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16 pages, 4354 KiB

Open AccessArticle

Impact of Microbiota Depletion by Antibiotics on SARS-CoV-2 Infection of K18-hACE2 Mice

by Patrícia Brito Rodrigues, Giovanni Freitas Gomes, Monara K. S. C. Angelim, Gabriela F. Souza, Stefanie Primon Muraro, Daniel A. Toledo-Teixeira, Bruna Amanda Cruz Rattis, Amanda Stephane Passos, Laís Passarielo Pral, Vinícius de Rezende Rodovalho, Arilson Bernardo dos Santos P. Gomes, Valquíria Aparecida Matheus, André Saraiva Leão Marcelo Antunes, Fernanda Crunfli, Krist Helen Antunes, Ana Paula Duarte de Souza, Sílvio Roberto Consonni, Luiz Osório Leiria, José Carlos Alves-Filho, Thiago M. Cunha, Pedro M. M. Moraes-Vieira, José Luiz Proença-Módena and Marco Aurélio R. Vinolo Show full author list Hide full author list

Cells 2022, 11(16), 2572; https://doi.org/10.3390/cells11162572 - 18 Aug 2022

Cited by 5 | Viewed by 2731

Abstract

Clinical and experimental data indicate that severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection is associated with significant changes in the composition and function of intestinal microbiota. However, the relevance of these effects for SARS-CoV-2 pathophysiology is unknown. In this study, we analyzed the [...] Read more.

Clinical and experimental data indicate that severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection is associated with significant changes in the composition and function of intestinal microbiota. However, the relevance of these effects for SARS-CoV-2 pathophysiology is unknown. In this study, we analyzed the impact of microbiota depletion after antibiotic treatment on the clinical and immunological responses of K18-hACE2 mice to SARS-CoV-2 infection. Mice were treated with a combination of antibiotics (kanamycin, gentamicin, metronidazole, vancomycin, and colistin, Abx) for 3 days, and 24 h later, they were infected with SARS-CoV-2 B lineage. Here, we show that more than 80% of mice succumbed to infection by day 11 post-infection. Treatment with Abx had no impact on mortality. However, Abx-treated mice presented better clinical symptoms, with similar weight loss between infected–treated and non-treated groups. We observed no differences in lung and colon histopathological scores or lung, colon, heart, brain and kidney viral load between groups on day 5 of infection. Despite some minor differences in the expression of antiviral and inflammatory markers in the lungs and colon, no robust change was observed in Abx-treated mice. Together, these findings indicate that microbiota depletion has no impact on SARS-CoV-2 infection in mice. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

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Review

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29 pages, 958 KiB

Open AccessReview

STING Targeting in Lung Diseases

by Dorian de Moura Rodrigues, Norinne Lacerda-Queiroz, Isabelle Couillin and Nicolas Riteau

Cells 2022, 11(21), 3483; https://doi.org/10.3390/cells11213483 - 3 Nov 2022

Cited by 3 | Viewed by 3892

Abstract

The cGAS–STING pathway displays important functions in the regulation of innate and adaptive immunity following the detection of microbial and host-derived DNA. Here, we briefly summarize biological functions of STING and review recent literature highlighting its important contribution in the context of respiratory [...] Read more.

The cGAS–STING pathway displays important functions in the regulation of innate and adaptive immunity following the detection of microbial and host-derived DNA. Here, we briefly summarize biological functions of STING and review recent literature highlighting its important contribution in the context of respiratory diseases. Over the last years, tremendous progress has been made in our understanding of STING activation, which has favored the development of STING agonists or antagonists with potential therapeutic benefits. Antagonists might alleviate STING-associated chronic inflammation and autoimmunity. Furthermore, pharmacological activation of STING displays strong antiviral properties, as recently shown in the context of SARS-CoV-2 infection. STING agonists also elicit potent stimulatory activities when used as an adjuvant promoting antitumor responses and vaccines efficacy. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

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18 pages, 1456 KiB

Open AccessReview

Detecting DNA: An Overview of DNA Recognition by Inflammasomes and Protection against Bacterial Respiratory Infections

by Juselyn D. Tupik, Justin W. Markov Madanick, Hannah M. Ivester and Irving C. Allen

Cells 2022, 11(10), 1681; https://doi.org/10.3390/cells11101681 - 19 May 2022

Cited by 3 | Viewed by 3393

Abstract

The innate immune system plays a key role in modulating host immune defense during bacterial disease. Upon sensing pathogen-associated molecular patterns (PAMPs), the multi-protein complex known as the inflammasome serves a protective role against bacteria burden through facilitating pathogen clearance and bacteria lysis. [...] Read more.

