Roles of antiviral sensing and type I interferon signaling in the restriction of SARS-CoV-2 replication

Geerling, Elizabeth; Pinski, Amanda N.; Stone, E. Taylor; DiPaolo, Richard J.; Zulu, Michael Z.; Maroney, Kevin J.; Brien, James D.; Messaoudi, Ilhem; Pinto, Amelia K.

doi:10.1016/j.isci.2021.103553

Cited by 5 publications

(5 citation statements)

References 77 publications

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“…Tissue homogenates were prepared for analyses of either viral burden, cytokine mRNA, or lipids. SARS-CoV-2 viral burden was measured by focus forming assays (FFAs) using Vero E6 cells transfected with hACE2 and TMPRSS2 as we have previously described ( Geerling et al, 2022 ). Inflammatory cytokine levels were measured via qRT-PCR using Taqman primer and probe sets from IDT as previously described ( Geerling et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Plasmalogen Loss in Sepsis and SARS-CoV-2 Infection

Pike

McGuffee

Geerling

et al. 2022

Front. Cell Dev. Biol.

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Plasmalogens are plasma-borne antioxidant phospholipid species that provide protection as cellular lipid components during cellular oxidative stress. In this study we investigated plasma plasmalogen levels in human sepsis as well as in rodent models of infection. In humans, levels of multiple plasmenylethanolamine molecular species were decreased in septic patient plasma compared to control subject plasma as well as an age-aligned control subject cohort. Additionally, lysoplasmenylcholine levels were significantly decreased in septic patients compared to the control cohorts. In contrast, plasma diacyl phosphatidylethanolamine and phosphatidylcholine levels were elevated in septic patients. Lipid changes were also determined in rats subjected to cecal slurry sepsis. Plasma plasmenylcholine, plasmenylethanolamine, and lysoplasmenylcholine levels were decreased while diacyl phosphatidylethanolamine levels were increased in septic rats compared to control treated rats. Kidney levels of lysoplasmenylcholine as well as plasmenylethanolamine molecular species were decreased in septic rats. Interestingly, liver plasmenylcholine and plasmenylethanolamine levels were increased in septic rats. Since COVID-19 is associated with sepsis-like acute respiratory distress syndrome and oxidative stress, plasmalogen levels were also determined in a mouse model of COVID-19 (intranasal inoculation of K18 mice with SARS-CoV-2). 3 days following infection, lung infection was confirmed as well as cytokine expression in the lung. Multiple molecular species of lung plasmenylcholine and plasmenylethanolamine were decreased in infected mice. In contrast, the predominant lung phospholipid, dipalmitoyl phosphatidylcholine, was not decreased following SARS-CoV-2 infection. Additionally total plasmenylcholine levels were decreased in the plasma of SARS-CoV-2 infected mice. Collectively, these data demonstrate the loss of plasmalogens during both sepsis and SARS-CoV-2 infection. This study also indicates plasma plasmalogens should be considered in future studies as biomarkers of infection and as prognostic indicators for sepsis and COVID-19 outcomes.

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Section: Methodsmentioning

confidence: 99%

Plasmalogen Loss in Sepsis and SARS-CoV-2 Infection

Pike

McGuffee

Geerling

et al. 2022

Front. Cell Dev. Biol.

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“…The support for PRKCE in anosmia is based on its involvement in neuronal signaling, its high expression levels in the OB, the involvement of various members of the protein kinase C (PKC) family in signaling triggered by SARS-CoV-2 infection 21 , and increased expression of PKC members in a cell line resistant to viral infection 22 .…”

Section: Discussionmentioning

confidence: 99%

Phenotype-driven identification of drug targets for post-COVID-19 anosmia

Catterson¹,

Sánchez²,

Musso³

2022

Preprint

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Anosmia (loss of sense of smell) is one symptom of COVID-19 which can linger long after acute infection has passed, with major impact on quality of life. Given the number of people impacted by COVID-19-related anosmia, there is an urgent need to identify effective therapeutics in a faster fashion than using traditional drug discovery and development methods. We used our knowledge graph, the Phenograph, to navigate from phenotypes to genes to drug targets, to rapidly find druggable targets associated with anosmia. This process shortlisted six targets: NRP1, SCN9A, EGR1, VEGFB, PRKCE, and FGFR1. Neuropilin-1 (NRP1) is under active study for its involvement in SARS-CoV-2 infection. Importantly, there is no direct link between anosmia and NRP1 in our knowledge graph; the relationship was inferred through the graph structure. Based on this external validation, we derived hypotheses for the involvement of the remaining five targets in COVID-19-related anosmia, and the mechanism of action desired in a drug candidate to correct the hypothesized dysregulation.

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“…The human lung epithelial cell line A549 (wild-type), and A549 knockouts (KO) for Toll-like receptor 3 (TLR3-KO), mitochondrial antiviral signaling protein (MAVS-KO), RNA-dependent protein kinase R (PKR-KO), and RNase L (RL6-KO) cells were culture in F12K medium supplemented with 5% fetal bovine serum (FBS), 100 IU/mL penicillin and 100 mg/mL streptomycin at 37 °C in humidified atmosphere with 5% CO2 ( Li et al., 2016 ; Geerling et al., 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional response to VZV infection is modulated by RNA polymerase III in lung epithelial cell lines

Doratt

Vance

Malherbe

et al. 2022

Front. Cell. Infect. Microbiol.

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Ancestral RNA polymerase III (Pol III) is a multi-subunit polymerase responsible for transcription of short non-coding RNA, such as double-stranded short interspersed nuclear elements (SINEs). Although SINE ncRNAs are generally transcriptionally repressed, they can be induced in response to viral infections and can stimulate immune signaling pathways. Indeed, mutations in RNA Pol III have been associated with poor antiviral interferon response following infection with varicella zoster virus (VZV). In this study, we probed the role of Pol III transcripts in the detection and initial immune response to VZV by characterizing the transcriptional response following VZV infection of wild type A549 lung epithelial cells as well as A549 cells lacking specific RNA sensors MAVS and TLR3, or interferon-stimulated genes RNase L and PKR in presence or absence of functional RNA Pol III. Multiple components of the antiviral sensing and interferon signaling pathways were involved in restricting VZV replication in lung epithelial cells thus suggesting an innate defense system with built-in redundancy. In addition, RNA Pol III silencing altered the antiviral transcriptional program indicating that it plays an essential role in the sensing of VZV infection.

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Roles of antiviral sensing and type I interferon signaling in the restriction of SARS-CoV-2 replication

Cited by 5 publications

References 77 publications

Plasmalogen Loss in Sepsis and SARS-CoV-2 Infection

Plasmalogen Loss in Sepsis and SARS-CoV-2 Infection

Phenotype-driven identification of drug targets for post-COVID-19 anosmia

Transcriptional response to VZV infection is modulated by RNA polymerase III in lung epithelial cell lines

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