Inhibition of Autophagy Suppresses SARS-CoV-2 Replication and Ameliorates Pneumonia in hACE2 Transgenic Mice and Xenografted Human Lung Tissues

Shang, Chao; Zhuang, Xinyu; Zhang, He; Li, Yiquan; Zhu, Yan; Lü, Jing; Ge, Chenchen; Cong, Jianan; Li, Tingyu; Li, Nan; Tian, Mingyao; Jin, Ningyi; Li, Xiao

doi:10.1128/jvi.01537-21

Cited by 41 publications

(46 citation statements)

References 50 publications

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“…The SARS-CoV-2 strain BetaCoV/Beijing/IME-BJ01/2020 was originally isolated by CFQ’s laboratory as described previously ( Gordon et al, 2020 ; Shang et al, 2021a , b ). SARS-CoV-2 stocks were propagated and titered on Vero E6 cells.…”

Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment

et al. 2022

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Mitochondria, which is essential for adequate innate immune response, energy metabolism and mitochondria reactive oxygen species (ROS) production, might be in the cross fire of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host cell defense. However, little is known about interactions between mitochondria and SARS-CoV-2. We performed fluorescent microscopy and found an enrichment of SARS-CoV-2 replication products double stranded RNA (dsRNA) within mitochondria. The entry process of dsRNA might be mediated by Tom20 as observed by reduced mitochondrial localization of SARS-CoV-2 dsRNA in Tom20 knockdown cells. Importantly, decreased mitochondrial localization of dsRNA, as well as mitochondrial membrane stabilizers mdivi-1 and cyclosporin A, inhibited viral load in cells. Next, we detected mitochondrial dysfunction caused by SARS-CoV-2 infection, including mitochondrial membrane depolarization, mitochondrial permeability transition pore opening and increased ROS release. In response to mitochondrial damage, we observed an increase in expression and mitochondrial accumulation of Pink1 and Parkin proteins, as well as Pink-1-mediated recruitment of P62 to mitochondria, suggesting initiated mitophagy for mitochondrial quality control and virus clearance. Nevertheless, we observed that mitophagy was inhibited and stayed in early stage with an unchanged Hsp60 expression post SARS-CoV-2 infection. This might be one of the anti-autophagy strategies of SARS-CoV-2 and we used co-immunoprecipitation to found that SARS-CoV-2 infection inhibited P62 and LC3 binding which plays a critical role in selective envelopment of substrates into autophagosomes. Our results suggest that mitochondria are closely involved in SARS-CoV-2 replication and mitochondrial homeostasis is disrupted by SARS-CoV-2 in the virus-cell confrontation.

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Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment

et al. 2022

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“…The SARS-CoV-2 strain BetaCoV/Beijing/IME-BJ01/2020 (Beijing, China) was originally isolated, as previously described [ 41 ]. Virus stocks were propagated and tittered on African green monkey kidney (Vero E6) cells.…”

Section: Methodsmentioning

confidence: 99%

Antiviral Properties of Silver Nanoparticles against SARS-CoV-2: Effects of Surface Coating and Particle Size

Lü

Liu

et al. 2022

Nanomaterials

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Coronavirus disease 2019 (COVID-19) has spread rapidly and led to over 5 million deaths to date globally. Due to the successively emerging mutant strains, therapeutics and prevention against the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are urgently needed. Prevention of SARS-CoV-2 infection in public and hospital areas is essential to reduce the frequency of infections. Silver nanoparticles (AgNPs) with virucidal effects have been reported. Therefore, we investigated the virucidal activity and safety of ten types of AgNPs with different surface modifications and particle sizes, in cells exposed to SARS-CoV-2 in vitro. The AgNPs could effectively inhibit the activity of SARS-CoV-2, and different surface modifications and particle sizes conferred different virucidal effects, of which 50-nm BPEI showed the strongest antiviral effect. We concluded that the efficacy of each type of AgNP type was positively correlated with the corresponding potential difference (R2 = 0.82). These in vitro experimental data provide scientific support for the development of therapeutics against COVID-19, as well as a research basis for the development of broad-spectrum virucides. Given the increasing acquired resistance of pathogens against conventional chemical and antibody-based drugs, AgNPs may well be a possible solution for cutting off the route of transmission, either as an external material or a potential medicine.

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“…Overall, γ 1 34.5 was able to inhibit the translational shutoff imposed during SARS-CoV-2 infection and which resulted in a decrease in virus replication and progeny virus production. During SARS-CoV-2 infection autophagy appears to supplement the viral membrane factories with membranes and metabolites required for virus replication (76)(77)(78). While γ 1 34.5 is known to interfere with autophagy by binding to Beclin-1, we observed that co-expression of γ 1 34.5 protein with E did not reduce, but rather enhanced LC3 lipidation (Figure 2D).…”

Section: Sars-cov-2 E Homologs and E Oligomerization Mutants Trigger ...mentioning

confidence: 85%

SARS-CoV-2 harnesses host translational shutoff and autophagy to optimize virus yields: The role of the envelope (E) protein

Waisner

Grieshaber

Saud

et al. 2022

Preprint

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The SARS-CoV-2 virion is composed of four structural proteins: spike (S), nucleocapsid (N), membrane (M), and envelope (E). E spans the membrane a single time and is the smallest, yet most enigmatic of the structural proteins. E is conserved among coronaviruses and has an essential role in virus-mediated pathogenesis. We found that ectopic expression of E had deleterious effects on the host cell as it activated stress responses, leading to phosphorylation of the translation initiation factor eIF2α and LC3 lipidation that resulted in host translational shutoff. During infection E is highly expressed although only a small fraction is incorporated into virions, suggesting that E activity is regulated and harnessed by the virus to its benefit. In support of this, we found that the γ1 34.5 protein of herpes simplex virus 1 (HSV-1) prevented deleterious effects of E on the host cell and allowed for E protein accumulation. This observation prompted us to investigate whether other SARS-CoV-2 structural proteins regulate E. We found that the N and M proteins enabled E protein accumulation, whereas S prevented E accumulation. While γ1 34.5 protein prevented deleterious effects of E on the host cells, it had a negative effect on SARS-CoV-2 replication. This negative effect of γ1 34.5 was most likely associated with failure of SARS-CoV-2 to divert the translational machinery and with deregulation of autophagy pathways. Overall, our data suggest that SARS-CoV-2 causes stress responses and subjugates these pathways, including host protein synthesis (phosphorylated eIF2α) and autophagy, to support optimal virus production.

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Inhibition of Autophagy Suppresses SARS-CoV-2 Replication and Ameliorates Pneumonia in hACE2 Transgenic Mice and Xenografted Human Lung Tissues

Cited by 41 publications

References 50 publications

SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment

SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment

Antiviral Properties of Silver Nanoparticles against SARS-CoV-2: Effects of Surface Coating and Particle Size

SARS-CoV-2 harnesses host translational shutoff and autophagy to optimize virus yields: The role of the envelope (E) protein

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