CD24 Expression Dampens the Basal Antiviral State in Human Neuroblastoma Cells and Enhances Permissivity to Zika Virus Infection

Kedarinath, Kritika; Fox, Candace; Crowgey, Erin L.; Mazar, Joseph; Phelan, Peter E.; Westmoreland, Tamarah; Alexander, Kenneth A.; Parks, Griffith D.

doi:10.3390/v14081735

Cited by 9 publications

(9 citation statements)

References 69 publications

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“…11 The resistance of the paediatric SK-N-AS cell line is governed by CD24 expression, which regulates the basal antiviral state of these cells. 13,37 Whilst LA-N-6 shows partial resistance to ZIKV infection (Table 1), analysis of bulk mRNA and protein show cell LA-N-6 to express CD24. 13 Potential reasoning for this partial resistance is that subpopulations within LA-N-6 may be CD24or a CD24-independent mechanism may be employed to infer resistance.…”

Section: Resultsmentioning

confidence: 99%

Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based oncolytic therapy in neuroblastoma

Sherwood,

Zhou,

Sui

et al. 2024

F1000Res

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Background Paediatric neuroblastoma and brain tumours account for a third of all childhood cancer-related mortality. High-risk neuroblastoma is highly aggressive and survival is poor despite intensive multi-modal therapies with significant toxicity. Novel therapies are desperately needed. The Zika virus (ZIKV) can access the nervous system and there is growing interest in employing ZIKV as a potential therapy against paediatric nervous system tumours, including neuroblastoma. Methods Here, we perform extensive data mining, integration and re-analysis of ZIKV infection datasets to highlight molecular mechanisms that may govern the oncolytic response in neuroblastoma cells. We collate infection data of multiple neuroblastoma cell lines by different ZIKV strains from a body of published literature to inform the susceptibility of neuroblastoma to the ZIKV oncolytic response. Integrating published transcriptomics, interaction proteomics, dependency factor and compound datasets we propose the involvement of multiple host systems during ZIKV infection. Results Through data mining of published literature, we observed most paediatric neuroblastoma cell lines to be highly susceptible to ZIKV infection and propose the PRVABC59 ZIKV strain to be the most promising candidate for neuroblastoma oncolytic virotherapy. ZIKV induces TNF signalling, lipid metabolism, the Unfolded Protein Response (UPR), and downregulates cell cycle and DNA replication processes. ZIKV infection is dependent on sterol regulatory element binding protein (SREBP)-regulated lipid metabolism and three protein complexes; V-ATPase, ER Membrane Protein Complex (EMC) and mammalian translocon. We propose ZIKV non-structural protein 4B (NS4B) as a likely mediator of ZIKVs interaction with IRE1-mediated UPR, lipid metabolism and mammalian translocon. Conclusions Our work provides a significant understanding of ZIKV infection in neuroblastoma cells, which will facilitate the progression of ZIKV-based oncolytic virotherapy through pre-clinical research and clinical trials.

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Section: Resultsmentioning

confidence: 99%

Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based oncolytic therapy in neuroblastoma

Sherwood,

Zhou,

Sui

et al. 2024

F1000Res

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“…The non-sympathetic nervous system and non-paediatric origin of the T-268 and JFEN cells likely explain their resistance to ZIKV infection, as ZIKV has a tropism for paediatric nervous system cancer cells. The resistance of the paediatric SK-N-AS cell line is governed by CD24 expression, which regulates the basal antiviral state of these cells (13, 19). In conclusion, our analysis demonstrates that ZIKV is a strong candidate to employ against paediatric neuroblastoma as oncolytic virotherapy.…”

Section: Resultsmentioning

confidence: 99%

Integrative transcriptomic and proteomic meta-analysis of Zika viral infection reveals potential mechanisms for oncolytic therapy in neuroblastoma

