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Antiviral Mechanism of Carvacrol on HSV-2 Infectivity Through Inhibition

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Antiviral Mechanism of Carvacrol on HSV-2 Infectivity Through Inhibition Wang et al. BMC Infectious Diseases (2020) 20:832 https://doi.org/10.1186/s12879-020-05556-9 RESEARCH ARTICLE Open Access Antiviral mechanism of carvacrol on HSV-2 infectivity through inhibition of RIP3- mediated programmed cell necrosis pathway and ubiquitin-proteasome system in BSC-1 cells Li Wang1†, Dan Wang2†, Xingan Wu3†, Rui Xu1 and Yunlan Li4* Abstract Background: Carvacrol, as the major components of aromatic plants used for treating human skin diseases including origanum, Satureja, thymus, and coridothymus species, presented a kind of antiviral activity. To explore the mechanisms of carvacrol against herpes simplex virus (HSV) in vitro. Method: The BSC-1 cells model of HSV infection was established, and from the two aspects of viral replication level and cell death pathway, the antiviral effects of carvacrol on HSV infected cells were also evaluated by plaque assay under the three modes including prevention, treatment, and direct inactivation. Results: In the three ways, the half-maximal effective concentration (EC50) of 2% true carvacrol solution on HSV-2 infected cells were severally 0.43, 0.19 and 0.51 mmol/L, and the corresponding therapeutic index (TI) were 4.02, 9.11 and 3.39, respectively. It’s the opposite of the increased levels caused by HSV-2 infection, that both the expressions at the transcription genes and protein levels of virus own replication key factors (including ICP4, ICP27, VP16, gB, and UL30) and cytokines (including RIP3, TNF-α, and MLKL) of infected cells treated with carvacrol were dose-dependently inhibited. Besides, HSV-2 infection can cause the decrease of intracellular protein ubiquitination level, and carvacrol can reverse the ubiquitination decrease level caused by HSV-2 infection. Conclusion: Carvacrol exhibits significant antiviral activity by inhibiting the HSV-2 proliferation process and HSV-2- induced TNF-α increasing levels, decreasing RIP3 and MLKL protein expressions through the intracellular RIP3- mediated programmed cell necrosis pathway. In addition, carvacrol also may exhibit anti-HSV-2 activity by reversing the ubiquitination decrease level caused by HSV-2 infection on the ubiquitin-proteasome system, which provides insights into the molecular mechanism. Keywords: Carvacrol, Herpes simplex virus-2 (HSV-2), Antiviral activity, Programmed cell necrosis, Ubiquitin- proteasome * Correspondence: [email protected] †Li Wang, Dan Wang and Xingan Wu contributed equally to this work. 4School of Pharmaceutical Science, Shanxi Medical University, No. 36, Xin Jian South Road, Taiyuan 030001, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. BMC Infectious Diseases (2020) 20:832 Page 2 of 16 Background trial in recent years [19, 20]. Carvacrol could exert anti- Herpes simplex virus (HSV) is enveloped, linear and viral activity by preventing the death of cells infected double-stranded DNA virus, which belongs to the with HSV, but the specific mechanism of it against HSV family herpesviridae,genusalphaherpesvirinae.Itis virus has not been reported up to now [21, 22]. As a one of the most common pathogenic agents in new alternative energy, carvacrol provides a new possi- humans and divided into two types: HSV-1 and HSV-2 bility for the development of HSV treatment and pre- [1]. There is increasing awareness of the importance ventive health care drugs with advantages of great of skin infection disease caused by HSV infection. source, safety, low toxicity, and nature. Several of emerging cases were found continuously in So the purpose of this paper was to explore the anti- recent years [2, 3], which indicated an upward trend in viral activity of carvacrol against HSV in vitro by plaque HSV incidence. Extensive evidence proved that HSV assay. The possible mechanisms of carvacrol’s antiviral viruses could typically cause severe afflictions, mainly effect on HSV-2 infected BSC-1 cells were studied from because of the generation of genital lesions and severe two aspects of viral replication level and cell death path- infections like life-threatening encephalitis and dis- way through molecular biological techniques, which can seminated