Lab-Attenuated Rabies Virus Facilitates Opening of the Blood-Brain Barrier by Inducing Matrix Metallopeptidase 8

Fang, An; Yuan, Yueming; Huang, Fei; Wang, Caiqian; Tian, Dayong; Zhou, Rui; Zhou, Ming; Chen, Huanchun; Fu, Zhen F.; Zhao, Ling

doi:10.1128/jvi.01050-22

Cited by 7 publications

(4 citation statements)

References 63 publications

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“…When performing experiments with recombinant RABVs, we found that the recombinant CVS-M-G57E RABV could still cause some ATP and NAD reduction, suggesting that factors other than the M protein influence the energy metabolism of neurons. We hypothesized that this was due to the G protein of CVS, since it has been reported that the G protein of non-pathogenic RABV strains (such as the CVS strain) can trigger apoptosis, whereas the G protein of pathogenic strains (such as the DRV strain) induces less or no apoptosis ( 43 , 44 ), and activation of the apoptotic pathway inhibits mitochondrial metabolism ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism

Yuan,

Fang,

Wang

et al. 2024

mBio

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Previous studies have suggested that RABV (rabies virus, the representative of lyssavirus) infection induces structural abnormalities in neurons. But there are few articles on the mechanism of lyssavirus’ effect on neurons, and the mechanism of how RABV infection induces neurological dysfunction remains incomplete. The M protein of lyssavirus can downregulate cellular ATP levels by interacting with Slc25a4, and this decrease in ATP leads to a decrease in the level of NAD + in the cytosol, which results in the release of Ca 2+ from the intracellular calcium pool, the endoplasmic reticulum, and mitochondria. The presence of large amounts of Ca 2+ in the cytoplasm activates Ca 2+ -dependent proteases and degrades microtubule proteins. The amino acid 57 of M protein is the key site determining its disruption of mitochondrial metabolism and subsequent neuron degeneration.

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Section: Discussionmentioning

confidence: 99%

Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism

Yuan,

Fang,

Wang

et al. 2024

mBio

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“…reported that intracerebroventricular microinjection of MMP8-specific shRNA lentivirus could diminish the magnitude of ischemia-induced brain injury. MMP8 levels have been found to be elevated in patients with ischemic stroke and are closely associated with both BBB leakage and inflammatory responses 30 – 32 . Furthermore, BMSC transplantation has the potential to downregulate MMP8 levels, possibly by influencing the differentiation of BMSC into multiple lineages 33 , 34 .…”

Section: Discussionmentioning

confidence: 99%

Ultrasound-Targeted Microbubble Destruction Increases BBB Permeability and Promotes Stem Cell–Induced Regeneration of Stroke by Downregulating MMP8

Bai,

Du,

Yang

et al. 2024

Cell Transplant

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The objective of this study was to evaluate the feasibility, safety, and effectiveness of intravenous stem cell delivery utilizing ultrasound-targeted microbubble destruction (UTMD) in a rat model of middle cerebral artery occlusion (MCAO), while investigating the underlying mechanisms. Acute cerebral infarction (ACI) was induced surgically in adult rats to create the MCAO rat model. Intravenous injection of SonoVue microbubbles and bone marrow–derived mesenchymal stem cells (BMSC) was performed concurrently, with or without ultrasound targeting the stroke. The animals were divided into four groups: sham-operated group, ACI-MCAO rats treated with phosphate-buffered saline (ACI+PBS), rats receiving intravenous delivery of BMSC expressing green fluorescent protein (GFP-BMSC; ACI+BMSC), and rats receiving intravenous GFP-BMSC with simultaneous UTMD exposure (ACI+BMSC+UTMD). The efficacy of the treatments was assessed by evaluating the animals’ neurological function using the Longa score and examining histopathological changes such as cerebral infarct volume, cerebral edema, and cell apoptosis. A rat cytokine array was utilized to identify the potential cytokines that may be responsible for the therapeutic effect of UTMD-mediated BMSC treatment. Optimal UTMD parameters resulted in an increase in blood–brain barrier (BBB) permeability after 30 min, which returned to baseline 72 h later without causing any residual injury. UTMD application significantly increased the homing of intravenously delivered BMSC, resulting in a 2.2-fold increase in GFP-BMSC cell count on day 3 and a 2.6-fold increase on day 7 compared with intravenous delivery alone. This effect persisted for up to 6 weeks after injection. Intravenous BMSC delivery significantly reduced the volume of cerebral infarct and decreased cerebral edema, leading to a lower Longa score. Furthermore, this effect was further enhanced by UTMD. Acute cerebral infarction induced by MCAO led to elevated matrix metalloproteinase 8 (MMP8) levels in the cerebrospinal fluid, which were significantly reduced following UTMD-mediated BMSC treatment. Ultrasound-targeted microbubble destruction facilitates the migration and homing of BMSC into the brain, possibly by transiently increasing blood–brain barrier (BBB) permeability, thereby improving therapeutic outcomes in an ACI rat model. The observed effect may be partly attributed to modulation of MMP8 levels. Advances in knowledge: UTMD-mediated intravenously delivered BMSC transplantation led to a significant increase in cell homing and reduction of MMP8 levels, resulting in increased therapeutic effect in an acute ischemic cerebral infarction model.

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“…Some studies have shown that neurotropic viruses enter the CNS by breaching the BBB ( 31 , 32 ). One study showed that laboratory-attenuated rabies virus, which is the same neurotropic virus as JEV, enhances BBB permeability ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Live-attenuated Japanese encephalitis virus inhibits glioblastoma growth and elicits potent antitumor immunity

Zhao

et al. 2023

Front. Immunol.

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Glioblastomas (GBMs) are highly aggressive brain tumors that have developed resistance to currently available conventional therapies, including surgery, radiation, and systemic chemotherapy. In this study, we investigated the safety of a live attenuated Japanese encephalitis vaccine strain (JEV-LAV) virus as an oncolytic virus for intracerebral injection in mice. We infected different GBM cell lines with JEV-LAV to investigate whether it had growth inhibitory effects on GBM cell lines in vitro. We used two models for evaluating the effect of JEV-LAV on GBM growth in mice. We investigated the antitumor immune mechanism of JEV-LAV through flow cytometry and immunohistochemistry. We explored the possibility of combining JEV-LAV with PD-L1 blocking therapy. This work suggested that JEV-LAV had oncolytic activity against GBM tumor cells in vitro and inhibited their growth in vivo. Mechanistically, JEV-LAV increased CD8+ T cell infiltration into tumor tissues and remodeled the immunosuppressive GBM microenvironment that is non-conducive to immunotherapy. Consequently, the results of combining JEV-LAV with immune checkpoint inhibitors indicated that JEV-LAV therapy improved the response of aPD-L1 blockade therapy against GBM. The safety of intracerebrally injected JEV-LAV in animals further supported the clinical use of JEV-LAV for GBM treatment.

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Lab-Attenuated Rabies Virus Facilitates Opening of the Blood-Brain Barrier by Inducing Matrix Metallopeptidase 8

Abstract: The ability to change BBB permeability was associated with the pathogenicity of RABV. BBB permeability was enhanced by infection with lab-attenuated RABV instead of wt RABV, allowing immune cells to infiltrate into the CNS.

Cited by 7 publications

References 63 publications

Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism

Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism

Ultrasound-Targeted Microbubble Destruction Increases BBB Permeability and Promotes Stem Cell–Induced Regeneration of Stroke by Downregulating MMP8

Live-attenuated Japanese encephalitis virus inhibits glioblastoma growth and elicits potent antitumor immunity

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