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      Reduction of soluble dipeptidyl peptidase 4 levels in plasma of patients infected with Middle East respiratory syndrome coronavirus

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          Abstract

          Dipeptidyl peptidase 4 (DPP4) is a receptor for MERS-CoV. The soluble form of DPP4 (sDPP4) circulates systematically and can competitively inhibit MERS-CoV entry into host cells. Here, we measured the concentration of sDPP4 in the plasma and sputa of 14 MERS-CoV-infected patients of various degrees of disease severity. The concentration of sDPP4 in the plasma of MERS patients (474.76 ± 108.06 ng/ml) was significantly lower than those of healthy controls (703.42 ± 169.96 ng/ml), but there were no significant differences among the patient groups. Interestingly, plasma levels of IL-10 and EGF were negatively and positively correlated with sDPP4 concentrations, respectively. The sDPP4 levels in sputa were less than 300 ng/ml. Viral infection was inhibited by 50% in the presence of more than 8000 ng/ml of sDPP4. Therefore, sDPP4 levels in the plasma of MERS patients are significantly reduced below the threshold needed to exert an antiviral effect against MERS-CoV infection.

          Highlights

          • •

            sDPP4, a soluble form of MERS-CoV receptor, in plasma is reduced in MERS patients.

          • •

            IL-10 and EGF in plasma are negatively and positively correlated with sDPP4.

          • •

            sDPP4 levels of MERS patients are not sufficient to exert an antiviral effect.

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          Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV.

          Anne-Marie Lambeir, Christine Durinx, Simon Scharpé … (2003)
          Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart from its catalytic activity, it interacts with several proteins, for instance, adenosine deaminase, the HIV gp120 protein, fibronectin, collagen, the chemokine receptor CXCR4, and the tyrosine phosphatase CD45. DPP IV is expressed on a specific set of T lymphocytes, where it is up-regulated after activation. It is also expressed in a variety of tissues, primarily on endothelial and epithelial cells. A soluble form is present in plasma and other body fluids. DPP IV has been proposed as a diagnostic or prognostic marker for various tumors, hematological malignancies, immunological, inflammatory, psychoneuroendocrine disorders, and viral infections. DPP IV truncates many bioactive peptides of medical importance. It plays a role in glucose homeostasis through proteolytic inactivation of the incretins. DPP IV inhibitors improve glucose tolerance and pancreatic islet cell function in animal models of type 2 diabetes and in diabetic patients. The role of DPP IV/ CD26 within the immune system is a combination of its exopeptidase activity and its interactions with different molecules. This enables DPP IV/CD26 to serve as a co-stimulatory molecule to influence T cell activity and to modulate chemotaxis. DPP IV is also implicated in HIV-1 entry, malignant transformation, and tumor invasion.
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            Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

            Erin Mulvihill, Daniel Drucker (2014)
            Abstract Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.
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              Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak in South Korea, 2015: epidemiology, characteristics and public health implications

              K.H. Kim, T.E. Tandi, J.W. Choi … (2016)
              Summary Background Since the first case of Middle East respiratory syndrome coronavirus (MERS-CoV) in South Korea was reported on 20th May 2015, there have been 186 confirmed cases, 38 deaths and 16,752 suspected cases. Previously published research on South Korea's MERS outbreak was limited to the early stages, when few data were available. Now that the outbreak has ended, albeit unofficially, a more comprehensive review is appropriate. Methods Data were obtained through the MERS portal by the Ministry for Health and Welfare (MOHW) and Korea Centres for Disease Control and Prevention, press releases by MOHW, and reports by the MERS Policy Committee of the Korean Medical Association. Cases were analysed for general characteristics, exposure source, timeline and infection generation. Sex, age and underlying diseases were analysed for the 38 deaths. Findings Beginning with the index case that infected 28 others, an in-depth analysis was conducted. The average age was 55 years, which was a little higher than the global average of 50 years. As in most other countries, more men than women were affected. The case fatality rate was 19.9%, which was lower than the global rate of 38.7% and the rate in Saudi Arabia (36.5%). In total, 184 patients were infected nosocomially and there were no community-acquired infections. The main underlying diseases were respiratory diseases, cancer and hypertension. The main contributors to the outbreak were late diagnosis, quarantine failure of ‘super spreaders’, familial care-giving and visiting, non-disclosure by patients, poor communication by the South Korean Government, inadequate hospital infection management, and ‘doctor shopping’. The outbreak was entirely nosocomial, and was largely attributable to infection management and policy failures, rather than biomedical factors.
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                Author and article information

                Contributors
                Yeon-Sook Kim
                Nam-Hyuk Cho
                Journal
                Journal ID (nlm-ta): Virology
                Journal ID (iso-abbrev): Virology
                Title: Virology
                Publisher: The Authors. Published by Elsevier Inc.
                ISSN (Print): 0042-6822
                ISSN (Electronic): 1096-0341
                Publication date PMC-release: 26 March 2018
                Publication date (Print): May 2018
                Publication date (Electronic): 26 March 2018
                Volume: 518
                Pages: 324-327
                Affiliations
                [a ]Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
                [b ]Department of Microbiology and Immunology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea
                [c ]Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
                [d ]Division of Infectious Diseases, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
                [e ]Institute of Endemic Disease, Seoul National University Medical Research Center and Bundang Hospital, Seoul, Republic of Korea
                Author notes
                [* ]Co-corresponding author. alice@ 123456cnuh.co.kr
                [** ]Corresponding author at: Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea. chonh@ 123456snu.ac.kr
                [1]

                These authors contributed equally.

                Article
                Publisher ID: S0042-6822(18)30095-3
                DOI: 10.1016/j.virol.2018.03.015
                PMC ID: 7112025
                PubMed ID: 29587190
                SO-VID: a5682370-c3fa-4f86-bce9-81eecd727243
                Copyright © © 2018 The Authors
                License:

                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
                Date received : 9 January 2018
                Date revision received : 26 February 2018
                Date accepted : 19 March 2018
                Categories
                Subject: Article

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: middle east respiratory syndrome coronavirus (mers-cov),dipeptidyl peptidase 4 (dpp4),soluble dpp4,antiviral therapy
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: middle east respiratory syndrome coronavirus (mers-cov), dipeptidyl peptidase 4 (dpp4), soluble dpp4, antiviral therapy

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