scholarly journals Activation of cGAS/STING pathway upon paramyxovirus infection

2020 ◽  
Author(s):  
Mathieu Iampietro ◽  
Claire Dumont ◽  
Cyrille Mathieu ◽  
Julia Spanier ◽  
Jonathan Robert ◽  
...  
Keyword(s):  
Measles Virus ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Severe Disease ◽  
Nipah Virus ◽  
Innate Immune ◽  
Type I ◽  
Interferon Production ◽  
Host Protection ◽  
Sting Pathway

SUMMARYDuring inflammatory diseases, cancer and infection, the cGAS/STING pathway is known to recognize foreign or self-DNA in the cytosol and activate an innate immune response. Here, we report that negative-strand RNA paramyxoviruses, Nipah virus (NiV) and Measles virus (MeV), can also trigger the cGAS/STING axis. While mice deficient for MyD88, TRIF and MAVS still moderately control NiV infection when compared to WT mice, additional STING deficiency resulted in 100% lethality, suggesting synergistic roles of these pathways in host protection. Moreover, deletion of cGAS or STING resulted in decreased type-I interferon production with enhanced paramyxoviral infection in both human and murine cells. Finally, the phosphorylation and ubiquitination of STING, observed during viral infections, confirmed the activation of cGAS/STING pathway by NiV and MeV. Our data suggest that cGAS/STING activation is critical in controlling paramyxovirus infection, and possibly represent attractive targets to develop countermeasures against severe disease induced by these pathogens.

scholarly journals Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 675
Author(s):  
Samira Elmanfi ◽  
Mustafa Yilmaz ◽  
Wilson W. S. Ong ◽  
Kofi S. Yeboah ◽  
Herman O. Sintim ◽  
...  
Keyword(s):  
Immune Response ◽  
Periodontal Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Vaccine Adjuvants ◽  
Cyclic Dinucleotides ◽  
Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

scholarly journals CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Infection ◽  
2021 ◽  
Author(s):  
Jan-Moritz Doehn ◽  
Christoph Tabeling ◽  
Robert Biesen ◽  
Jacopo Saccomanno ◽  
Elena Madlung ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Disease Severity ◽  
Clinical Studies ◽  
Viral Infections ◽  
Severe Disease ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Signaling ◽  
Expression Levels

AbstractCoronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.

scholarly journals COVID-19 in Children: Expressions of Type I/II/III Interferons, TRIM28, SETDB1, and Endogenous Retroviruses in Mild and Severe Cases

2021 ◽  
Vol 22 (14) ◽  
pp. 7481
Author(s):  
Pier-Angelo Tovo ◽  
Silvia Garazzino ◽  
Valentina Daprà ◽  
Giulia Pruccoli ◽  
Cristina Calvi ◽  
...  
Keyword(s):  
Viral Infections ◽  
Severe Disease ◽  
Endogenous Retroviruses ◽  
Type I ◽  
Human Endogenous Retroviruses ◽  
Moderate Disease ◽  
Amplification Assay ◽  
Positive Correlations ◽  
Inducible Genes ◽  
Inflammatory Syndrome

Children with the new coronavirus disease 2019 (COVID-19) have milder symptoms and a better prognosis than adult patients. Several investigations assessed type I, II, and III interferon (IFN) signatures in SARS-CoV-2 infected adults, however no data are available for pediatric patients. RIM28 and SETDB1 regulate the transcription of multiple genes involved in the immune response as well as of human endogenous retroviruses (HERVs). Exogenous viral infections can trigger the activation of HERVs, which in turn can induce inflammatory and immune reactions. Despite the potential cross-talks between SARS-CoV-2 infection and TRIM28, SETDB1, and HERVs, information on their expressions in COVID-19 patients is lacking. We assessed, through a PCR real time Taqman amplification assay, the transcription levels of six IFN-I stimulated genes, IFN-II and three of its sensitive genes, three IFN-lIIs, as well as of TRIM28, SETDB1, pol genes of HERV-H, -K, and -W families, and of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis-associated retrovirus (MRSV) in peripheral blood from COVID-19 children nd in control uninfected subjects. Higher expression levels of IFN-I and IFN-II inducible genes were observed in 36 COVID-19-infected children with mild or moderate disease as compared to uninfected controls, whereas their concentrations decreased in 17 children with severe disease and in 11 with multisystem inflammatory syndrome (MIS-C). Similar findings were found for the expression of TRIM-28, SETDB1, and every HERV gene. Positive correlations emerged between the transcriptional levels of type I and II IFNs, TRIM28, SETDB1, and HERVs in COVID-19 patients. IFN-III expressions were comparable in each group of subjects. This preserved induction of IFN-λs could contribute to the better control of the infection in children as compared to adults, in whom IFN-III deficiency has been reported. The upregulation of IFN-I, IFN-II, TRIM28, SETDB1, and HERVs in children with mild symptoms, their declines in severe cases or with MIS-C, and the positive correlations of their transcription in SARS-CoV-2-infected children suggest that they may play important roles in conditioning the evolution of the infection.

scholarly journals Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+Macrophage Function during Viral Infection

2015 ◽  
Vol 89 (9) ◽  
pp. 4748-4759 ◽  
Author(s):  
Haifeng C. Xu ◽  
Jun Huang ◽  
Vishal Khairnar ◽  
Vikas Duhan ◽  
Aleksandra A. Pandyra ◽  
...  
Keyword(s):  
B Cells ◽  
Viral Infection ◽  
B Cell ◽  
Viral Infections ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
Immune Priming ◽  
Adaptive Immune ◽  
Deficient Mice

