Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

Targhetta, Vitor Pedro; Amaral, Mariana Abrantes do; Câmara, Niels Olsen Saraiva

doi:10.1590/1678-9199-jvatitd-2020-0183

Cited by 5 publications

(5 citation statements)

References 112 publications

(143 reference statements)

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“…Numerous inter-related factors conspire to enhance the cytokine storm and multiple organ failure associated with COVID-19 disease severity and mortality, including elevated sPLA2-IIA, development of pro-inflammatory M1 macrophages, activation of HIF-1α, conversion to Warburg-type metabolism of immune cells, damage to mitochondria, massive release of cytokines, oxidative stress, etc. [ 117 – 120 ] (Fig. 1 ); each of these actions have been shown to be counteracted by melatonin.…”

Section: Discussionmentioning

confidence: 99%

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection

Reíter

Sharma

Šimko

et al. 2022

Cell. Mol. Life Sci.

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Numerous pharmaceutical drugs have been repurposed for use as treatments for COVID-19 disease. These drugs have not consistently demonstrated high efficacy in preventing or treating this serious condition and all have side effects to differing degrees. We encourage the continued consideration of the use of the antioxidant and anti-inflammatory agent, melatonin, as a countermeasure to a SARS-CoV-2 infection. More than 140 scientific publications have identified melatonin as a likely useful agent to treat this disease. Moreover, the publications cited provide the rationale for the use of melatonin as a prophylactic agent against this condition. Melatonin has pan-antiviral effects and it diminishes the severity of viral infections and reduces the death of animals infected with numerous different viruses, including three different coronaviruses. Network analyses, which compared drugs used to treat SARS-CoV-2 in humans, also predicted that melatonin would be the most effective agent for preventing/treating COVID-19. Finally, when seriously infected COVID-19 patients were treated with melatonin, either alone or in combination with other medications, these treatments reduced the severity of infection, lowered the death rate, and shortened the duration of hospitalization. Melatonin’s ability to arrest SARS-CoV-2 infections may reduce health care exhaustion by limiting the need for hospitalization. Importantly, melatonin has a high safety profile over a wide range of doses and lacks significant toxicity. Some molecular processes by which melatonin resists a SARS-CoV-2 infection are summarized. The authors believe that all available, potentially beneficial drugs, including melatonin, that lack toxicity should be used in pandemics such as that caused by SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection

Reíter

Sharma

Šimko

et al. 2022

Cell. Mol. Life Sci.

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“…Given that SARS-CoV-2 RNA locates on both nucleus and mitochondria in host cells, SARS-CoV-2 might also hijack the mitochondria to conduct virus replication in this organelle. 28 , 42 , 43 Here, we proved that SARS-CoV-2 invasion induced the damage of mitochondria as well as the release and accumulation of mtDNA in cytosol, subsequently triggering cGAS-STING pathway to activate IFN-I signaling. These results together demonstrated the crucial effect of mitochondria in virus replication and immune response.…”

Section: Discussionmentioning

confidence: 66%

Phase-separated nucleocapsid protein of SARS-CoV-2 suppresses cGAS-DNA recognition by disrupting cGAS-G3BP1 complex

Cai

Zhang

Zhuang

et al. 2023

Sig Transduct Target Ther

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Currently, the incidence and fatality rate of SARS-CoV-2 remain continually high worldwide. COVID-19 patients infected with SARS-CoV-2 exhibited decreased type I interferon (IFN-I) signal, along with limited activation of antiviral immune responses as well as enhanced viral infectivity. Dramatic progresses have been made in revealing the multiple strategies employed by SARS-CoV-2 in impairing canonical RNA sensing pathways. However, it remains to be determined about the SARS-CoV-2 antagonism of cGAS-mediated activation of IFN responses during infection. In the current study, we figure out that SARS-CoV-2 infection leads to the accumulation of released mitochondria DNA (mtDNA), which in turn triggers cGAS to activate IFN-I signaling. As countermeasures, SARS-CoV-2 nucleocapsid (N) protein restricts the DNA recognition capacity of cGAS to impair cGAS-induced IFN-I signaling. Mechanically, N protein disrupts the assembly of cGAS with its co-factor G3BP1 by undergoing DNA-induced liquid-liquid phase separation (LLPS), subsequently impairs the double-strand DNA (dsDNA) detection ability of cGAS. Taken together, our findings unravel a novel antagonistic strategy by which SARS-CoV-2 reduces DNA-triggered IFN-I pathway through interfering with cGAS-DNA phase separation.

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“…However, although the rapid induction of IFN-I limits the spread of the virus, a continuous increase in IFN-I levels during the late stage of infection is related to abnormal inflammation and adverse clinical outcomes. [174][175][176] In conclusion, cGAS and STING may limit further RNA virus infection by a mechanism different from resisting DNA virus infection.…”

Section: Activation Of the Cgas-sting Signaling Pathway By Rna Virusmentioning

confidence: 95%

“…Recent studies have found that SARS‐CoV‐2 infection also activates cGAS–STING signal transduction in macrophages and endothelial cells by releasing mtDNA, resulting in cell death and IFN‐I production. However, although the rapid induction of IFN‐I limits the spread of the virus, a continuous increase in IFN‐I levels during the late stage of infection is related to abnormal inflammation and adverse clinical outcomes 174–176 . In conclusion, cGAS and STING may limit further RNA virus infection by a mechanism different from resisting DNA virus infection.…”

Section: Activation and Inhibition Of Cgas–sting Under The Pathologic...mentioning

confidence: 99%

cGAS–STING, an important signaling pathway in diseases and their therapy

Li,

Wu,

et al. 2024

MedComm

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Since cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway was discovered in 2013, great progress has been made to elucidate the origin, function, and regulating mechanism of cGAS–STING signaling pathway in the past decade. Meanwhile, the triggering and transduction mechanisms have been continuously illuminated. cGAS–STING plays a key role in human diseases, particularly DNA‐triggered inflammatory diseases, making it a potentially effective therapeutic target for inflammation‐related diseases. Here, we aim to summarize the ancient origin of the cGAS–STING defense mechanism, as well as the triggers, transduction, and regulating mechanisms of the cGAS–STING. We will also focus on the important roles of cGAS–STING signal under pathological conditions, such as infections, cancers, autoimmune diseases, neurological diseases, and visceral inflammations, and review the progress in drug development targeting cGAS–STING signaling pathway. The main directions and potential obstacles in the regulating mechanism research and therapeutic drug development of the cGAS–STING signaling pathway for inflammatory diseases and cancers will be discussed. These research advancements expand our understanding of cGAS–STING, provide a theoretical basis for further exploration of the roles of cGAS–STING in diseases, and open up new strategies for targeting cGAS–STING as a promising therapeutic intervention in multiple diseases.

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Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

Cited by 5 publications

References 112 publications

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection

Phase-separated nucleocapsid protein of SARS-CoV-2 suppresses cGAS-DNA recognition by disrupting cGAS-G3BP1 complex

cGAS–STING, an important signaling pathway in diseases and their therapy

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