Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5

Solà-Riera, Carles; Gupta, Shawon; Maleki, Kimia T.; González-Rodríguez, Patricia; Saidi, Dalel; Zimmer, C.; Vangeti, Sindhu; Rivino, Laura; Leo, Yee‐Sin; Lye, David C.; MacAry, Paul A.; Ahlm, Clas; Smed‐Sörensen, Anna; Joseph, Bertrand; Björkström, Niklas K.; Ljunggren, Hans‐Gustaf; Klingström, Jonas

doi:10.1016/j.celrep.2019.07.066

Cited by 28 publications

(20 citation statements)

References 54 publications

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“…TNF-related apoptosis-inducing ligand (TRAIL)-death receptor 5 (DR5) signaling through TNFSF10–TNFRSF10B will activate IKK–JNK–MEK–MK2 in many nontransformed cells 100 . The multiplex kinase-activity fluctuations are consistent with the hypothesis that autocrine TRAIL-DR5 signaling is asynchronously downregulated in cardiomyocytes during CVB3 infection, as just reported for another single-stranded RNA virus 101 .…”

Section: Discussionsupporting

confidence: 89%

An ultrasensitive fiveplex activity assay for cellular kinases

Smolko

Janes

2019

Sci Rep

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Protein kinases are enzymes whose abundance, protein-protein interactions, and posttranslational modifications together determine net signaling activity in cells. Large-scale data on cellular kinase activity are limited, because existing assays are cumbersome, poorly sensitive, low throughput, and restricted to measuring one kinase at a time. Here, we surmount the conventional hurdles of activity measurement with a multiplexing approach that leverages the selectivity of individual kinase-substrate pairs. We demonstrate proof of concept by designing an assay that jointly measures activity of five pleiotropic signaling kinases: Akt, IκB kinase (IKK), c-jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK)-extracellular regulated kinase kinase (MEK), and MAPK-activated protein kinase-2 (MK2). The assay operates in a 96-well format and specifically measures endogenous kinase activation with coefficients of variation less than 20%. Multiplex tracking of kinase-substrate pairs reduces input requirements by 25-fold, with ~75 µg of cellular extract sufficient for fiveplex activity profiling. We applied the assay to monitor kinase signaling during coxsackievirus B3 infection of two different host-cell types and identified multiple differences in pathway dynamics and coordination that warrant future study. Because the Akt–IKK–JNK–MEK–MK2 pathways regulate many important cellular functions, the fiveplex assay should find applications in inflammation, environmental-stress, and cancer research.

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Section: Discussionsupporting

confidence: 89%

An ultrasensitive fiveplex activity assay for cellular kinases

Smolko

Janes

2019

Sci Rep

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“…Clinical evidence has shown that HTNV infection is related to the upregulation of sTRAIL in HFRS patients (34,42). We document that HTNV infection leads to an increase of TRAIL expression in HUVECs, and TRAIL exhibits striking antiviral activities by inducing apoptosis in vitro.…”

Section: Discussionmentioning

confidence: 62%

HTNV Sensitizes Host Toward TRAIL-Mediated Apoptosis—A Pivotal Anti-hantaviral Role of TRAIL

et al. 2020

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“…Moreover, HTNV has also been shown to inhibit the extrinsic pathway of apoptosis through the downregulation of dead receptor 5, in a TRAIL-mediated mechanism activated by cytotoxic granules. 79 Despite the viral strategies to avoid the innate immune system, in the late stages of infection type I IFN Hantaviruses infect endothelial cells, monocytes and macrophages without cytopathic effect but producing an endothelial disruption. The detection of virions activates the immune response, with the primary production of cytokines from innate immune cells such as types I and III IFNs, IL-1b, TNF, IL-6 and IL-15, and chemokines such as CCL5 and CXCL10, among others.…”

Section: Hantavirus Recognition By Innate Immunitymentioning

confidence: 99%

“…78,84 Despite significant TRAIL upregulation in infected ECs and NK cells, HTNV-infected cells are protected by TRAIL-mediated killing, as previously discussed. 79 Moreover, inhibition of cell-mediated apoptosis has been observed in pathogenic and non-pathogenic hantaviruses, associated with NP-driven inhibition of granzyme B and caspase-3. 86 Those events would explain why infected ECs are not damaged despite strong cytotoxic lymphocyte activation in patients, according to the authors.…”

Section: Natural Killer Cellsmentioning

confidence: 99%

Immune response during hantavirus diseases: implications for immunotherapies and vaccine design

et al. 2021

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Orthohantaviruses, previously named hantaviruses, cause two emerging zoonotic diseases: haemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Overall, over 200 000 cases are registered every year worldwide, with a fatality rate ranging between 0Á1% and 15% for HFRS and between 20% and 40% for HCPS. No specific treatment or vaccines have been approved by the U.S. Food and Drug Administration (FDA) to treat or prevent hantavirus-caused syndromes. Currently, little is known about the mechanisms at the basis of hantavirus-induced disease. However, it has been hypothesized that an excessive inflammatory response plays an essential role in the course of the disease. Furthermore, the contributions of the cellular immune response to either viral clearance or pathology have not been fully elucidated. This article discusses recent findings relative to the immune responses elicited to hantaviruses in subjects suffering HFRS or HCPS, highlighting the similarities and differences between these two clinical diseases. Also, we summarize the most recent data about the cellular immune response that could be important for designing new vaccines to prevent this global public health problem.

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Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5

Cited by 28 publications

References 54 publications

An ultrasensitive fiveplex activity assay for cellular kinases

An ultrasensitive fiveplex activity assay for cellular kinases

HTNV Sensitizes Host Toward TRAIL-Mediated Apoptosis—A Pivotal Anti-hantaviral Role of TRAIL

Immune response during hantavirus diseases: implications for immunotherapies and vaccine design

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