scholarly journals Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhuo Zhou ◽  
Xinyi Zhang ◽  
Xiaobo Lei ◽  
Xia Xiao ◽  
Tao Jiao ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Cell Fusion ◽  
Innate Immune Response ◽  
Rna Virus ◽  
Cellular Level ◽  
Innate Immune ◽  
Host Cells ◽  
Host Immune System ◽  
Sting Pathway

AbstractThe global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.

scholarly journals Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

2021 ◽  
Author(s):  
Zhuo Zhou ◽  
Xinyi Zhang ◽  
Xiaobo Lei ◽  
Xia Xiao ◽  
Tao Jiao ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Cell Fusion ◽  
Innate Immune Response ◽  
Rna Virus ◽  
Cellular Level ◽  
Innate Immune ◽  
Host Cells ◽  
Host Immune System ◽  
Sting Pathway

Abstract The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain to be determined. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2'3'-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.

scholarly journals Bacterial lipids: powerful modifiers of the innate immune response

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1334 ◽  
Author(s):  
Courtney E. Chandler ◽  
Robert K. Ernst
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Lipoteichoic Acid ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Host Immune System ◽  
Receptor Proteins ◽  
Bacterial Membranes ◽  
Host Innate Immune Response

The innate immune system serves as a first line of defense against microbial pathogens. The host innate immune response can be triggered by recognition of conserved non-self-microbial signature molecules by specific host receptor proteins called Toll-like receptors. For bacteria, many of these molecular triggers reside on or are embedded in the bacterial membrane, the interface exposed to the host environment. Lipids are the most abundant component of membranes, and bacteria possess a unique set of lipids that can initiate or modify the host innate immune response. Bacterial lipoproteins, peptidoglycan, and outer membrane molecules lipoteichoic acid and lipopolysaccharide are key modulators of the host immune system. This review article will highlight some of the research emerging at the crossroads of bacterial membranes and innate immunity.

scholarly journals TRIM21 Promotes Innate Immune Response to RNA Viral Infection through Lys27-Linked Polyubiquitination of MAVS

2018 ◽  
Vol 92 (14) ◽  
Author(s):  
Binbin Xue ◽  
Huiyi Li ◽  
Mengmeng Guo ◽  
Jingjing Wang ◽  
Yan Xu ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Viral Infection ◽  
Signaling Pathway ◽  
Innate Immune Response ◽  
Rna Virus ◽  
Critical Role ◽  
Innate Immune ◽  
Host Cells ◽  
Lysine Residues

ABSTRACT Human innate immunity responds to viral infection by activating the production of interferons (IFNs) and proinflammatory cytokines. The mitochondrial adaptor molecule MAVS plays a critical role in innate immune response to viral infection. In this study, we show that TRIM21 (tripartite motif-containing protein 21) interacts with MAVS to positively regulate innate immunity. Under viral infection, TRIM21 is upregulated through the IFN/JAK/STAT signaling pathway. Knockdown of TRIM21 dramatically impairs innate immune response to viral infection. Moreover, TRIM21 interacts with MAVS and catalyzes its K27-linked polyubiquitination, thereby promoting the recruitment of TBK1 to MAVS. Specifically, the PRY-SPRY domain of TRIM21 is the key domain for its interaction with MAVS, while the RING domain of TRIM21 facilitates the polyubiquitination chains of MAVS. In addition, the MAVS-mediated innate immune response is enhanced by both the PRY-SPRY and RING domains of TRIM21. Mutation analyses of all the lysine residues of MAVS further revealed that Lys325 of MAVS is catalyzed by TRIM21 for the K27-linked polyubiquitination. Overall, this study reveals a novel mechanism by which TRIM21 promotes the K27-linked polyubiquitination of MAVS to positively regulate innate immune response, thereby inhibiting viral infection. IMPORTANCE Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. MAVS plays a critical role in innate immune response to RNA viral infection. In this study, we demonstrated that TRIM21 targets MAVS to positively regulate innate immunity. Notably, TRIM21 targets and catalyzes K27-linked polyubiquitination of MAVS and then promotes the recruitment of TBK1 to MAVS, leading to upregulation of innate immunity. Our study outlines a novel mechanism by which the IFN signaling pathway blocks RNA virus to escape immune elimination.

