ARF6 is a host factor for SARS-CoV-2 infection in vitro

Mirabelli, Carmen; Cunha, Juliana Bragazzi; Wotring, Jesse W; Sherman, Eric J.; Saghir, Jamal El; Harder, Jennifer L.; Kretzler, Matthias; Sexton, Jonathan Z.; Emmer, Brian T.; Wobus, Christiane E.

doi:10.1099/jgv.0.001868

Cited by 8 publications

(4 citation statements)

References 23 publications

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“…Other genes are involved in cell processes that are hijacked by the virus during infection. For example, ARF6 was identified as involved in exocytosis, but is used by the virus to infiltrate and infect the cell [114]. Overall, the findings of our functional analysis highlight some key mechanisms involved in the viral response to COVID-19.…”

Section: Pathway Enrichment Analysesmentioning

confidence: 81%

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

Waman,

Ashford,

Lam

et al. 2023

Preprint

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The COVID-19 disease is an ongoing global health concern. Although vaccination provides some protection, people are still susceptible to re-infection. Ostensibly, certain populations or clinical groups may be more vulnerable. Factors causing these differences are unclear and whilst socioeconomic and cultural differences are likely to be important, human genetic factors could influence susceptibility. Experimental studies indicate SARS-CoV-2 uses innate immune suppression as a strategy to speed-up entry and replication into the host cell. Therefore, it is necessary to understand the impact of variants in immunity-associated human proteins on susceptibility to COVID-19.In this work, we analysed missense coding variants in several SARS-CoV-2 proteins and its human protein interactors that could enhance binding affinity to SARS-CoV-2. We curated a dataset of 19 SARS-CoV-2: human protein 3D-complexes, from the experimentally determined structures in the Protein Data Bank and models built using AlphaFold2-multimer, and analysed impact of missense variants occurring in the protein-protein interface region. We analysed 468 missense variants from human proteins and 212 variants from SARS-CoV-2 proteins and computationally predicted their impacts on binding affinities to SARS-CoV-2 proteins, using 3D-complexes.We predicted a total of 26 affinity-enhancing variants from 14 human proteins implicated in increased binding affinity to SARS-CoV-2. These include key-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, RAE1, AXL, ARF6, TRIMM, TRIM25) as well as important spike receptors (KREMEN1, AXL and ACE2). We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss their likely structural and functional impact, using information on known and predicted functional sites. Potential mechanisms associated with immune suppression implicated by these variants are discussed.Occurrence of certain predicted affinity-enhancing variants should be monitored as they could lead to increased susceptibility and reduced immune response to SARS-CoV-2 infection in individuals/populations carrying them. Our analyses aid in understanding the potential impact of genetic variation in immunity-associated proteins on COVID-19 susceptibility and help guide drug-repurposing strategies.

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Section: Pathway Enrichment Analysesmentioning

confidence: 81%

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

Waman,

Ashford,

Lam

et al. 2023

Preprint

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“…The 16 variants on chromosome 8 mapped in intronic regions of the PSD3 gene, also known as EFA6R , a member of the family of guanine nucleotide exchange factors, that activate ADP-ribosylation factor 6 (ARF6) 37 . This protein is involved in endocytosis, and it has been reported to play a role in SARS-CoV-2 cell entry 38 , 39 . So far, it has not yet been reported any role of PSD3 variants in the regulation of ARF6 activation.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

Minnai,

Biscarini,

Esposito

et al. 2024

Sci Rep

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The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10−8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10−8). A total of 113 variants were associated with survival at P-value < 1.0 × 10−5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways.

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“…At 14 days post-transduction, a total of ~40 million cells in four T175 flasks at approximately 50% density were infected with SARS-CoV-2 WA1 strain in 10 mL infection media (DMEM with 2% FBS). The amount of virus for each infection was calculated to correspond to an MOI of 1.0 based on titering in Vero E6 cells; the proportion of SARS-CoV-2-infected cells at 48 h was also assessed by immunofluorescence of SARS-CoV-2 nucleocapsid protein, as previously described ( 91 , 92 ). Two days post-infection, with the incursion of visual cytopathic effect, 15 mL of maintenance media (DMEM with 10% FBS) was added.…”

Section: Methodsmentioning

confidence: 99%

Type I interferon signaling induces a delayed antiproliferative response in respiratory epithelial cells during SARS-CoV-2 infection

Bragazzi Cunha,

Leix,

Sherman

et al. 2023

J Virol

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Disease progression during SARS-CoV-2 infection is tightly linked to the fate of lung epithelial cells, with severe cases of COVID-19 characterized by direct injury of the alveolar epithelium and an impairment in its regeneration from progenitor cells. The molecular pathways that govern respiratory epithelial cell death and proliferation during SARS-CoV-2 infection, however, remain unclear. We now report a high-throughput CRISPR screen for host genetic modifiers of the survival and proliferation of SARS-CoV-2-infected Calu-3 respiratory epithelial cells. The top four genes identified in our screen encode components of the same type I interferon (IFN-I) signaling complex —IFNAR1 , IFNAR2 , JAK1 , and TYK2 . The fifth gene, ACE2 , was an expected control encoding the SARS-CoV-2 viral receptor. Surprisingly, despite the antiviral properties of IFN-I signaling, its disruption in our screen was associated with an increase in Calu-3 cell fitness. We validated this effect and found that IFN-I signaling did not sensitize SARS-CoV-2-infected cultures to cell death but rather inhibited the proliferation of surviving cells after the early peak of viral replication and cytopathic effect. We also found that IFN-I signaling alone, in the absence of viral infection, was sufficient to induce this delayed antiproliferative response in both Calu-3 cells and iPSC-derived type 2 alveolar epithelial cells. Together, these findings highlight a cell autonomous antiproliferative response by respiratory epithelial cells to persistent IFN-I signaling during SARS-CoV-2 infection. This response may contribute to the deficient alveolar regeneration that has been associated with COVID-19 lung injury and represents a promising area for host-targeted therapeutic development. IMPORTANCE The proliferation of respiratory epithelial cells is crucial to host recovery from acute lung injury caused by SARS-CoV-2 and other viral pathogens, but the molecular pathways that govern this process are poorly understood. We performed a high-throughput CRISPR screen that surprisingly revealed a detrimental effect of specific host response, type I interferon (IFN-I) signaling, on the fitness of SARS-CoV-2-infected Calu-3 cells. While IFN-I signaling has been previously associated with several potential downstream responses, we found this effect to be primarily mediated by an inhibition of Calu-3 cellular proliferation after the early peak of SARS-CoV-2-induced cell death. Our findings provide a plausible mechanism for how sustained IFN-I signaling during SARS-CoV-2 infection might worsen lung pathology by blocking the regeneration of the alveolar epithelium from progenitor cells.

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ARF6 is a host factor for SARS-CoV-2 infection in vitro

Cited by 8 publications

References 23 publications

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

Type I interferon signaling induces a delayed antiproliferative response in respiratory epithelial cells during SARS-CoV-2 infection

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