Induction of Atypical Autophagy by Porcine Hemagglutinating Encephalomyelitis Virus Contributes to Viral Replication

Ding, Ning; Zhao, Kui; Lan, Yungang; Li, Zi; Liu, Xiaoling; Su, Juanjuan; Lu, Huijun; Gao, Feng; He, Wenqi

doi:10.3389/fcimb.2017.00056

Cited by 30 publications

(25 citation statements)

References 38 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most coronaviruses enter their target cells via plasma membrane fusion, a further entry mechanism is the endosomal acidic pH-dependent endocytosis [48]. Once the virus is internalized, only then does the fusion of virus with lysosomes depend on a low endosomal and lysosomal pH [49]. Following this, the S glycoprotein is cleaved into S1 and S2 subunits by endosomal proteases cathepsin B/L, with the resulting S2 subunit-mediating membrane fusion [50].…”

Section: Inhibition Of Cathepsin B/lmentioning

confidence: 99%

Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Depfenhart

Villiers²,

Lemperle

et al. 2020

Intern Emerg Med

View full text Add to dashboard Cite

Of huge importance now is to provide a fast, cost-effective, safe, and immediately available pharmaceutical solution to curb the rapid global spread of SARS-CoV-2. Recent publications on SARS-CoV-2 have brought attention to the possible benefit of chloroquine in the treatment of patients infected by SARS-CoV-2. Whether chloroquine can treat SARS-CoV-2 alone and also work as a prophylactic is doubtful. An effective prophylactic medication to prevent viral entry has to contain, at least, either a protease inhibitor or a competitive virus ACE2-binding inhibitor. Using bromhexine at a dosage that selectively inhibits TMPRSS2 and, in so doing, inhibits TMPRSS2-specific viral entry is likely to be effective against SARS-CoV-2. We propose the use of bromhexine as a prophylactic and treatment. We encourage the scientific community to assess bromhexine clinically as a prophylactic and curative treatment. If proven to be effective, this would allow a rapid, accessible, and cost-effective application worldwide.

show abstract

Section: Inhibition Of Cathepsin B/lmentioning

confidence: 99%

Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Depfenhart

Villiers²,

Lemperle

et al. 2020

Intern Emerg Med

View full text Add to dashboard Cite

show abstract

“…Porcine hemagglutinating encephalomyelitis virus (PHEV), a member of the Coronaviridae family, is a highly neurovirulent virus that spreads to the central nervous system via peripheral nerves ( 7 ). Pig is the natural host of PHEV, but the virus has been adapted to replicate in mouse and mouse neuroblastoma N2a cells (N2a cells) ( 8 ). PHEV infection induces neurite damage and neuronal death, which may be the cause of neurological symptoms ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Porcine Hemagglutinating Encephalomyelitis Virus Activation of the Integrin α5β1-FAK-Cofilin Pathway Causes Cytoskeletal Rearrangement To Promote Its Invasion of N2a Cells

Liu

Guan

et al. 2019

J Virol

Self Cite

View full text Add to dashboard Cite

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic virus that causes diffuse neuronal infection with neurological damage and high mortality. Virus-induced cytoskeletal dynamics are thought to be closely related to this type of nerve damage. Currently, the regulation pattern of the actin cytoskeleton and its molecular mechanism remain unclear when PHEV enters the host cells. Here, we demonstrate that entry of PHEV into N2a cells induces a biphasic remodeling of the actin cytoskeleton and a dynamic change in cofilin activity. Viral entry is affected by the disruption of actin kinetics or alteration of cofilin activity. PHEV binds to integrin ␣5␤1 and then initiates the integrin ␣5␤1-FAK signaling pathway, leading to virus-induced early cofilin phosphorylation and F-actin polymerization. Additionally, Ras-related C3 botulinum toxin substrate 1 (Rac1), cell division cycle 42 (Cdc42), and downstream regulatory gene p21-activated protein kinases (PAKs) are recruited as downstream mediators of PHEV-induced dynamic changes of the cofilin activity pathway. In conclusion, we demonstrate that PHEV utilizes the integrin ␣5␤1-FAK-Rac1/Cdc42-PAK-LIMK-cofilin pathway to cause an actin cytoskeletal rearrangement to promote its own invasion, providing theoretical support for the development of PHEV pathogenic mechanisms and new antiviral targets. IMPORTANCE PHEV, a member of the Coronaviridae family, is a typical neurotropic virus that primarily affects the nervous system of piglets to produce typical neurological symptoms. However, the mechanism of nerve damage caused by the virus has not been fully elucidated. Actin is an important component of the cytoskeleton of eukaryotic cells and serves as the first obstacle to the entry of pathogens into host cells. Additionally, the morphological structure and function of nerve cells depend on the dynamic regulation of the actin skeleton. Therefore, exploring the mechanism of neuronal injury induced by PHEV from the perspective of the actin cytoskeleton not only helps elucidate the pathogenesis of PHEV but also provides a theoretical basis for the search for new antiviral targets. This is the first report to define a mechanistic link between alterations in signaling from cytoskeleton pathways and the mechanism of PHEV invading nerve cells.

show abstract

“…We found that PHEV localized to the lysosomes and resulted in enlarged lysosomes (Fig 1a). Indeed, PHEV infection resulted in increased LAMP1 expression levels in vitro [19] and increased lysosome enlargement in vivo (Additional file 1). These results showed that PHEV infection leads directly to lysosomal dysfunction and indicated that there was a similarly pathological feature between PHE and several neurodegenerative diseases.…”

Section: Resultsmentioning

confidence: 99%

An Experimental Model of Neurodegenerative Disease Based on Porcine Hemagglutinating Encephalomyelitis Virus–Related Lysosomal Abnormalities

Lan

Wang

et al. 2020

Mol Neurobiol

Self Cite

View full text Add to dashboard Cite

Lysosomes are involved in pathogenesis of a variety of neurodegenerative diseases and play a large role in neurodegenerative disorders caused by virus infection. However, whether virus-infected cells or animals can be used as experimental models of neurodegeneration in humans based on virus-related lysosomal dysfunction remain unclear. Porcine hemagglutinating encephalomyelitis virus displays neurotropism in mice, and neural cells are its targets for viral progression. PHEV infection was confirmed to be a risk factor for neurodegenerative diseases in the present. The findings demonstrated for the first time that PHEV infection can lead to lysosome disorders and showed that the specific mechanism of lysosome dysfunction is related to PGRN expression deficiency and indicated similar pathogenesis compared with human neurodegenerative diseases upon PHEV infection. Trehalose can also increase progranulin expression and rescue abnormalities in lysosomal structure in PHEV-infected cells. In conclusion, these results suggest that PHEV probably serve as a disease model for studying the pathogenic mechanisms and prevention of other degenerative diseases.

show abstract

Induction of Atypical Autophagy by Porcine Hemagglutinating Encephalomyelitis Virus Contributes to Viral Replication

Cited by 30 publications

References 38 publications

Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Porcine Hemagglutinating Encephalomyelitis Virus Activation of the Integrin α5β1-FAK-Cofilin Pathway Causes Cytoskeletal Rearrangement To Promote Its Invasion of N2a Cells

An Experimental Model of Neurodegenerative Disease Based on Porcine Hemagglutinating Encephalomyelitis Virus–Related Lysosomal Abnormalities

Contact Info

Product

Resources

About