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 Tumour viruses and innate immunity

2017 ◽  
Vol 372 (1732) ◽  
pp. 20160267 ◽  
Author(s):  
Sharon E. Hopcraft ◽  
Blossom Damania
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Host Cells ◽  
Oncogenic Viruses ◽  
Barr Virus ◽  
Human T Cell ◽  
Epstein Barr

Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRRs are localized to several different cellular compartments and are stimulated by viral proteins and nucleic acids. PRR activation initiates signal transduction events that ultimately result in an inflammatory response. Human tumour viruses, which include Kaposi's sarcoma-associated herpesvirus, Epstein–Barr virus, human papillomavirus, hepatitis C virus, hepatitis B virus, human T-cell lymphotropic virus type 1 and Merkel cell polyomavirus, are detected by several different PRRs. These viruses engage in a variety of mechanisms to evade the innate immune response, including downregulating PRRs, inhibiting PRR signalling, and disrupting the activation of transcription factors critical for mediating the inflammatory response, among others. This review will describe tumour virus PAMPs and the PRRs responsible for detecting viral infection, PRR signalling pathways, and the mechanisms by which tumour viruses evade the host innate immune system. This article is part of the themed issue ‘Human oncogenic viruses’.

scholarly journals Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Tanvir Bamra ◽  
Taj Shafi ◽  
Sushmita Das ◽  
Manjay Kumar ◽  
Manas Ranjan Dikhit ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Parasite Burden ◽  
Host Immune Response ◽  
Host Cells ◽  
Interleukin 4 ◽  
Host Immune System ◽  
Mevalonate Kinase

Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.

scholarly journals CSIG-19. THE DEUBIQUITINASE BRCC3 LINKS ALT TELOMERES TO SUPPRESSION OF INNATE IMMUNITY IN IDH1-MUTANT GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii31-ii32
Author(s):  
Joydeep Mukherjee ◽  
Yongjian Tang ◽  
Tor-Christian Johanessen ◽  
Ajay Pandita ◽  
Shigeo Ohba ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Lower Grade ◽  
Astrocytoma Cells ◽  
Double Stranded Dna ◽  
Alternative Lengthening ◽  
Lower Grade Glioma ◽  
Exogenous Expression ◽  
Sting Pathway

Abstract Approximately 10% of tumors including all IDH1-mutant lower-grade glioma resolve telomeric shortening using Alternative Lengthening of Telomere (ALT) mechanism. Although the ALT process lengthens telomeres, it also generates small bits of extrachromosomal, telomere-containing DNA (ECTRs). These ECTRs can bind and activate cyclic GMP-AMP synthase (cGAS), the major cytosolic sensor of double-stranded DNA, which in turn can activate expression of stimulator of IFN genes (STING) and the interferon-based innate immune response. To limit the immune response, ALT cells inactivate the cGAS-STING pathway, although the mechanism by which this occurs is unknown. Here we show that the deubiquitinase BRCC3 links ALT telomeres to suppression of the cGAS-STING pathway and the innate immune response. Astrocytoma cells dependent on the ALT-mechanism (IDH1-mutant and ATRX-deficient genetically-modified human astrocytes and MGG119 PDX) contained ECTR and had reduced expression of the cGAS and the downstream components of the cGAS-STING pathway (STING, and IFN-β) relative to matched non-ALT (isogenic ATRX WT astrocytes and MGG152 PDX) cells lacking ECTRs. Decreased levels of cGAS in ALT cells were in turn associated with deubiquitiantion and destabilization of cGAS. The telomere-derived ECTR in ALT-dependent cells lacked two proteins normally found in ALT telomeres (TRF2 or PARP), but retained two other proteins, Mre11 and its binding partner, normally nuclear deubiquitinase BRCC3. Furthermore, either pharmacologic inhibition or genetic suppression of BRCC3 levels had no effect on ECTR levels but stabilized cGAS and activated the cGAS-STING pathway. This cGAS-mediated activation could be blocked by exogenous expression of WT BRCC3, but not by expression of a mutant BRCC3 incapable of deubiquitination. These results show that BRCC3 translocated along with ECTRs to the cytoplasm degrades cGAS and protects ALT-dependent cells from activating the innate immune response. The BRCC3-controlled cGAS-STING pathway may therefore represent a therapeutically targetable means to enhance the immune response in IDH1-mutant lower grade glioma.

The C-terminal domain of Salmonid Alphavirus nonstructural protein 2 (nsP2) is essential and sufficient to block RIG-I pathway induction and interferon-mediated antiviral response.

