JC Polyomavirus Infection of Primary Human Renal Epithelial Cells Is Controlled by a Type I IFN-Induced Response

Assetta, Benedetta; Cecco, Marco De; O’Hara, Bethany A.; Atwood, Walter J.

doi:10.1128/mbio.00903-16

Cited by 43 publications

(40 citation statements)

References 97 publications

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“…Other studies reported that BKPyV infection of RPTECs can occur without induction of innate immune sensors by as yet unknown mechanisms (Abend et al, 2010;An et al, 2019;de Kort et al, 2017). However, these studies failed to reveal inhibition of BKPyV replication by type-1 interferons, which is in contrast to our results for BKPyV shown here and those recently reported for JCPyV (Assetta et al, 2016).…”

Section: Innate Immune Sensors Have Been Characterized In Primary Humcontrasting

confidence: 99%

BK polyomavirus evades innate immune sensing by disrupting the mitochondrial network and membrane potential and by promoting mitophagy

Manzetti

Weissbach

Unterstab

et al. 2020

Preprint

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Immune escape contributes to viral persistence, yet little is known about human polyomaviruses. BK-polyomavirus (BKPyV) asymptomatically infects 90% of the human population, but causes early allograft failure in 10% of kidney transplants. Despite inducing potent virus-specific T-cells and neutralizing antibodies, BKPyV persists in the kidneys and regularly escapes from immune control as indicated by urinary shedding in immunocompetent individuals. Here, we report that BKPyV disrupts the mitochondrial network and its membrane potential when expressing the 66aa-long agnoprotein during late replication. Agnoprotein impairs nuclear IRF3-translocation, interferon-β expression, and promotes p62-mitophagy in vitro and in kidney transplant biopsies. Agnoprotein-mutant viruses unable to disrupt mitochondria show reduced replication, which can be rescued by type-I-interferon-blockade, TBK1-inhibition, or CoCl 2 treatment. Agnoprotein is necessary and sufficient, using its amino-terminal and central domain for mitochondrial targeting and disruption, respectively. JCPyV-and SV40-infection similarly disrupt the mitochondrial network indicating a conserved mechanism facilitating polyomavirus persistence and posttransplant disease.

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Section: Innate Immune Sensors Have Been Characterized In Primary Humcontrasting

confidence: 99%

BK polyomavirus evades innate immune sensing by disrupting the mitochondrial network and membrane potential and by promoting mitophagy

Manzetti

Weissbach

Unterstab

et al. 2020

Preprint

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“…All cells were grown in a humidified incubator at 37°C with 5% CO 2 . SVG-A cells, RPTECs (70), and HEK293A-5-HT 2A R cells (19) were generously provided by the Atwood laboratory (Brown University) and authenticated by the ATCC.…”

Section: Discussionmentioning

confidence: 99%

ERK Is a Critical Regulator of JC Polyomavirus Infection

DuShane

Wilczek

Mayberry

et al. 2018

J Virol

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The human JC polyomavirus (JCPyV) infects the majority of the population worldwide and presents as an asymptomatic, persistent infection in the kidneys. In individuals who are immunocompromised, JCPyV can become reactivated and cause a lytic infection in the central nervous system resulting in the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). Infection is initiated by interactions between the capsid protein viral protein 1 (VP1) and the α2,6-linked sialic acid on lactoseries tetrasaccharide c (LSTc), while JCPyV internalization is facilitated by 5-hydroxytryptamine 2 receptors (5-HTRs). The mechanisms by which the serotonin receptors mediate virus entry and the signaling cascades required to drive viral infection remain poorly understood. JCPyV was previously shown to induce phosphorylation of extracellular signal-regulated kinase (ERK), a downstream target of the mitogen-activated protein kinase (MAPK) pathway, upon virus entry. However, it remained unclear whether ERK activation was required for JCPyV infection. Both ERK-specific small interfering RNA (siRNA) and ERK inhibitor treatments resulted in significantly diminished JCPyV infection in both kidney and glial cells yet had no effect on the infectivity of the polyomavirus simian virus 40 (SV40). Experiments characterizing the role of ERK during steps in the viral life cycle indicate that ERK activation is required for viral transcription, as demonstrated by a significant reduction in production of large T antigen (TAg), a key viral protein associated with the initiation of viral transcription and viral replication. These findings delineate the role of the MAPK-ERK signaling pathway in JCPyV infection, elucidating how the virus reprograms the host cell to promote viral pathogenesis. Viral infection is dependent upon host cell factors, including the activation of cellular signaling pathways. These interactions between viruses and host cells are necessary for infection and play an important role in viral disease outcomes. The focus of this study was to determine how the human JC polyomavirus (JCPyV), a virus that resides in the kidney of the majority of the population and can cause the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brains of immunosuppressed individuals, usurps a cellular signaling pathway to promote its own infectious life cycle. We demonstrated that the activation of extracellular signal-regulated kinase (ERK), a component of the mitogen-activated protein kinase (MAPK) pathway, promotes JCPyV transcription, which is required for viral infection. Our findings demonstrate that the MAPK-ERK signaling pathway is a key determinant of JCPyV infection, elucidating new information regarding the signal reprogramming of host cells by a pathogenic virus.

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“…A list of candidate immune function genes was curated from the following main sources: genome-wide study of rare copy number variants in 70 PML cases (Dis cohort) that impact immune function genes (data not shown), genes from the ClinVar database (43) using search terms "immune deficiency" and "immunodeficiency, " IUIS and other immunodeficiency reviews (29,30,(44)(45)(46)(47)(48)(49)(50), type I interferon pathway genes (51)(52)(53)(54)(55)(56)(57)(58), complement pathway genes (59), and JCV or PML linked biology (23,26,33,(60)(61)(62)(63)(64). The full list of 711 unique genes were cross-checked against genes that were found with DV-called variants in the Dis and/or Rep cohorts.…”

Section: Immune Function Genesmentioning

confidence: 99%