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  • sigakingone sigakingone Feb 16, 2013 9:56 AM Flag

    Emergence of Cowpox: Study of the Virulence of Clinical Strains and Evaluation of Antivirals

     

    Abstract

    The last years, cowpox infections are being increasingly reported through Eurasia. Cowpox viruses (CPXVs) have been reported to have different genotypes and may be subdivided in at least five genetically distinct monophyletic clusters. However, little is known about their in vitro and in vivo features. In this report, five genetically diverse CPXVs, including one reference strain (CPXV strain Brighton) and four clinical isolates from human and animal cases, were compared with regard to growth in cells, pathogenicity in mice and inhibition by antivirals. While all CPXVs replicated similarly in vitro and showed comparable antiviral susceptibility, marked discrepancies were seen in vivo, including differences in virulence with recorded mortality rates of 0%, 20% and 100%. The four CPXV clinical isolates appeared less pathogenic than two reference strains, CPXV Brighton and vaccinia virus Western-Reserve. Disease severity seemed to correlate with high viral DNA loads in several organs, virus titers in lung tissues and levels of IL-6 cytokine in the sera. Our study highlighted that the species CPXV consists of viruses that not only differ considerably in their genotypes but also in their in vivo phenotypes, indicating that CPXVs should not be longer classified as a single species. Lung virus titers and IL-6 cytokine level in mice may be used as biomarkers for predicting disease severity. We further demonstrated the potential benefit of cidofovir, CMX001 and ST-246 use as antiviral therapy.
    Citation: Duraffour S, Mertens B, Meyer H, van den Oord JJ, Mitera T, et al. (2013) Emergence of Cowpox: Study of the Virulence of Clinical Strains and Evaluation of Antivirals. PLoS ONE 8(2): e55808. doi:10.1371/journal.pone.0055808
    Editor: John E. Tavis, Saint Louis University, United States of America

    Received: November 16, 2012; Accepted: January 2, 2013; Published: February 15, 2013

    Copyright: © 2013 Duraffour et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Funding: This work was supported by FWO (Fund for Scientific Research-Flanders, Belgium, Grant G.0680.08) and by GOA (Geconcerteerd Onderzoek Actie, Grant 10/014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Competing interests: The authors have declared that no competing interests exist.

    Introduction

    Cowpox virus (CPXV) belongs to the Orthopoxvirus (OPV) genus, Poxviridae family. Recently, pet rat associated cowpox infections in humans have been reported through Europe with usually mild and self-limiting lesions [1]–[4]. In 1790s, Edward Jenner provided the first exhaustive descriptions of human cowpox in the publication of “An Inquiry Into the Causes and Effects of the VariolaeVaccinae or Cow-Pox (1798)”. Additional reports have further led to the extensive characterization of cowpox illness. Lesions, comparable to those seen with other OPVs, develop from cutaneous papules to vesicules and pustules [1], [3]–[5]. However, severe and/or fatal outcomes have been observed in individuals with impaired immunity such as those suffering of Darier’s disease [6], atopic dermatitis [5], [7], [8], or under steroid therapy [5]. Wild rodents are thought to be the reservoir of CPXV [9], [10].

    The recent and numerous cowpox cases in humans have highlighted the difficulties that exist in the differential clinical diagnosis of cowpox and treatment. Since no specific therapy is officially available, antibiotics are given to prevent bacterial infection of lesions. In some cases, due to delayed diagnostic, lesions were surgically excised [1], [3], [4], [11]. However, the off-label use of cidofovir was reported in one clinical case of cowpox [11]. Promising antivirals, although not FDA- or EMA-approved for the therapy of OPV-related diseases, are available and might be beneficial for cowpox-related illnesses. They include viral DNA polymerase inhibitors such as cidofovir [Vistide™], requiring intravenous administration, and its lipid derivative CMX001 [HDP-cidofovir], with improved oral bioavailability [12], [13]. ST-246, orally available, inhibits the egress of virus from infected cells [14]. These compounds showed potent antiviral activities against various OPV in vitro and in vivo, as well as against vaccinia virus (VACV) infections in humans under emergency use [12]–[14].

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