Sherwood

Zhou

Sui

et al. 2022

Preprint

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BACKGROUND: Paediatric neuroblastoma and brain tumours account for a third of all childhood cancer-related mortality. High-risk neuroblastoma is highly aggressive and survival is poor despite intensive multi-modal therapies with significant toxicity. Novel therapies are desperately needed. The Zika virus (ZIKV) is neurotropic and there is growing interest in employing ZIKV as a potential therapy against paediatric nervous system tumours, including neuroblastoma. METHODS: Here, we perform an extensive meta-analysis of ZIKV infection studies to identify molecular mechanisms that may govern the oncolytic response in neuroblastoma cells. We summarise the neuroblastoma cell lines and ZIKV strains utilised and re-evaluate the infection data to deduce the susceptibility of neuroblastoma to the ZIKV oncolytic response. Integrating transcriptomics, interaction proteomics, dependency factor and compound datasets we show the involvement of multiple host systems during ZIKV infection. RESULTS: We identify that most paediatric neuroblastoma cell lines are highly susceptible to ZIKV infection and that the PRVABC59 ZIKV strain is the most promising candidate for neuroblastoma oncolytic virotherapy. ZIKV induces TNF signalling, lipid metabolism, the Unfolded Protein Response (UPR), and downregulates cell cycle and DNA replication processes. ZIKV is dependent on SREBP-regulated lipid metabolism and three protein complexes; V-ATPase, ER Membrane Protein Complex (EMC) and mammalian translocon. We propose ZIKV nonstructural protein 4B (NS4B) as a likely mediator of ZIKVs interaction with IRE1-mediated UPR, lipid metabolism and mammalian translocon. CONCLUSIONS: Our work provides a significant understanding of ZIKV infection in neuroblastoma cells, which will facilitate the progression of ZIKV-based oncolytic virotherapy through pre-clinical research and clinical trials.

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“…Lazear and colleagues indicated that WT C57BL/6 mice exhibited no morbidity or mortality due to ZIKV infection, whereas Ifnar1 − / − mice that could not respond to IFNα/β were highly vulnerable to ZIKV infection, losing weight by day 5, and beginning to succumb by day 7 ( 64 ). Furthermore, changes in intracellular antiviral pathways were observed by Kedarinath and colleagues after the modulation of CD24 in neuroblastoma cells in vitro ( 49 ). Together, these data suggest that CD24 may promote an immunomodulatory role in the tumor, presenting a possible explanation for the profound differences observed between tumor and host outcomes in vivo .…”

Section: Discussionmentioning

confidence: 99%

The Oncolytic Activity of Zika Viral Therapy in Human Neuroblastoma In Vivo Models Confers a Major Survival Advantage in a CD24-dependent Manner

Mazar,

Brooks,

Peloquin

et al. 2024

Cancer Research Communications

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Neuroblastoma is the most common extracranial tumor, accounting for 15% of all childhood cancer-related deaths. The long-term survival of patients with high-risk tumors is less than 40%, and MYCN amplification is one of the most common indicators of poor outcomes. Zika virus (ZIKV) is a mosquito-borne flavivirus associated with mild constitutional symptoms outside the fetal period. Our published data showed that high-risk and recurrent neuroblastoma cells are permissive to ZIKV infection, resulting in cell type–specific lysis. In this study, we assessed the efficacy of ZIKV as an oncolytic treatment for high-risk neuroblastoma using in vivo tumor models. Utilizing both MYCN-amplified and non-amplified models, we demonstrated that the application of ZIKV had a rapid tumoricidal effect. This led to a nearly total loss of the tumor mass without evidence of recurrence, offering a robust survival advantage to the host. Detection of the viral NS1 protein within the tumors confirmed that a permissive infection preceded tissue necrosis. Despite robust titers within the tumor, viral shedding to the host was poor and diminished rapidly, correlating with no detectable side effects to the murine host. Assessments from both primary pretreatment and recurrent posttreatment isolates confirmed that permissive sensitivity to ZIKV killing was dependent on the expression of CD24, which was highly expressed in neuroblastomas and conferred a proliferative advantage to tumor growth. Exploiting this viral sensitivity to CD24 offers the possibility of its use as a prognostic target for a broad population of expressing cancers, many of which have shown resistance to current clinical therapies. Significance: Sensitivity to the tumoricidal effect of ZIKV on high-risk neuroblastoma tumors is dependent on CD24 expression, offering a prognostic marker for this oncolytic therapy in an extensive array of CD24-expressing cancers.

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CD24 Expression Dampens the Basal Antiviral State in Human Neuroblastoma Cells and Enhances Permissivity to Zika Virus Infection

Cited by 9 publications

References 69 publications

Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based oncolytic therapy in neuroblastoma

Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based oncolytic therapy in neuroblastoma

Integrative transcriptomic and proteomic meta-analysis of Zika viral infection reveals potential mechanisms for oncolytic therapy in neuroblastoma

The Oncolytic Activity of Zika Viral Therapy in Human Neuroblastoma In Vivo Models Confers a Major Survival Advantage in a CD24-dependent Manner

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