infections in neonates [4–6]. The HSV is provide adequate theoretical supports for the discovery also associated with potentially fatal viral stromal of new antiviral drugs and alternative energy. keratitis, an ocular disease, which is a leading cause of cornea-derived blindness in developed countries [7]. Methods Currently, the approved primary anti-HSV therapeutic Carvacrol, cells, virus strains and major reagents drugs are acyclovir (ACV) and its derivatives, which Carvacrol (Oregano oil; Purity: 99.8%) and 2% carvacrol interfere with viral DNA synthesis to reduce viral rep- true solution, prepared by dissolving 2 mL carvacrol with lication and transmission. But all mentioned nucleo- 33% sulfur-β-paste in distilled water at 100 mL, were side analogs drugs, including ACV, ganciclovir and kindly provided by prof. S. W from the air force medical penciclovir, were oriented on the same molecular university in China. Vero cells and HSV laboratory mechanisms of action that hinders viral DNA synthe- standard virus strain (HSV-1-F strain and HSV-2-G sis by competitively inhibiting viral DNA polymerase strain) were kindly gifted by prof. X. A from the air force or adding itself to viral DNA, and the multi-drug medical university. BSC-1 cells were kindly donated by resistant HSV viral strains were starting to show up prof. Z. Q from Wuhan University. Vero and BSC-1 cells more and more with heavy use of nucleoside analogs were incubated under Dulbecco-modified eagle’s agents. Besides, the disadvantages of their narrow anti- medium (DMEM, high glucose) with 10% fetal bovine viral spectrum and high costs gradually also aggra- serum (FBS) at 37 °C in the atmosphere containing 5% vated people’s living burden [8–10], extremely in CO2. HSV strains were grown for 3 ~ 4 days on cells in America [11]. For these reasons, there is a need for an atmosphere of 5% CO2 at 37, and the virus stock the development of novel antiherpes drugs which are solution was stored at − 80 °C until use. Whereafter, the safe and preferably inexpensive with limiting the pri- plaque assay [23] was performed to determinate viral mary infection and supporting further treatment. multiplicity of infection (MOI) on cells. Of which, high A large number of herbs and aromatic plants are fre- glucose DMEM medium, FBS and cell counting CCK8 quently used for treating human skin diseases, especially kits were purchased from Shanghai sangon biological from the family of Lamiaceae including origanum, engineering co. Ltd. The following antibodies were used: satureja, thymus, and coridothymus species [12]. Carva- anti-ICP4 polyclonal antibody (Abcam; ab96432), anti- crol, a monoterpene phenol that is also known as 2- ICP27 monoclonal antibody (Abcam; ab31631), anti- methyl-5-(1- methyl ethyl)-phenol, is one of the signifi- VP16 monoclonal antibody (Abcam; ab110226), anti-gB cant components of oregano essential oils, and presents monoclonal antibody (Abcam; ab6506), anti-Caspase-3 a wide diversity of biological activities, such as antiviral antibody (Abcam; ab 90,437), anti-Ub antibody (Abcam; [13–15], anticancer [12], antimicrobial [16], antioxidant ab7780), anti-RIP3 (Abcam; ab56164), anti-MLKL anti- and anti-inflammatory [17, 18]. Besides, carvacrol also body (Abcam; ab184718), anti-Caspase-1 (Proteintech; has been identified as a natural, economical food preser- 22,915–1-AP), anti-TNF-α (Proteintech; 60,291–1-lg). vative. Currently, the carvacrol-related health products, Goat anti-rabbit infrared secondary antibody (IR including 60 soft gels and 60 vegetarian capsules, are Dye800CW, 926–32,211) and goat anti-mouse infrared available for antioxidant treatments on the market. The secondary (IR Dye680RD; 926–68,070) were purchased relevant literature have also indicated that carvacrol has from American LICOR biosciences. Secondary antibody an safety and tolerability effect on healthy volunteers binding to Alexa Fluor 488 or Cy3 was purchased from through a phaseIclinical trial and possible therapeutic Xi’an Zhuangzhi biotechnology co.Ltd. Fast 1000 total effect on asthmatic patients through a phase II clinical RNA rapid extraction kit, 5 × PrimeScript RT Master Wang et al. BMC Infectious Diseases (2020) 20:832 Page 3 of 16 Mix (TakaRa), RNase Free dH2O (TakaRa) and TB Ab stands for the blank control. Subsequently,
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