Starvation after infection restricts enterovirus D68 replication

Jassey, Alagie; Wagner, Michael A.; Galitska, Ganna; Paudel, Bimal; Miller, Katelyn; Jackson, William T.

doi:10.1080/15548627.2022.2062888

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…TFEB cleavage during enteroviral infection could be significant for many reasons. First, even though EV-D68 and other enteroviruses are known to use components of autophagic signaling for their benefit, we have recently shown that stress-induced autophagy via amino acid starvation during infection (starvation after infection) impairs the infection of multiple enteroviruses, including EV-D68, CVB3, Rhinovirus-14, and Poliovirus (6). Recent unpublished data from our lab shows that TFEB regulates this stress-induced antiviral autophagy (Jassey et al manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

“…EV-D68 belongs to the Piconarviridae family of positive sense single-strand RNA viruses, with a genome size of about 7500 nucleotides, encoding a single polyprotein post-translationally processed to structural and nonstructural proteins (4). Like other enteroviruses, infection with EV-D68 leads to an extensive reconfiguration of cellular membranes, and double-membrane autophagosome-like vesicles, which support various phases of the viral life cycle, including genomic RNA replication and nonlytic release, can be observed late during EV-D68 infection (5, 6).…”

Section: Introductionmentioning

confidence: 99%

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Transcription factor EB (TFEB) interaction with RagC is disrupted during Enterovirus D68 Infection

Jassey,

Pollack,

Wagner

et al. 2024

Preprint

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Enterovirus D68 (EV-D68) is a picornavirus associated with severe respiratory illness and a paralytic disease called acute flaccid myelitis in infants. Currently, no protective vaccines or antivirals are available to combat this virus. Like other enteroviruses, EV-D68 uses components of the cellular autophagy pathway to rewire membranes for its replication. Here, we show that transcription factor EB (TFEB), the master transcriptional regulator of autophagy and lysosomal biogenesis, is essential for EV-D68 infection. Knockdown of TFEB attenuated EV-D68 genomic RNA replication but did not impact viral binding or entry into host cells. The 3C protease of EV-D68 cleaves TFEB at the N-terminus immediately post-peak viral RNA replication, disrupting TFEB-RagC interaction and restricting TFEB transport to the surface of the lysosome. Despite this, TFEB remained mostly cytosolic during EV-D68 infection. Overexpression of a TFEB mutant construct lacking the RagC binding domain, but not the wild-type construct, blocks autophagy and increases EV-D68 nonlytic release in H1HeLa cells, but not in autophagy defective ATG7 KO H1HeLa cells. Our results identify TFEB as a vital host factor regulating multiple stages of the EV-D68 lifecycle and suggest that TFEB could be a promising target for antiviral development against EV-D68.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcription factor EB (TFEB) interaction with RagC is disrupted during Enterovirus D68 Infection

Jassey,

Pollack,

Wagner

et al. 2024

Preprint

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“…This finding also recapitulates earlier studies showing that the Fermon strain does not infect neuronal cell lines (SH-SY5Y) or cause paralysis in mice ( 12 , 14 ) but differs from another study that demonstrated that Fermon infects human iPSC-derived cortical neuron and astrocyte cultures ( 16 ). It is unknown whether these differences are attributable to differences in cell type and receptor expression, viral multiplicity of infection (MOI), or availability of exosomes, as recent studies have suggested that EV-D68 may use exosomal association as a receptor-independent cell-entry mechanism ( 17 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…Human spinal cord tissue is infrequently available for study, as patients rarely expire during their acute illness, and the spinal cord cannot be safely biopsied. Prior human CNS models for EV-D68 infection include neuronal cell lines and induced pluripotent stem cell (iPSC)-derived neurons or astrocytes ( 14 - 18 ) as well as brain organoids ( 19 ). However, EV-D68 is not a pathogen that commonly causes encephalitis.…”

