Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier

Faist, Aileen; Schloer, Sebastian; Mecate-Zambrano, Angeles; Janowski, Josua; Schreiber, André; Boergeling, Yvonne; Conrad, Beate Claudine Gisela; Kumar, Sriram; Toebben, Leonie; Schughart, Klaus; Baumgardt, Morris; Kessler, Mirjana; Hoenzke, Katja; Hocke, Andreas C.; Trautmann, Marcel; Hartmann, Wolfgang; Kato, Hiroki; Rescher, Ursula; Christersson, Anmari; Kuehn, Joachim; Mellmann, Alexander; Wolff, Thorsten; Kuempers, Philip; Rovas, Alexandros; Wiewrodt, Rainer; Wiebe, Karsten; Barth, Peter; Ludwig, Stephan; Brunotte, Linda

doi:10.1016/j.antiviral.2022.105475

Cited by 16 publications

(14 citation statements)

References 51 publications

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“…ERK pathway was reported to be a potential target for antiviral strategy of SARS-CoV-2 [41][42][43]. IAV escapes from antiviral innate immunity by activating ERK signaling [35].…”

Section: Discussionmentioning

confidence: 99%

The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection

Ning

Chiu

et al. 2023

IJMS

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The clinical benefits of targeting programmed death-ligand 1 (PD-L1) in various cancers represent a strategy for the treatment of immunosuppressive diseases. Here, it was demonstrated that the expression levels of PD-L1 in cells were greatly upregulated in response to H1N1 influenza A virus (IAV) infection. Overexpression of PD-L1 promoted viral replication and downregulated type-I and type-III interferons and interferon-stimulated genes. Moreover, the association between PD-L1 and Src homology region-2, containing protein tyrosine phosphatase (SHP2), during IAV/H1N1 infection was analyzed by employing the SHP2 inhibitor (SHP099), siSHP2, and pNL-SHP2. The results showed that the expressions of PD-L1 mRNA and protein were decreased under SHP099 or siSHP2 treatment, whereas the cells overexpressing SHP2 exhibited the opposite effects. Additionally, the effects of PD-L1 on the expression of p-ERK and p-SHP2 were investigated in PD-L1-overexpressed cells following WSN or PR8 infection, determining that the PD-L1 overexpression led to the decreased expression of p-SHP2 and p-ERK induced by WSN or PR8 infection. Taken together, these data reveal that PD-L1 could play an important role in immunosuppression during IAV/H1N1 infection; thus, it may serve as a promising therapeutic target for development of novel anti-IAV drugs.

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“…ERK pathway was reported to be a potential target for antiviral strategy of SARS-CoV-2 [41][42][43]. IAV escapes from antiviral innate immunity by activating ERK signaling [35].…”

Section: Discussionmentioning

confidence: 99%

The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection

Ning

Chiu

et al. 2023

IJMS

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“…S638 phosphorylation inhibits the GYF:PRS-mediated interactions between GIGYF1 and RBPs such as TTP and ZNF598 (Nordgaard et al, 2021). Importantly, both p38 and JNK kinases have been implicated in the host antiviral response (Faist et al, 2023; Mikkelsen et al, 2009; Wang et al, 2019). Conversely, excessive activation of p38 can lead to cytokine storm and tissue damage (Boccuni et al, 2022; Faist et al, 2023) and pharmacological inhibition of p38 has been shown to suppress the expression of pro-inflammatory cytokines, including IFN-β, in cells infected with SARS-CoV-2 (Faist et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, both p38 and JNK kinases have been implicated in the host antiviral response (Faist et al, 2023; Mikkelsen et al, 2009; Wang et al, 2019). Conversely, excessive activation of p38 can lead to cytokine storm and tissue damage (Boccuni et al, 2022; Faist et al, 2023) and pharmacological inhibition of p38 has been shown to suppress the expression of pro-inflammatory cytokines, including IFN-β, in cells infected with SARS-CoV-2 (Faist et al, 2023). Thus, it is plausible that under resting conditions, the RBP/GIGYF1/eIF3 axis maintains mRNAs that encode the pro-inflammatory cytokines such as IFN-β in a translationally repressed state.…”

Section: Discussionmentioning

confidence: 99%

“…The GYF domain in the mid-region of GIGYF1/2, adopts a structurally conserved fold shared among a variety of proteins across diverse eukaryotic species. The GYF domain mediates interactions with proline-rich sequences (PRS) (Freund et al, 1999), allowing GIGYF1/2 to engage with several RBPs that possess one or more proline-rich sequences, including Tristetraprolin (TTP), ZNF598, and the TNRC6(A, B, C) proteins that are among the core components of the microRNA-Induced Silencing Complex (miRISC). Thereby, through interactions with these RBPs, GIGYF1/2 can be recruited to specific mRNAs.…”

Section: Introductionmentioning

confidence: 99%

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Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction

Choi,

Luo,

Hesketh

et al. 2023

Preprint

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Viruses commonly interfere with the function of the eukaryotic translation initiation factor 4G1 (eIF4G1), a pivotal factor in the recruitment of the eIF3 complex and ribosome to the mRNA. This results in the inhibition of general host protein synthesis and redirecting ribosomes toward viral mRNAs. Certain viruses also selectively repress the translation of mRNAs involved in the host antiviral response. GIGYF2 and its interacting cap-binding protein 4EHP enable the transcript-specific repression of mRNA translation mediated by microRNAs and RNA-binding proteins (RBPs). RNA viruses, such as SARS-CoV-2, exploit the GIGYF2/4EHP complex to selectively repress the translation of transcripts such as Ifnb1 mRNA, which encodes the antiviral cytokine Interferon β (IFN-β). Herein, we reveal that GIGYF1, a paralogue of GIGYF2, robustly represses cellular mRNA translation through a distinct mechanism independent of 4EHP. Upon recruitment to a target mRNA by RBPs, the C-terminal region of GIGYF1 binds to subunits of eIF3 at the interaction interface of eIF3-eIF4G1. This disrupts the recruitment of eIF3 to the mRNA by eIF4G1, resulting in mRNA-specific translational repression. This mechanism exerts profound influences on the host cell's response to viral infection. Depletion of GIGYF1 induces a robust immune response by derepressing Ifnb1 mRNA translation. Overall, our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism can be utilized by RBPs that interact with GIGYF1 to specifically repress the translation of their target mRNAs, significantly affecting critical biological processes, including host-pathogen interactions.

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“…The SARS-CoV virus causes p38 MAPK phosphorylation in infected cells, thereby activating physiological intracellular signaling cascades (221). Spike-mediated entry of SARS-CoV-2 triggers activation of p38 MAPK, occurring within the first 15-75 min after viral infection (222). SARS-CoV-2 directly upregulates p38 MAPK genes, rewiring host cell phosphorylations in 97 of 518 human kinases.…”

Section: P38 Map Kinase (P38 Mapk) Regulation Of Proinflammatory Cyto...mentioning

confidence: 99%

A review of cytokine-based pathophysiology of Long COVID symptoms

Low¹,

Low

Akrami

2023

Front. Med.

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The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with “brain fog,” arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

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Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier

Cited by 16 publications

References 51 publications

The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection

The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection

Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction

A review of cytokine-based pathophysiology of Long COVID symptoms

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