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      Coronavirus infections and immune responses

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          Abstract

          Coronaviruses (CoVs) are by far the largest group of known positive‐sense RNA viruses having an extensive range of natural hosts. In the past few decades, newly evolved Coronaviruses have posed a global threat to public health. The immune response is essential to control and eliminate CoV infections, however, maladjusted immune responses may result in immunopathology and impaired pulmonary gas exchange. Gaining a deeper understanding of the interaction between Coronaviruses and the innate immune systems of the hosts may shed light on the development and persistence of inflammation in the lungs and hopefully can reduce the risk of lung inflammation caused by CoVs. In this review, we provide an update on CoV infections and relevant diseases, particularly the host defense against CoV‐induced inflammation of lung tissue, as well as the role of the innate immune system in the pathogenesis and clinical treatment.

          Highlights

          • This highlights the importance of immune responses under coronavirus infection and improve the understanding of the features of CoV‐induced inflammatory response.

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          Most cited references63

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          Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease.

          The source of the severe acute respiratory syndrome (SARS) epidemic was traced to wildlife market civets and ultimately to bats. Subsequent hunting for novel coronaviruses (CoVs) led to the discovery of two additional human and over 40 animal CoVs, including the prototype lineage C betacoronaviruses, Tylonycteris bat CoV HKU4 and Pipistrellus bat CoV HKU5; these are phylogenetically closely related to the Middle East respiratory syndrome (MERS) CoV, which has affected more than 1,000 patients with over 35% fatality since its emergence in 2012. All primary cases of MERS are epidemiologically linked to the Middle East. Some of these patients had contacted camels which shed virus and/or had positive serology. Most secondary cases are related to health care-associated clusters. The disease is especially severe in elderly men with comorbidities. Clinical severity may be related to MERS-CoV's ability to infect a broad range of cells with DPP4 expression, evade the host innate immune response, and induce cytokine dysregulation. Reverse transcription-PCR on respiratory and/or extrapulmonary specimens rapidly establishes diagnosis. Supportive treatment with extracorporeal membrane oxygenation and dialysis is often required in patients with organ failure. Antivirals with potent in vitro activities include neutralizing monoclonal antibodies, antiviral peptides, interferons, mycophenolic acid, and lopinavir. They should be evaluated in suitable animal models before clinical trials. Developing an effective camel MERS-CoV vaccine and implementing appropriate infection control measures may control the continuing epidemic.
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            Signalling through C-type lectin receptors: shaping immune responses

            Key Points Crosstalk between pattern recognition receptors (PRRs) expressed by dendritic cells orchestrates T helper (TH) cell differentiation through the induction of specific cytokine expression profiles, tailored to invading pathogens. C-type lectin receptors (CLRs) have an important role in orchestrating the induction of signalling pathways that regulate adaptive immune responses. CLRs can control adaptive immunity at various levels by inducing signalling on their own, through crosstalk with other PRRs or by inducing carbohydrate-specific signalling pathways. DC-specific ICAM3-grabbing non-integrin (DC-SIGN) interacts with mannose-carrying pathogens including Mycobacterium tuberculosis, HIV-1, measles virus and Candida albicans to activate the serine/threonine protein kinase RAF1. RAF1 signalling leads to the acetylation of Toll-like receptor (TLR)-activated nuclear factor-κB (NF-κB) subunit p65 and affects cytokine expression, such as inducing the upregulation of interleukin-10 (IL-10). DC-associated C-type lectin 1 (dectin 1) triggering by a broad range of fungal pathogens, such as C. albicans, Aspergillus fumigatus and Pneumocystis carinii, results in protective antifungal immunity through the crosstalk of two independent signalling pathways — one through spleen tyrosine kinase (SYK) and one through RAF1 — that are essential for the expression of TH1 and TH17 cell polarizing cytokines. Crosstalk between the SYK and RAF1 pathways is both synergistic and antagonizing to fine-tune NF-κB activity: although Ser276 phosphorylation of p65 leads to enhanced transcriptional activity of p65 itself through acetylation, it also inhibits the transcriptional activity of the NF-κB subunit RELB by sequestering it in p65–RELB dimers, which are transcriptionally inactive. The diversity in CLR-mediated signalling provides some major challenges for the researches to elucidate and manipulate the signalling properties of this exciting family of receptors. However, the recent advances strongly support the use of CLR targeting vaccination strategies using dendritic cells to induce or redirect adaptive immune responses as well as improve antigen delivery.
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              Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.

