Coordination of Different Ligands to Copper(II) and Cobalt(III) Metal Centers Enhances Zika Virus and Dengue Virus Loads in Both Arthropod Cells and Human Keratinocytes

Authors

Shovan Dutta, Old Dominion University
Michael J. Celestine, Old Dominion UniversityFollow
Supreet Khanal, Old Dominion University
Alexis Huddleston, Old Dominion University
Colin Simms, Old Dominion University
Jessa Faye Arca, Old Dominion University
Amlam Mitra, Old Dominion University
Loree Heller, Old Dominion UniversityFollow
Piotr Kraj, Old Dominion UniversityFollow
Michael Ledizet
John F. Anderson
Girish Neelakanta, Old Dominion UniversityFollow
Alvin A. Holder, Old Dominion UniversityFollow
Hameeda Sultana, Old Dominion UniversityFollow

Document Type

Article

Publication Date

2018

DOI

10.1016/j.bbagen.2017.10.004

Publication Title

Biochimica Et Biophysica Acta-General Subjects

Volume

1862

Issue

1

Pages

40-50

Abstract

Trace elements such as copper and cobalt have been associated with virus-host interactions. However, studies to show the effect of conjugation of copper(II) or cobalt(III) metal centers to thiosemicarbazone ligand(s) derived from either food additives or mosquito repellent such as 2-acetylethiazole or citral, respectively, on Zika virus (ZIKV) or dengue virus (serotype 2; DENV2) infections have not been explored. In this study, we show that four compounds comprising of thiosemicarbazone ligand derived from 2-acetylethiazole viz., (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide (acetylethTSC) (compound 1), a copper(II) complex with acetylethTSC as a ligand (compound 2), a thiosemicarbazone ligand-derived from citral (compound 3) and a cobalt(III) complex with a citral-thiosemicarbazone ligand (compound 4) increased DENV2 and ZIKV replication in both mosquito C6/36 cells and human keratinocytes (HaCaT cells). Treatment of both cell lines with compounds 2 or 4 showed increased dengue viral titers at all three tested doses. Enhanced dengue viral plaque formation was also noted at the tested dose of 100 μM, suggesting higher production of infectious viral particles. Treatment with the compounds 2 or 4 enhanced ZIKV and DENV2 RNA levels in HeLa cell line and primary cultures of mouse bone marrow derived dendritic cells. Also, pre- or post treatments with conjugated compounds 2 or 4 showed higher loads of ZIKV or DENV2 envelope (E) protein in HaCaT cells. No changes in loads of E-protein were found in ZIKV-infected C6/36 cells, when compounds were treated after infection. In addition, we tested bis(1,10-phenanthroline)copper(II) chloride ([Cu(phen)₂]Cl₂, (compound 5) and tris(1,10-phenanthroline)cobalt(III) chloride ([Co(phen)₃]Cl₃, (compound 6) that also showed enhanced DENV2 loads. Also, we found that copper(II) chloride dehydrate (CuCl₂·2H₂O) or cobalt(II) chloride hexahydrate (CoCl₂·6H₂O) alone had no effects as “free” cations. Taken together, these findings suggest that use of Cu(II) or Co(III) conjugation to organic compounds, in insect repellents and/or food additives could enhance DENV2/ZIKV loads in human cells and perhaps induce pathogenesis in infected individuals or individuals pre-exposed to such conjugated complexes.

Importance

Mosquito-borne diseases are of great concern to the mankind. Use of chemicals/repellents against mosquito bites and transmission of microbes has been the topic of interest for many years. Here, we show that thiosemicarbazone ligand(s) derived from 2-acetylethiazole or citral or 1,10-phenanthroline upon conjugation with copper(II) or cobalt(III) metal centers enhances dengue virus (serotype 2; DENV2) and/or Zika virus (ZIKV) infections in mosquito, mouse and human cells. Enhanced ZIKV/DENV2 capsid mRNA or envelope protein loads were evident in mosquito cells and human keratinocytes, when treated with compounds before/after infections. Also, treatment with copper(II) or cobalt(III) conjugated compounds increased viral titers and number of plaque formations. These studies suggest that conjugation of compounds in repellents/essential oils/natural products/food additives with copper(II) or cobalt(III) metal centers may not be safe, especially in tropical and subtropical places, where several dengue infection cases and deaths are reported annually or in places with increased ZIKV caused microcephaly.

Comments

This is the author's unedited manuscript that has been accepted for publication. The final edited form was published as:

Dutta, S., Celestine, M. J., Khanal, S., Huddleston, A., Simms, C., Arca, J. F., . . . Sultana, H. (2018). Coordination of different ligands to copper(II) and cobalt(III) metal centers enhances Zika virus and Dengue virus loads in both arthropod cells and human keratinocytes. Biochimica Et Biophysica Acta-General Subjects, 1862(1), 40-50. doi:10.1016/j.bbagen.2017.10.004

Original Publication Citation

Dutta, S., Celestine, M. J., Khanal, S., Huddleston, A., Simms, C., Arca, J. F., . . . Sultana, H. (2018). Coordination of different ligands to copper(II) and cobalt(III) metal centers enhances zika virus and dengue virus loads in both arthropod cells and human keratinocytes. Biochimica Et Biophysica Acta-General Subjects, 1862(1), 40-50. doi:10.1016/j.bbagen.2017.10.004

Repository Citation

Dutta, Shovan; Celestine, Michael J.; Khanal, Supreet; Huddleston, Alexis; Simms, Colin; Arca, Jessa Faye; Mitra, Amlam; Heller, Loree; Kraj, Piotr; Ledizet, Michael; Anderson, John F.; Neelakanta, Girish; Holder, Alvin A.; and Sultana, Hameeda, "Coordination of Different Ligands to Copper(II) and Cobalt(III) Metal Centers Enhances Zika Virus and Dengue Virus Loads in Both Arthropod Cells and Human Keratinocytes" (2018). Biological Sciences Faculty Publications. 332.
https://digitalcommons.odu.edu/biology_fac_pubs/332

ORCID

0000-0001-8084-0787 (Heller)