ABSTRACTThe B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169+macrophage compartment. Consequently,Baffr−/−mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells inBaffr−/−animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169+cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.IMPORTANCEViruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169+macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.

scholarly journals Type I Interferon Production Induced by Streptococcus pyogenes-Derived Nucleic Acids Is Required for Host Protection

2011 ◽  
Vol 7 (5) ◽  
pp. e1001345 ◽  
Author(s):  
Nina Gratz ◽  
Harald Hartweger ◽  
Ulrich Matt ◽  
Franz Kratochvill ◽  
Marton Janos ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Streptococcus Pyogenes ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
Host Protection

scholarly journals How fragile we are. Influence of STimulator of INterferon Genes, STING, variants on pathogen recognition and immune response efficiency

2021 ◽  
Author(s):  
Jeremy Morere ◽  
Cecilia Hognon ◽  
Tom Miclot ◽  
Tao Jiang ◽  
Elise Dumont ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Dynamical Behavior ◽  
Structural Features ◽  
Type I Interferons ◽  
Machine Learning Techniques ◽  
Type I ◽  
Interaction Patterns

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue...), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

scholarly journals Highly Potent Host-Specific Small-Molecule Inhibitor of Paramyxovirus and Pneumovirus Replication with High Resistance Barrier

mBio ◽  
2021 ◽  
Author(s):  
Neeta Shrestha ◽  
Flavio Max Gall ◽  
Cyrille Mathieu ◽  
Melanie Michaela Hierweger ◽  
Melanie Brügger ◽  
...  
Keyword(s):  
Measles Virus ◽  
Canine Distemper Virus ◽  
Viral Infections ◽  
Rna Viruses ◽  
Treatment Options ◽  
Nipah Virus ◽  
Canine Distemper ◽  
Molecule Inhibitor ◽  
Syncytial Virus ◽  
Clinically Significant

Measles virus, respiratory syncytial virus, canine distemper virus, and Nipah virus are some of the clinically significant RNA viruses that threaten substantial number of lives each year. Limited to no availability of treatment options for these viral infections makes it arduous to handle the outbreaks.

scholarly journals How the Innate Immune DNA Sensing cGAS–STING Pathway Is Involved in Autophagy

2021 ◽  
Vol 22 (24) ◽  
pp. 13232
Author(s):  
Wanglong Zheng ◽  
Nengwen Xia ◽  
Jiajia Zhang ◽  
Nanhua Chen ◽  
François Meurens ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Complex Interaction ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Innate Immune Responses ◽  
Homeostatic Process ◽  
Sting Pathway ◽  
Dna Complex

The cGAS–STING pathway is a key component of the innate immune system and exerts crucial roles in the detection of cytosolic DNA and invading pathogens. Accumulating evidence suggests that the intrinsic cGAS–STING pathway not only facilitates the production of type I interferons (IFN-I) and inflammatory responses but also triggers autophagy. Autophagy is a homeostatic process that exerts multiple effects on innate immunity. However, systematic evidence linking the cGAS–STING pathway and autophagy is still lacking. Therefore, one goal of this review is to summarize the known mechanisms of autophagy induced by the cGAS–STING pathway and their consequences. The cGAS–STING pathway can trigger canonical autophagy through liquid-phase separation of the cGAS–DNA complex, interaction of cGAS and Beclin-1, and STING-triggered ER stress–mTOR signaling. Furthermore, both cGAS and STING can induce non-canonical autophagy via LC3-interacting regions and binding with LC3. Subsequently, autophagy induced by the cGAS–STING pathway plays crucial roles in balancing innate immune responses, maintaining intracellular environmental homeostasis, alleviating liver injury, and limiting tumor growth and transformation.

scholarly journals Zoonotic potential of a novel bat morbillivirus

2021 ◽  
Author(s):  
Satoshi Ikegame ◽  
Jillian C Carmichael ◽  
Heather Wells ◽  
Robert L Furler ◽  
Joshua A Acklin ◽  
...  
Keyword(s):  
Measles Virus ◽  
Reverse Genetics ◽  
Ebola Virus ◽  
Severe Disease ◽  
Nipah Virus ◽  
Lymphoid Cells ◽  
Zoonotic Potential ◽  
Specific Expression ◽  
Animal Populations ◽  
Species Specific

Bats are significant reservoir hosts for many viruses with zoonotic potential. SARS-CoV-2, Ebola virus, and Nipah virus are examples of such viruses that have caused deadly epidemics and pandemics when spilled over from bats into human and animal populations. Careful surveillance of viruses in bats is critical for identifying potential zoonotic pathogens. However, metagenomic surveys in bats often do not result in full-length viral sequences that can be used to regenerate such viruses for targeted characterization. Here, we identify and characterize a novel morbillivirus from a vespertilionid bat species (Myotis riparius) in Brazil, which we term myotis bat morbillivirus (MBaMV). There are 7 species of morbilliviruses including measles virus (MeV), canine distemper virus (CDV) and rinderpest virus (RPV). All morbilliviruses cause severe disease in their natural hosts, and pathogenicity is largely determined by species specific expression of canonical morbillivirus receptors, CD150/SLAMF1 and NECTIN4. MBaMV used Myotis spp CD150 much better than human and dog CD150 in fusion assays. We confirmed this using live MBaMV that was rescued by reverse genetics. Surprisingly, MBaMV replicated efficiently in primary human myeloid but not lymphoid cells. Furthermore, MBaMV replicated in human epithelial cells and used human NECTIN4 almost as well as MeV. Our results demonstrate the unusual ability of MBaMV to infect and replicate in some human cells that are critical for MeV pathogenesis and transmission. This raises the specter of zoonotic transmission of a bat morbillivirus.

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