2021 ◽  
Author(s):  
Raphaël Jami ◽  
Emilie Mérour ◽  
Julie Bernard ◽  
Annie Lamoureux ◽  
Jean K. Millet ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Nuclear Localization ◽  
Innate Immune ◽  
Type I ◽  
Annual Growth Rate ◽  
Structural Protein ◽  
Terminal Domain ◽  
Nuclear Localization Sequences

Salmonid alphavirus (SAV) is an atypical alphavirus, which has a considerable impact on salmon and trout farms. Unlike other alphaviruses such as the chikungunya virus, SAV is transmitted without an arthropod vector, and does not cause cell shut-off during infection. The mechanisms by which SAV escapes the host immune system remain unknown. By studying the role of SAV proteins on the RIG-I signaling cascade, the first line of defense of the immune system during infection, we demonstrated that non-structural protein 2 (nsP2) effectively blocks the induction of type I interferon (IFN). This inhibition, independent of the protease activity carried by nsP2, occurs downstream of IRF3 which is the transcription factor allowing the activation of the IFN promoter and its expression. The inhibitory effect of nsP2 on the RIG-I pathway depends on the localization of nsP2 in the host cell nucleus which is linked to two nuclear localization sequences (NLS) located in its C-terminal part. The C-terminal domain of nsP2 by itself is sufficient and necessary to block IFN induction. Mutation of the NLS of nsP2 is deleterious to the virus. Finally, nsP2 does not interact with IRF3, indicating that its action is possible through a targeted interaction within discrete areas of chromatin, as suggested by its punctate distribution observed in the nucleus. These results therefore demonstrate a major role for nsP2 in the control by SAV of the host cell’s innate immune response. Importance The global consumption of fish continues to rise and the future demand cannot be met by capture fisheries alone due to limited stocks of wild fish. Aquaculture is currently the world’s fastest growing food production sector with an annual growth rate of 6-8 %. Recurrent outbreaks of SAV result in significant economic losses with serious environmental consequences on wild stocks. While the clinical and pathological signs of SAV infection are fairly well known, the molecular mechanisms involved are poorly described. In the present study, we focus on the non-structural protein nsP2 and characterize a specific domain containing nuclear localization sequences that are critical for the inhibition of the host innate immune response mediated by the RIG-I pathway.

RNA sensors as a mechanism of innate immune evasion among SARS-CoV2, HIV and Nipah viruses

2021 ◽  
Vol 22 ◽  
Author(s):  
Dalia Cicily Kattiparambil Dixon ◽  
Chameli Ratan ◽  
Bhagyalakshmi Nair ◽  
Sabitha Mangalath ◽  
Rachy Abraham ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Vaccine Development ◽  
Innate Immune ◽  
Interferon Response ◽  
Host Immune System ◽  
Type I ◽  
Adaptive Responses ◽  
Rna Sensors

: Innate immunity is the first line of defence elicited by the host immune system to fight against invading pathogens such as viruses and bacteria. From this elementary immune response, the more complex antigen-specific adaptive responses are recruited to provide a long-lasting memory against the pathogens. Innate immunity gets activated when the host cell utilizes a diverse set of receptors known as pattern recognition receptors (PRR) to recognize the viruses that have penetrated the host and respond with cellular processes like complement system, phagocytosis, cytokine release and inflammation and destruction of NK cells. Viral RNA or DNA or viral intermediate products are recognized by receptors like toll-like receptors(TLRs), nucleotide oligomerization domain(NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) thereby, inducing type I interferon response (IFN) and other proinflammatory cytokines in infected cells or other immune cells. But certain viruses can evade the host innate immune response to replicate efficiently, triggering the spread of the viral infection. The present review describes the similarity in the mechanism chosen by viruses from different families -HIV, SARS-CoV2 and Nipah viruses to evade the innate immune response and how efficiently they establish the infection in the host. The review also addresses the stages of developments of various vaccines against these viral diseases and the challenges encountered by the researchers during vaccine development.

2. First responders: the innate immune response

2017 ◽  
pp. 17-29
Author(s):  
Paul Klenerman
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Acute Phase Response ◽  
First Responders ◽  
Fundamental Question ◽  
Innate Immune ◽  
Rapid Action ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

How does the immune system know when to respond? ‘First responders: the innate immune response’ considers this fundamental question that is central to understanding both normal (e.g. to infections) and abnormal (e.g. in auto-immune diseases) responses; and designing vaccines and new therapies in cancer and infectious diseases. It looks at how ‘danger’ is sensed by the immune system through pathogen-associated molecular patterns and damage-associated molecular patterns. Having been alerted, it is important that rapid action is taken to limit the spread of a pathogen. A number of responses can be initiated immediately, forming a critical part of our innate immunity, which are followed by the acute phase response.

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