine; ACTB: actin beta; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole, dihydrochloride; DMSO: dimethyl sulfoxide; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GFP: green fluorescent protein; HTNV: Hantan virus; IAV: influenza A virus; IFN: interferon; LAMP1: lysosomal associated membraneprotein 1; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associatedprotein 1 light chain 3 beta; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MT-CO2/COXII: mitochondrially encoded cytochrome C oxidase II; NP: nucleoprotein; NSs: nonstructural proteins; poly(I:C): polyinosinic:polycytidylic acid; RIGI: RNA sensor RIG-I; RLR: RIGI-like receptor; SFTSV: severe fever withthrombocytopenia syndrome virus; TCID50: 50% tissue culture infectiousdose; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20:translocase of outer mitochondrial membrane 20; TUFM: Tu translation elongationfactor, mitochondrial.

The combined effect of handgrip strength and obesity phenotype on the risk of stroke in Chinese middle-aged and elderly: A cohort study.

OBJECTIVE: The aim of this study was to investigate the combined effect of handgrip strength (HGS) and obesity phenotype on the risk of stroke in Chinese middle-aged and elderly people. METHODS: The data was used from the China Health and Retirement Longitudinal Study (CHARLS). Middle-aged and older adults who participated in surveys between 2011 and 2018 were included in the study. They were divided into 4 different types of obesity phenotypes based on obesity and metabolic status: metabolically healthy non-overweight/obesity (MHNO), metabolically healthy overweight/obesity (MHO), metabolically abnormal non-overweight/obesity (MANO), and metabolically abnormal overweight/obesity (MAO). The HGS level was divided into low and high groups according to the median values. Cox proportional risk regression model was used to analyze the joint effect of HGS and obesity phenotype on the risk of stroke among participants. RESULTS: A total of 7904 participants aged 58.89±9.08 years were included in this study. After adjusting for potential confounders, high HGS&MHO (HR=1.86, 95 % CI=1.12-3.09), high HGS&MANO (HR=2.01, 95 %CI=1.42-2.86), high HGS&MAO (HR=2.01, 95 % CI=1.37-2.93), low HGS&MHNO (HR=1.57, 95 % CI=1.00-2.46), low HGS&MHO (HR=2.09, 95 % CI=1.29-3.38), low HGS&MANO (HR=2.02, 95 % CI=1.35-3.03), and low HGS&MAO (HR=2.48, 95 % CI=1.72-3.58) group had significantly higher risks of stroke than the high HGS&MHNO group. CONCLUSION: The coexistence of metabolically unhealthy and low HGS can synergistically increase the risk of stroke in Chinese middle-aged and elderly people.

Bunyavirus SFTSV exploits autophagic flux for viral assembly and egress.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging negatively stranded enveloped RNA bunyavirus that causes SFTS with a high case fatality rate of up to 30%. Macroautophagy/autophagy is an evolutionarily conserved process involved in the maintenance of host homeostasis, which exhibits anti-viral or pro-viral responses in reaction to different viral challenges. However, the interaction between the bunyavirus SFTSV and the autophagic process is still largely unclear. By establishing various autophagy-deficient cell lines, we found that SFTSV triggered RB1CC1/FIP200-BECN1-ATG5-dependent classical autophagy flux. SFTSV nucleoprotein induced BECN1-dependent autophagy by disrupting the BECN1-BCL2 association. Importantly, SFTSV utilized autophagy for the viral life cycle, which not only assembled in autophagosomes derived from the ERGIC and Golgi complex, but also utilized autophagic vesicles for exocytosis. Taken together, our results suggest a novel virus-autophagy interaction model in which bunyavirus SFTSV induces classical autophagy flux for viral assembly and egress processes, suggesting that autophagy inhibition may be a novel therapy for treating or releasing SFTS.

Integrated transcriptome profiling in THP-1 macrophages infected with bunyavirus SFTSV.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne bunyavirus that causes an emerging hemorrhagic fever termed SFTS with high mortality. However, knowledge of SFTSV-host interactions is largely limited. Here, we performed a global transcriptome analysis of mRNAs and lncRNAs in THP-1 macrophages infected with SFTSV for 24 and 48 h. A total of 2,334 differentially expressed mRNAs and 154 differentially expressed lncRNAs were identified with 577 mRNAs and 31 lncRNAs commonly changed at both time points. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that differentially expressed mRNAs were mainly associated with innate immune, cytokine signaling, systemic lupus erythematosus, and alcoholism. Differentially expressed lncRNAs were enriched in systemic lupus erythematosus, alcoholism, and ribosome. Bioinformatic analysis also revealed hub regulatory mRNAs including IL6, TNF, UBA52, SRC, IL10, CXCL10, and CDK1 and core regulatory lncRNAs including XLOC_083027 and XLOC_113317. Transcription factor analysis of the differentially expressed mRNAs revealed that IRF1, SPI1, SPIB, ELF5, and FEV were enriched during SFTSV infection. Taken together, our studies illustrate the complex interaction between THP-1 macrophages and SFTSV.

Accumulation of EBI3 induced by virulent Mycobacterium tuberculosis inhibits apoptosis in murine macrophages.

Macrophages are the primary host target cells of Mycobacterium tuberculosis (M. tb). As a subunit of immunoregulatory cytokines IL-27 and IL-35, Epstein-Barr virus-induced gene 3 (EBI3) has typically been explored as the secreted form and assessed in terms of its effects triggered by extracellular EBI3. However, little is known about intracellular EBI3 function. In the current study, we report that EBI3 production by macrophages is elevated in TB patients. We further demonstrate that increased EBI3 accumulates in virulent M. tb-treated murine macrophages. Eukaryotic translation elongation factor 1-alpha 1 (eEF1A1) binds to intracellular EBI3 to reduce Lys48 (K48)-linked ubiquitination of EBI3, leading to EBI3 accumulation. Moreover, the intracellular EBI3 inhibits caspase-3-mediated apoptosis in M. tb-treated macrophages. Herein, we propose a novel mechanism for accumulating intracellular EBI3 and its regulation of macrophage apoptosis in response to virulent M. tb.