Section: Introductionmentioning

confidence: 99%

Contemporary enterovirus-D68 isolates infect human spinal cord organoids

Aguglia,

Coyne,

Dermody

et al. 2023

mBio

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Enterovirus D68 (EV-D68) is a nonpolio enterovirus associated with severe respiratory illness and acute flaccid myelitis (AFM), a polio-like illness causing paralysis in children. AFM outbreaks have been associated with increased circulation and genetic diversity of EV-D68 since 2014, although the virus was discovered in the 1960s. The mechanisms by which EV-D68 targets the central nervous system are unknown. Since enteroviruses are human pathogens that do not routinely infect other animal species, establishment of a human model of the central nervous system is essential for understanding pathogenesis. Here, we describe two human spinal cord organoid (hSCO)-based models for EV-D68 infection derived from induced, pluripotent stem cell (iPSC) lines. One hSCO model consists primarily of spinal motor neurons, while the another model comprises multiple neuronal cell lineages, including motor neurons, interneurons, and glial cells. These hSCOs can be productively infected with contemporary strains, but not a historic strain, of EV-D68 and produce extracellular virus for at least 2 weeks without appreciable cytopathic effect. By comparison, infection with hSCO with another enterovirus, echovirus 11, causes significant structural destruction and apoptosis. Together, these findings suggest that EV-D68 infection is not the sole mediator of neuronal cell death in the spinal cord in those with AFM and that secondary injury from the immune response likely contributes to pathogenesis. IMPORTANCE AFM is a rare condition that causes significant morbidity in affected children, often contributing to life-long sequelae. It is unknown how EV-D68 causes paralysis in children, and effective therapeutic and preventative strategies are not available. Mice are not native hosts for EV-D68, and thus, existing mouse models use immunosuppressed or neonatal mice, mouse-adapted viruses, or intracranial inoculations. To complement existing models, we report two hSCO models for EV-D68 infection. These three-dimensional, multicellular models comprised human cells and include multiple neural lineages, including motor neurons, interneurons, and glial cells. These new hSCO models for EV-D68 infection will contribute to understanding how EV-D68 damages the human spinal cord, which could lead to new therapeutic and prophylactic strategies for this virus.

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“…Although EV-D68 is known to induce autophagy and block the downstream autophagic maturation, how exactly EV-D68 infection causes autophagy and the specific viral protein(s) involved is not entirely understood (30, 31). Our finding that EV-D68 infection induces SIRT-1 translocation starting at 3 hpi, which coincides with the emergence of lipidated LC3, suggests that SIRT-1 may be essential for virus-induced changes in the autophagic pathway.…”

Section: Discussionmentioning

confidence: 99%

SIRT-1 is required for release of enveloped enteroviruses

Jassey

Logue

Weston

et al. 2022

Preprint

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Enterovirus D68 is a re-emerging enterovirus which causes acute respiratory illness in infants. EV-D68 infection has recently been associated with Acute Flaccid Myelitis, a severe polio-like neurological disease that causes limb weakness and loss of muscle tone in infants. There is currently no FDA-approved drug or prophylactic vaccine against EV-D68. Here, we investigated the role of the histone deacetylase, SIRT-1, in autophagy and EV-D68 infection. We show that SIRT-1 plays an important role in both autophagy and EV-D68 infection. siRNA-mediated knockdown of the cellular protein blocks basal and stress-induced autophagy and reduces EV-D68 extracellular viral titers. The proviral activity of SIRT-1 does not require deacetylase activity, since transient expression of both wild-type and deacetylase-inactive SIRT-1 mutant plasmids increased EV-D68 release. In non-lytic conditions, EV-D68 is primarily released in extracellular vesicles, and SIRT-1 is required for this process. Knockdown of SIRT-1 further impedes EV-D68 release in the autophagy-deficient ATG-7 knockout cells. Knockdown of SIRT-1 also decreases titers of poliovirus (PV) and SARS-CoV-2, but not Coxsackievirus-B3 (CVB3). CVB3 is the only tested virus that fails to induce SIRT-1 translocation to the cytosol. Our data suggest a correlation between SIRT-1 translocation during viral infection and extracellular vesicle-mediated non-lytic release of infectious viral particles.

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Starvation after infection restricts enterovirus D68 replication

Cited by 8 publications

References 36 publications

Transcription factor EB (TFEB) interaction with RagC is disrupted during Enterovirus D68 Infection

Transcription factor EB (TFEB) interaction with RagC is disrupted during Enterovirus D68 Infection

Contemporary enterovirus-D68 isolates infect human spinal cord organoids

SIRT-1 is required for release of enveloped enteroviruses

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