The innate immune system plays a key role in modulating host immune defense during bacterial disease. Upon sensing pathogen-associated molecular patterns (PAMPs), the multi-protein complex known as the inflammasome serves a protective role against bacteria burden through facilitating pathogen clearance and bacteria lysis. This can occur through two mechanisms: (1) the cleavage of pro-inflammatory cytokines IL-1β/IL-18 and (2) the initiation of inflammatory cell death termed pyroptosis. In recent literature, AIM2-like Receptor (ALR) and Nod-like Receptor (NLR) inflammasome activation has been implicated in host protection following recognition of bacterial DNA. Here, we review current literature synthesizing mechanisms of DNA recognition by inflammasomes during bacterial respiratory disease. This process can occur through direct sensing of DNA or indirectly by sensing pathogen-associated intracellular changes. Additionally, DNA recognition may be assisted through inflammasome–inflammasome interactions, specifically non-canonical inflammasome activation of NLRP3, and crosstalk with the interferon-inducible DNA sensors Stimulator of Interferon Genes (STING) and Z-DNA Binding Protein-1 (ZBP1). Ultimately, bacterial DNA sensing by inflammasomes is highly protective during respiratory disease, emphasizing the importance of inflammasome involvement in the respiratory tract. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

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19 pages, 3857 KiB

Open AccessFeature PaperReview

DEAD/H-Box Helicases in Immunity, Inflammation, Cell Differentiation, and Cell Death and Disease

by Parimal Samir and Thirumala-Devi Kanneganti

Cells 2022, 11(10), 1608; https://doi.org/10.3390/cells11101608 - 11 May 2022

Cited by 17 | Viewed by 5607

Abstract

DEAD/H-box proteins are the largest family of RNA helicases in mammalian genomes, and they are present in all kingdoms of life. Since their discovery in the late 1980s, DEAD/H-box family proteins have been a major focus of study. They have been found to [...] Read more.

DEAD/H-box proteins are the largest family of RNA helicases in mammalian genomes, and they are present in all kingdoms of life. Since their discovery in the late 1980s, DEAD/H-box family proteins have been a major focus of study. They have been found to play central roles in RNA metabolism, gene expression, signal transduction, programmed cell death, and the immune response to bacterial and viral infections. Aberrant functions of DEAD/H-box proteins have been implicated in a wide range of human diseases that include cancer, neurodegeneration, and inherited genetic disorders. In this review, we provide a historical context and discuss the molecular functions of DEAD/H-box proteins, highlighting the recent discoveries linking their dysregulation to human diseases. We will also discuss the state of knowledge regarding two specific DEAD/H-box proteins that have critical roles in immune responses and programmed cell death, DDX3X and DDX58, also known as RIG-I. Given their importance in homeostasis and disease, an improved understanding of DEAD/H-box protein biology and protein–protein interactions will be critical for informing strategies to counteract the pathogenesis associated with several human diseases. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

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17 pages, 1077 KiB

Open AccessReview

Fas/CD95 Signaling Pathway in Damage-Associated Molecular Pattern (DAMP)-Sensing Receptors

by Gael Galli, Pierre Vacher, Bernhard Ryffel, Patrick Blanco and Patrick Legembre

Cells 2022, 11(9), 1438; https://doi.org/10.3390/cells11091438 - 24 Apr 2022

Cited by 8 | Viewed by 4825

Abstract

Study of the initial steps of the CD95-mediated signaling pathways is a field of intense research and a long list of actors has been described in the literature. Nonetheless, the dynamism of protein-protein interactions (PPIs) occurring in the presence or absence of its [...] Read more.

