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Targeting ATP2B1 impairs PI3K/Akt/Forkhead box (Fox) transcription factor signaling and reduces SARS-COV-2 infection and replication.

ABSTRACT: De Antonellis et al. shows the importance of the Ca2+ channel pump ATP2B1 in the regulation of intracellular Ca2+ levels that positively influence SARS-CoV-2 replication in human cells. Our study identifies the mechanism of action of SARS-CoV-2 in the regulation of the expression of ATP2B1 and ATP2A1 loci during infection via FOXO3 transcriptional factor. Furthermore, a small caloxin-derivative molecule (compound PI-7) can inhibit ATP2B1 activity, thus resulting in SARSCoV- 2 impairment. In further support, we have identified a genetic variant within the noncoding upstream region of ATP2B1 in symptomatic patients affected by severe COVID19, thus indicating this polymorphism as a genetic predisposition factor to SARS-CoV-2 infection

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hek-293t Cell

SUBMITTER: Vittoria Monaco

LAB HEAD: Massimo Zollo

PROVIDER: PXD051059 | Pride | 2024-05-17

REPOSITORIES: Pride

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Project description:Objective: COVID19 is caused by the SARS-CoV-2 virus and has been associated with severe inflammation leading to organ dysfunction and mortality. Our aim was to profile the transcriptome in leukocytes from critically ill ICU patients positive for COVID19 vs. those negative for COVID19 to better understand the COVID19 associated host response. Design: Transcriptome profiling of buffy coat cells via ribonucleic acid sequencing (RNAseq) at the time of admission to the ICU. Setting: Tertiary care ICU and academic laboratory. Subjects: All patients admitted to the ICU suspected of being infected with SARS-CoV-2, using standardized hospital screening methodologies, had blood samples collected at the time of admission to the ICU. Interventions: None. Measurement and Main Results: Age- and sex-matched ICU patients that were either COVID19+ (PCR positive, 2 genes) or COVID19- (PCR negative) were enrolled. Cohorts were well-balanced with the exception that COVID19- patients had significantly higher total white blood cell counts and circulating neutrophils and COVID19+ patients were more likely to suffer bilateral pneumonia compared to COVID19- patients. Further, the mortality rate for this cohort of COVID19+ ICU patients was 29%. Transcriptional analysis revealed that when compared to COVID19- patients, the altered transcriptional responses of leukocytes in critically ill COVID19+ ICU patients appeared to be associated with multiple interrelated outcomes, including but not limited to robust interferon (IFN)-associated transcriptional responses, a marked decrease in the transcriptional activity of genes contributing to protein synthesis and the dysregulated expression of genes that contribute to coagulation, platelet activation, Toll-like receptor activation, neurotrophin signaling, and protein SUMOylation/ubiquitination. Conclusions: COVID19+ patients on day 1 of admission to the ICU display a unique leukocyte transcriptional profile that distinguishes them from COVID19- patients. Identification of this profile provides guidance for future targeted studies exploring novel prognostic/therapeutic aspects of COVID19.

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Targeting ATP2B1 impairs PI3K/Akt/Forkhead box (Fox) transcription factor signaling and reduces SARS-COV-2 infection and replication.

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