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      Function and regulation of cGAS-STING signaling in infectious diseases

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          Abstract

          The efficacious detection of pathogens and prompt induction of innate immune signaling serve as a crucial component of immune defense against infectious pathogens. Over the past decade, DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have emerged as key mediators of type I interferon (IFN) and nuclear factor-κB (NF-κB) responses in health and infection diseases. Moreover, both cGAS-STING pathway and pathogens have developed delicate strategies to resist each other for their survival. The mechanistic and functional comprehension of the interplay between cGAS-STING pathway and pathogens is opening the way for the development and application of pharmacological agonists and antagonists in the treatment of infectious diseases. Here, we briefly review the current knowledge of DNA sensing through the cGAS-STING pathway, and emphatically highlight the potent undertaking of cGAS-STING signaling pathway in the host against infectious pathogenic organisms.

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          Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

          Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
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            Pattern recognition receptors and inflammation.

            Infection of cells by microorganisms activates the inflammatory response. The initial sensing of infection is mediated by innate pattern recognition receptors (PRRs), which include Toll-like receptors, RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors. The intracellular signaling cascades triggered by these PRRs lead to transcriptional expression of inflammatory mediators that coordinate the elimination of pathogens and infected cells. However, aberrant activation of this system leads to immunodeficiency, septic shock, or induction of autoimmunity. In this Review, we discuss the role of PRRs, their signaling pathways, and how they control inflammatory responses. 2010 Elsevier Inc. All rights reserved.
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              Pathogen recognition and innate immunity.

              Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                06 February 2023
                2023
                : 14
                : 1130423
                Affiliations
                [1] 1 Department of Medicine, and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, CA, United States
                [2] 2 Research Center of Medical Sciences, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University , Guangzhou, Guangdong, China
                [3] 3 Department of Immunology, School of Basic Medical Sciences, Southern Medical University , Guangzhou, Guangdong, China
                [4] 4 Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University , Guangzhou, Guangdong, China
                [5] 5 Department of Pediatrics, Children’s Hospital, Keck School of Medicine, University of Southern California , Los Angeles, CA, United States
                [6] 6 Guangdong Provincial Key Lab of Single Cell Technology and Application, Southern Medical University , Guangzhou, Guangdong, China
                Author notes

                Edited by: Tuo Li, University of Texas Southwestern Medical Center, United States

                Reviewed by: Sheng Sean Su, University of Texas Southwestern Medical Center, United States; Wei Ye, Air Force Medical University, China; Wanwan Huai, University of Texas Southwestern Medical Center, United States

                *Correspondence: Rong-Fu Wang, rongfuwa@ 123456usc.edu ; Xiao Yu, xiaoyu523@ 123456smu.edu.cn

                †These authors have contributed equally to this work

                This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2023.1130423
                9941744
                36825026
                2ebbbe0c-1243-4b51-8bbd-5371aeb6b71e
                Copyright © 2023 Du, Hu, Luo, Wang, Yu and Wang

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 December 2022
                : 24 January 2023
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 255, Pages: 17, Words: 9703
                Funding
                This work was in part supported by grants from the NCI, NIH (R01CA101795, R01CA246547 and U54CA210181), Department of Defense (DoD) CDMRP BCRP (BC151081) and LCRP (LC200368) to R-FW. This work was also partially supported by grants from National Natural Science Foundation of China (82171741), Guangdong Basic and Applied Basic Research Foundation (2019B1515120033 and 2021A1515012140) to XY.
                Categories
                Immunology
                Review

                Immunology
                cgas,sting,infectious diseases,immune regulation,innate immunity
                Immunology
                cgas, sting, infectious diseases, immune regulation, innate immunity

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