Study of the initial steps of the CD95-mediated signaling pathways is a field of intense research and a long list of actors has been described in the literature. Nonetheless, the dynamism of protein-protein interactions (PPIs) occurring in the presence or absence of its natural ligand, CD95L, and the cellular distribution where these PPIs take place render it difficult to predict what will be the cellular outcome associated with the receptor engagement. Accordingly, CD95 stimulation can trigger apoptosis, necroptosis, pyroptosis, or pro-inflammatory signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphatidylinositol-3-kinase (PI3K). Recent data suggest that CD95 can also activate pattern recognition receptors (PRRs) known to sense damage-associated molecular patterns (DAMPs) such as DNA debris and dead cells. This activation might contribute to the pro-inflammatory role of CD95 and favor cancer development or severity of chronic inflammatory and auto-immune disorders. Herein, we discuss some of the molecular links that might connect the CD95 signaling to DAMP sensors. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

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10 pages, 1680 KiB

Open AccessReview

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

by Danilo Guerini

Cells 2022, 11(7), 1159; https://doi.org/10.3390/cells11071159 - 29 Mar 2022

Cited by 27 | Viewed by 6332

Abstract

The cGAS STING pathway has received much attention in recent years, and it has been recognized as an important component of the innate immune response. Since the discovery of STING and that of cGAS, many observations based on preclinical models suggest that the [...] Read more.

The cGAS STING pathway has received much attention in recent years, and it has been recognized as an important component of the innate immune response. Since the discovery of STING and that of cGAS, many observations based on preclinical models suggest that the faulty regulation of this pathway is involved in many type I IFN autoinflammatory disorders. Evidence has been accumulating that cGAS/STING might play an important role in pathologies beyond classical immune diseases, as in, for example, cardiac failure. Human genetic mutations that result in the activation of STING or that affect the activity of cGAS have been demonstrated as the drivers of rare interferonopathies affecting young children and young adults. Nevertheless, no data is available in the clinics demonstrating the therapeutic benefit in modulating the cGAS/STING pathway. This is due to the lack of STING/cGAS-specific low molecular weight modulators that would be qualified for clinical exploration. The early hopes to learn from STING agonists, which have reached the clinics in recent years for selected oncology indications, have not yet materialized since the initial trials are progressing very slowly. In addition, transforming STING agonists into potent selective antagonists has turned out to be more challenging than expected. Nevertheless, there has been progress in identifying novel low molecular weight compounds, in some cases with unexpected mode of action, that might soon move to clinical trials. This study gives an overview of some of the potential indications that might profit from modulation of the cGAS/STING pathway and a short overview of the efforts in identifying STING modulators (agonists and antagonists) suitable for clinical research and describing their potential as a “drug”. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

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16 pages, 1402 KiB

Open AccessReview

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

by Clémence David and Marie-Louise Frémond

Cells 2022, 11(3), 318; https://doi.org/10.3390/cells11030318 - 18 Jan 2022

Cited by 43 | Viewed by 5384

Abstract

STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies [...] Read more.

STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

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20 pages, 1412 KiB

Open AccessFeature PaperReview

Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

by Erika S. Guimarães, Fabio V. Marinho, Nina M. G. P. de Queiroz, Maísa M. Antunes and Sergio C. Oliveira

Cells 2022, 11(1), 74; https://doi.org/10.3390/cells11010074 - 28 Dec 2021

Cited by 13 | Viewed by 4511

Abstract

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING [...] Read more.

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING detects bacteria by directly recognizing cyclic dinucleotides or indirectly by bacterial genomic DNA sensing through the cyclic GMP-AMP synthase (cGAS). Upon activation, STING triggers a plethora of powerful signaling pathways, including the production of type I interferons and proinflammatory cytokines. STING activation has also been associated with the induction of endoplasmic reticulum (ER) stress and the associated inflammatory responses. Recent reports indicate that STING-dependent pathways participate in the metabolic reprogramming of macrophages and contribute to the establishment and maintenance of a robust inflammatory profile. The induction of this inflammatory state is typically antimicrobial and related to pathogen clearance. However, depending on the infection, STING-mediated immune responses can be detrimental to the host, facilitating bacterial survival, indicating an intricate balance between immune signaling and inflammation during bacterial infections. In this paper, we review recent insights regarding the role of STING in inducing an inflammatory profile upon intracellular bacterial entry in host cells and discuss the impact of STING signaling on the outcome of infection. Unraveling the STING-mediated inflammatory responses can enable a better understanding of the pathogenesis of certain bacterial diseases and reveal the potential of new antimicrobial therapy. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

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