Activation of cGAS/STING pathway upon paramyxovirus infection

Iampietro, Mathieu; Dumont, Claire; Mathieu, Cyrille; Spanier, Julia; Robert, Jonathan; Charpenay, Aude; Dupichaud, Sébastien; Dhondt, Kévin P.; Aurine, Noémie; Pelissier, Rodolphe; Ferren, Marion; Mély, Stéphane; Gerlier, Denis; Kalinke, Ulrich; Horvat, Branka

doi:10.1016/j.isci.2021.102519

Cited by 29 publications

(21 citation statements)

References 87 publications

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“…Although the role of cGAS-STING in sensing of DNA viruses is clearly elucidated, many RNA viruses of families Flaviviridae and Coronaviridae have been shown to be restricted by a cGAS and/or STING signaling, and on the other side, the RNA viral proteins can function as antagonists of cGAS-STING pathway, which has been summarized in review [35]. More recent evidence showed that the cGAS-STING pathway is involved in sensing and subjected to evasion of other RNA viruses including murine norovirus (MNV) of family Caliciviridae [36], nipah virus (NiV), and measles virus (MeV) of family Paramyxovirdae [26], chikungunya virus of family Togaviridae [37]. Here, we add one more RNA virus-PRRSV of family Arteriviridae to the list.…”

Section: Discussionmentioning

confidence: 99%

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The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function

Zhang

Luo

et al. 2021

Viruses

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Porcine reproductive and respiratory syndrome virus (PRRSV) modulates host innate immunity which plays a key role against PRRSV infection. As a RNA virus, PRRSV is mainly sensed by innate immune RNA receptors, whereas the role of innate immune DNA sensors in the PRRSV infection has not been elucidated. Here, we investigated the roles of DNA sensing cGAS-STING pathway in both PRRSV infected Marc-145 cells and porcine macrophages. The results show that in Marc-145 cells, the stable expression of STING with or without stimulations exhibited anti-PRRSV activity, and STING knockout heightened PRRSV infection. In CD163-3D4/21 porcine macrophages, either expression of STING or stimulation of cGAS-STING signaling obviously suppressed PRRSV infection, whereas in STING knockdown macrophages, the PRRSV infection was upregulated. Our results clearly demonstrate that the host cGAS-STING signal exerts an important antiviral role in PRRSV infection.

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Section: Discussionmentioning

confidence: 99%

“…Then, 2 3 -cGAMP, as a second message, activates the signaling adaptor STING to induce antiviral IFN response. However, accumulated evidence shows that cGAS-STING pathway harbors a broad range antiviral function [26,27]. The DNA pathway during PPRSV infection has not been investigated and its role remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function

Zhang

Luo

et al. 2021

Viruses

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“…Therefore, RLR-MAVS seems have a central role in the sensing of, and defense against, PRRSV infection. The CDR cGAS-STING pathway is mainly involved in sensing DNA viruses, but it is also shown to sense RNA infection to supplement RNA sensors during RNA infections [39,40]. Here our results demonstrate that expression of STING and agonist stimulations induced intermediate anti-PRRSV activity, whereas knockdown of STING enhanced PRRSV replication.…”

Section: Discussionmentioning

confidence: 52%

Screening of Porcine Innate Immune Adaptor Signaling Revealed Several Anti-PRRSV Signaling Pathways

Zhang

et al. 2021

Vaccines

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Porcine reproductive and respiratory syndrome virus (PRRSV) causes PRRS and is known to effectively suppress host innate immunity. The current strategies for controlling PRRSV are limited and complete understanding of anti-PRRSV innate immunity is needed. Here, we utilized nine porcine innate immune signaling adaptors which represent all currently known innate immune receptor signaling pathways for screening of anti-PRRSV activity. The analysis of PRRSV N gene transcription and protein expression both suggested that the multiple ectopic adaptors exhibited varying degrees of anti-PRRSV activities, with TRIF and MAVS most effective. To better quantify the PRRSV replication, the GFP signal of PRRSV from reverse genetics were measured by flow cytometry and similarly varying anti-PRRSV activities by different signaling adaptors were observed. Based on the screening data, and considering the importance of viral nucleic acid in innate immune response, endogenous TRIF, MAVS and STING were selected for further examination of anti-PRRSV activity. Agonist stimulation assay showed that MAVS and STING signaling possessed significant anti-PRRSV activities, whereas siRNA knockdown assay showed that TRIF, MAVS and STING are all involved in anti-PRRSV activity, with TLR3-TRIF displaying discrepancy in anti-PRRSV infection. Nevertheless, our work suggests that multiple pattern recognition receptor (PRR) signaling pathways are involved in anti-PRRSV innate immunity, which may have implications for the development of future antiviral strategies.

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“…Early studies of cGAS focused on its classical function in regulating innate immunity. Activation of this signaling pathway plays an important role in the host response to infection by multiple types of pathogens, including viruses [ 51 , 52 ], bacteria including Mycobacterium tuberculosis [ 53 ], Listeria monocytogenes [ 54 ], and Neisseria gonorrhoeae [ 55 ], as well as parasites [ 22 – 27 ], which is largely dependent on STING. However, the novel functions of cGAS beyond sensing DNA and innate immunity have been extensively revealed in last decade.…”

Section: Discussionmentioning

confidence: 99%

cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner

Liang

Shen

et al. 2022

PLoS Pathog

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Schistosomiasis, which is caused by infection with Schistosoma spp., is characterized by granuloma and fibrosis in response to egg deposition. Pattern recognition receptors are important to sense invading Schistosoma, triggering an innate immune response, and subsequently shaping adaptive immunity. Cyclic GMP-AMP synthase (cGAS) was identified as a major cytosolic DNA sensor, which catalyzes the formation of cyclic GMP-AMP (cGAMP), a critical second messenger for the activation of the adaptor protein stimulator of interferon genes (STING). The engagement of STING by cGAMP leads to the activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and the subsequent type I interferon (IFN) response. cGAS is suggested to regulate infectious diseases, autoimmune diseases, and cancer. However, the function of cGAS in helminth infection is unclear. In this study, we found that Cgas deficiency enhanced the survival of mice infected with S. japonicum markedly, without affecting the egg load in the liver. Consistently, Cgas deletion alleviated liver pathological impairment, reduced egg granuloma formation, and decreased fibrosis severity. In contrast, Sting deletion reduced the formation of egg granulomas markedly, but not liver fibrosis. Notably, Cgas or Sting deficiency reduced the production of IFNβ drastically in mice infected with S. japonicum. Intriguingly, intravenous administration of recombinant IFNβ exacerbated liver damage and promoted egg granuloma formation, without affecting liver fibrosis. Clodronate liposome-mediated depletion of macrophages indicated that macrophages are the major type of cells contributing to the induction of the type I IFN response during schistosome infection. Moreover, cGAS is important for type I IFN production and phosphorylation of TBK1 and IRF3 in response to stimulation with S. japonicum egg- or adult worm-derived DNA in macrophages. Our results clarified the immunomodulatory effect of cGAS in the regulation of liver granuloma formation during S. japonicum infection, involving sensing schistosome-derived DNA and producing type I IFN. Additionally, we showed that cGAS regulates liver fibrosis in a STING-type I–IFN-independent manner.

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Activation of cGAS/STING pathway upon paramyxovirus infection

Cited by 29 publications

References 87 publications

The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function

The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function

Screening of Porcine Innate Immune Adaptor Signaling Revealed Several Anti-PRRSV Signaling Pathways

cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner

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