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      MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile

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          Highlights

          • MERS is caused by a single-stranded RNA virus named MERS-corona virus.

          • Infection with MERS-CoV elicits a type-I and type-II interferon response.

          • MERS-CoV infected patients show a prominent Th1 and Th17 cytokine profile.

          • MERS-CoV infection induces the expression of IL-10.

          Abstract

          The Middle East respiratory syndrome coronavirus (MERS-CoV) has been recognized as a highly pathogenic virus to humans that infects the respiratory tract and is associated with high morbidity and mortality. Studies in animal models suggest that MERS-CoV infection induces a strong inflammatory response, which may be related to the severity of disease. Data showing the cytokine profiles in humans during the acute phase of MERS-CoV infection are limited. In this study, we have analyzed the profile of cytokine responses in plasma samples from patients with confirmed MERS-CoV infections (n = 7) compared to healthy controls (n = 13). The cytokine profiles, including T helper (Th) 1, Th2 and Th17 responses, were analyzed using cytometric bead array (CBA). A prominent pro-inflammatory Th1 and Th17 response was clearly seen in patients with MERS-CoV infection, with markedly increased concentrations of IFN-γ, TNF-α, IL-15 and IL-17 compared to controls. IL-12 expression levels showed no difference between patients with MERS-CoV infection and the healthy controls despite the significantly increased levels of IFN-α2 and IFN-γ (P < .01). No changes were observed in the levels of IL-2, IL-4, IL-5, IL-13, and TGF-α (P > .05). Our results demonstrate a marked pro-inflammatory cytokine response during the acute phase of MERS-CoV infection in humans.

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          Most cited references47

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          Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.

          A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.
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            Hospital Outbreak of Middle East Respiratory Syndrome Coronavirus

            In September 2012, the World Health Organization reported the first cases of pneumonia caused by the novel Middle East respiratory syndrome coronavirus (MERS-CoV). We describe a cluster of health care-acquired MERS-CoV infections. Medical records were reviewed for clinical and demographic information and determination of potential contacts and exposures. Case patients and contacts were interviewed. The incubation period and serial interval (the time between the successive onset of symptoms in a chain of transmission) were estimated. Viral RNA was sequenced. Between April 1 and May 23, 2013, a total of 23 cases of MERS-CoV infection were reported in the eastern province of Saudi Arabia. Symptoms included fever in 20 patients (87%), cough in 20 (87%), shortness of breath in 11 (48%), and gastrointestinal symptoms in 8 (35%); 20 patients (87%) presented with abnormal chest radiographs. As of June 12, a total of 15 patients (65%) had died, 6 (26%) had recovered, and 2 (9%) remained hospitalized. The median incubation period was 5.2 days (95% confidence interval [CI], 1.9 to 14.7), and the serial interval was 7.6 days (95% CI, 2.5 to 23.1). A total of 21 of the 23 cases were acquired by person-to-person transmission in hemodialysis units, intensive care units, or in-patient units in three different health care facilities. Sequencing data from four isolates revealed a single monophyletic clade. Among 217 household contacts and more than 200 health care worker contacts whom we identified, MERS-CoV infection developed in 5 family members (3 with laboratory-confirmed cases) and in 2 health care workers (both with laboratory-confirmed cases). Person-to-person transmission of MERS-CoV can occur in health care settings and may be associated with considerable morbidity. Surveillance and infection-control measures are critical to a global public health response.
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              Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction.

              Dysregulated cytokine expression and signaling are major contributors to a number of autoimmune diseases. Interleukin-17A (IL-17A) and IL-6 are important in many disorders characterized by immune self-recognition, and IL-6 is known to induce the differentiation of T helper 17 (Th17) cells. Here we described an IL-17A-triggered positive-feedback loop of IL-6 signaling, which involved the activation of the transcription factors nuclear factor (NF)-kappaB and signal transducer and activator of transcription 3 (STAT3) in fibroblasts. Importantly, enhancement of this loop caused by disruption of suppressor of cytokine signaling 3 (SOCS3)-dependent negative regulation of the IL-6 signal transducer gp130 contributed to the development of arthritis. Because this mechanism also enhanced experimental autoimmune encephalomyelitis (EAE) in wild-type mice, it may be a general etiologic process underlying other Th17 cell-mediated autoimmune diseases.
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                Author and article information

                Contributors
                Journal
                Cytokine
                Cytokine
                Cytokine
                Elsevier Ltd.
                1043-4666
                1096-0023
                2 February 2018
                April 2018
                2 February 2018
                : 104
                : 8-13
                Affiliations
                [a ]Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
                [b ]Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, United Kingdom
                [c ]Molecular Biomedicine Program, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
                [d ]Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan
                Author notes
                [* ]Corresponding author at: College of Applied Medical Sciences, Taibah University, Prince Naif bin Abdulaziz Rd, Madinah 41541, Saudi Arabia. ofkhabour@ 123456taibahu.edu.sa
                Article
                S1043-4666(18)30038-3
                10.1016/j.cyto.2018.01.025
                7129230
                29414327
                b54a2dd5-0b5d-4db0-bdd5-b2418c4068f0
                © 2018 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 24 November 2017
                : 29 January 2018
                : 30 January 2018
                Categories
                Article

                Cell biology
                mers-cov,cytokines,interferons,humans
                Cell biology
                mers-cov, cytokines, interferons, humans

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