              Toll-like receptors (TLRs) are activated by pathogen-associated molecular patterns to induce innate immune responses and production of pro-inflammatory cytokines, interferons and anti-inflammatory cytokines. TLRs activate downstream effectors through adaptors that contain Toll/interleukin-1 receptor (TIR) domains, but the mechanisms accounting for diversification of TLR effector functions are unclear. To dissect biochemically TLR signalling, we established a system for isolating signalling complexes assembled by dimerized adaptors. Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. Using myeloid cells from TRAF3- and TRAF6-deficient mice, we show that TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. In fact, TRAF3-deficient cells overproduce pro-inflammatory cytokines owing to defective IL-10 production. Despite their structural similarity, the functions of TRAF3 and TRAF6 are largely distinct. TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes, thereby explaining its unique role in activation of the IFN response.
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                Author and article information

                Contributors
                jwu898@jnu.edu.cn
                Journal
                J Med Virol
                J. Med. Virol
                10.1002/(ISSN)1096-9071
                JMV
                Journal of Medical Virology
                John Wiley and Sons Inc. (Hoboken )
                0146-6615
                1096-9071
                07 February 2020
                April 2020
                : 92
                : 4 , 2019 Novel Coronavirus Origin, Evolution, Disease, Biology and Epidemiology: Part‐I ( doiID: 10.1002/jmv.v92.4 )
                : 424-432
                Affiliations
                [ 1 ] Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology Jinan University Guangzhou China
                [ 2 ] Laboratory Animal Center Guangzhou University of Chinese Medicine Guangzhou China
                [ 3 ] The First Clinical Medical College Guangzhou University of Chinese Medicine Guangzhou China
                [ 4 ] State Key Laboratory of Virology, College of Life Sciences Wuhan University Wuhan China
                [ 5 ] The First Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou China
                [ 6 ] School of Pubic Health Southern Medical University Guangzhou China
                Author notes
                [*] [* ] Correspondence Jianguo Wu, Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, 510632 Guangzhou, China.

                Email: jwu898@ 123456jnu.edu.cn

                Author information
                http://orcid.org/0000-0002-2441-2427
                http://orcid.org/0000-0002-1287-3760
                http://orcid.org/0000-0002-9715-5871
                http://orcid.org/0000-0002-4635-7174
                http://orcid.org/0000-0003-3703-3634
                http://orcid.org/0000-0002-3755-4037
                http://orcid.org/0000-0003-1457-7057
                http://orcid.org/0000-0003-4944-764X
                http://orcid.org/0000-0001-5062-459X
                http://orcid.org/0000-0003-4795-3039
                http://orcid.org/0000-0003-0134-1985
                http://orcid.org/0000-0002-8326-2895
                Article
                JMV25685
                10.1002/jmv.25685
                7166547
                31981224
                b7b23e0d-fe1a-43ed-b233-94fe397db2b4
                © 2020 Wiley Periodicals, Inc.

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 21 January 2020
                : 22 January 2020
                Page count
                Figures: 2, Tables: 0, Pages: 9, Words: 7182
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81730061
                Award ID: 81902066
                Award ID: 81471942
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                April 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:16.04.2020

                Microbiology & Virology
                chemokine,coronavirus,cytokines,inflammation,interferon
                Microbiology & Virology
                chemokine, coronavirus, cytokines, inflammation, interferon

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