ABSTRACT
ATP2B1 is a known regulator of calcium (Ca2+) cellular export and homeostasis. Diminished levels of extra- or intra-cellular Ca2+ content have been suggested to block SARS-CoV-2 replication. Here, we demonstrate that a newly nontoxic caloxin-derivative compound (PI-7) inhibits ATP2B1, reduces the extra- and intra-cellular Ca2+ levels and impairs SARS-CoV-2 replication and propagation (VOCs: Delta and Omicron 2), as also measured by inhibition of syncytia in vitro. Furthermore, a FOXO3 transcriptional site of regulation of expression at the 5 end of the ATP2B1 locus, together with a rare homozygous intronic variant in the ATP2B1 locus (rs11337717; chr12:89643729, T>C), are shown to be associated with severity of COVID19 (symptomatic versus asymptomatic patients). Here, we identify the mechanism of action during SARS-CoV-2 infection, which involves the PI3K/Akt signaling pathway, inactivation of FOXO3 (i.e., phosphorylation), and inhibition of transcriptional control of both membrane and reticulum Ca2+ pumps (ATP2B1 and ATP2A1 [i.e., SERCA1], respectively). The pharmacological action of compound PI-7 on sustaining both ATP2B1 and ATP2A1 expression reduces the intracellular cytoplasmic Ca2+ pool and thus negatively influences SARS-CoV-2 replication and propagation. As compound PI-7 shows a lack of toxicity, its prophylactic use as a therapy against the COVID19 pandemic is here proposed. In briefDe Antonellis et al. shows the importance of the Ca2+ channel pump ATP2B1 in the regulation of extracellular and 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 SARS-CoV-2 impairment. In further support, we have identified a genetic variant within the noncoding upstream region of ATP2B1 in symtomatic patients affected by severe COVID19, thus indicating this polymorphism as a genetic predisposition factor to SARS-CoV-2 infection. HighlightsO_LIAn anti-viral model of network of action for ATP2B1 against SARS-CoV-2 at the intracellular level that involves the PI3K/Akt signaling pathway, inactivation (i.e., phosphorylation) of FOXO3 and its transcriptional control, and inhibition of both membrane and reticulum Ca2+ pumps (i.e., ATP2B1, ATP2A1, respectively). C_LIO_LIA new drug and its lack of toxicity "compound PI-7", thus envisioning both preventive and therapeutic applications in patients with COVID-19. C_LIO_LIThe specificity of action in the context of Ca2+ homeostasis is one of the strategies that coronaviruses (including SARS-CoV-2 and any new VOC, including Omicron 2) use to infect host cells and promote organ dysfunction. C_LIO_LITherapeutic applications for compound PI-7 against all other viruses belonging to the Coronoviridae family (e.g., SARS-CoV, MERS-CoV), and against the main families of positive sense ssRNA viruses from other hosts (e.g., Nidovirales), as these are all Ca2+ dependent. C_LIO_LIIdentification of a rare homozygous intronic variant in the ATP2B1 locus (rs11337717; chr12:89643729, T>C) that is associated with severity of COVID19 (i.e., symptomatic versus asymptomatic patients). This variant can be used as a marker to identify those patients that might show severe COVID19 following their SARS-COV-2 infection. C_LI
ABSTRACT
The COVID-19 disease, caused by the SARS-Cov-2, presents a heterogeneous clinical spectrum. The risk factors do not fully explain the wide spectrum of disease manifestations, so it is possible that genetic factors could account for novel insights into its pathogenesis. In our previous study, we hypothesized that common variants on chromosome 21, near TMPRSS2 and MX1 genes, may be genetic risk factors associated to the different clinical manifestations of COVID-19. Here, we performed an in-depth genetic analysis of chromosome 21 exploiting the genome-wide association study data including 6,406 individuals hospitalized for COVID-19 and 902,088 controls with European genetic ancestry from COVID-19 Host Genetics Initiative. We found that five single nucleotide polymorphisms (SNPs) within TMPRSS2 and near MX1 gene show suggestive associations (P[≤]1x10-5) with severe COVID-19. All five SNPs replicated the association in two independent cohorts of Asian subjects while two and one out of the 5 SNPs replicated in African and Italian populations, respectively (P[≤]0.05). The minor alleles of these five SNPs correlated with a reduced risk of developing severe COVID-19 and increased level of MX1 expression in blood. Our findings provide further evidence that host genetic factors can contribute to determine the different clinical presentations of COVID-19 and that MX1, an antiviral effector of type I and III interferon pathway, may be a potential therapeutic target.
ABSTRACT
The infection coronavirus disease 2019 (COVID-19) is caused by a virus classified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At cellular level, virus infection initiates with binding of viral particles to the host surface cellular receptor angiotensin converting enzyme 2 (ACE2). SARS-CoV-2 engages ACE2 as the entry receptor and employs the cellular serine protease 2 (TMPRSS2) for S protein priming. TMPRSS2 activity is essential for viral spread and pathogenesis in the infected host. Understanding how TMPRSS2 protein expression in the lung varies in the population could reveal important insights into differential susceptibility to influenza and coronavirus infections. Here, we systematically analyzed coding-region variants in TMPRSS2 and the eQTL variants, which may affect the gene expression, to compare the genomic characteristics of TMPRSS2 among different populations. Our findings suggest that the lung-specific eQTL variants may confer different susceptibility or response to SARS-CoV-2 infection from different populations under the similar conditions. In particular, we found that the eQTL variant rs35074065 is associated with high expression of TMPRSS2 but with a low expression of the interferon (IFN)-/{beta}-inducible gene, MX1, splicing isoform. Thus, these subjects could account for a more susceptibility either to viral infection or to a decrease in cellular antiviral response.
