Identification and characterization of the role of c-terminal Src kinase in dengue virus replication

Kumar, Rinki; Agrawal, Tanvi; Khan, Naseem Ahmed; Nakayama, Yuji; Medigeshi, Guruprasad R.

doi:10.1038/srep30490

Cited by 27 publications

(38 citation statements)

References 50 publications

(65 reference statements)

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“…Interestingly, the IR has recently been shown to be required for DENV replication in mammalian cells (Kumar et al, 2016). The decrease in both abundance and phosphorylation levels of IR in Wolbachia-positive mosquito cells might contribute to the block of DENV and ZIKV replication in Wolbachia-infected mosquitoes (Caragata et al, 2016).…”

Section: The Ir Plays An Important Role In Virus Replication In Mosqumentioning

confidence: 99%

A Role for the Insulin Receptor in the Suppression of Dengue Virus and Zika Virus in Wolbachia-Infected Mosquito Cells

et al. 2019

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Section: The Ir Plays An Important Role In Virus Replication In Mosqumentioning

confidence: 99%

A Role for the Insulin Receptor in the Suppression of Dengue Virus and Zika Virus in Wolbachia-Infected Mosquito Cells

et al. 2019

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“…Viruses often hijack host cellular signaling pathways to facilitate their infection and replication. Several pathways, such as the MAPK, PKA, and AMPK pathways, have been reported to play important roles in flavivirus replication (35)(36)(37)(38)(39). To determine if these pathways are essential for ZIKV infection, HUVEC were first preincubated with either an inhibitor or an agonist of a corresponding signaling pathway and then infected with ZIKV in the presence of the chemical compound.…”

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confidence: 99%

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

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The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application.IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV strains tested with minimal cytotoxicity to human endothelial cells and astrocytes, two key cell types for ZIKV infection. Furthermore, we show that PKI inhibits ZIKV negative-sense RNA synthesis and viral protein translation. This study has identified a potent inhibitor of ZIKV infection which could be further explored for future therapeutic application.

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“…Two of these RTKs (Axl and Tyro3) are members of the Tyro3-Axl-Mer (TAM) family, and seven [erythropoietin-producing hepatocellular receptor A2 (EphA2), epidermal growth factor receptor (EGFR), avian erythroblastosis oncogene B (ErbB2), fibroblast growth factor receptor 1 (FGFR1), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR; also known as c-Met), and tropomyosin receptor kinase C (TrkC)] are members of the growth factor receptor (GFR) family. A 10th RTK, the insulin receptor, is an outlier that plays a role in the replication of dengue and Zika viruses (DENV and ZIKV) in cells of both the human host and the mosquito vector (10,11); in both cases, the underlying mechanisms remain to be elucidated.…”

Section: Crucial Roles Of Rtks In the Life Cycle Of Intracellular Patmentioning

confidence: 99%

Targeting of host cell receptor tyrosine kinases by intracellular pathogens

Haqshenas

Doerig

2019

Sci. Signal.

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Intracellular pathogens use complex and tightly regulated processes to enter host cells. Upon initial interactions with signaling proteins at the surface of target cells, intracellular microbes activate and co-opt specific host signaling pathways that mediate cell surface-cytosol communications to facilitate pathogen internalization. Here, we discuss the roles of host receptor tyrosine kinases (RTKs) in the establishment of productive infections by major intracellular pathogens. We evaluate the gaps in the current understanding of this process and propose a comprehensive approach for assessing the role of host cell signaling in the biology of intracellular microorganisms and viruses. We also discuss RTK-targeting strategies for the treatment of various infections.

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Identification and characterization of the role of c-terminal Src kinase in dengue virus replication

Cited by 27 publications

References 50 publications

A Role for the Insulin Receptor in the Suppression of Dengue Virus and Zika Virus in Wolbachia-Infected Mosquito Cells

A Role for the Insulin Receptor in the Suppression of Dengue Virus and Zika Virus in Wolbachia-Infected Mosquito Cells

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Targeting of host cell receptor tyrosine kinases by intracellular pathogens

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