Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

Abstract

Zinc is an essential micronutrient which regulates diverse physiological functions and has been shown to play a crucial role in viral infections. Zinc has a necessary role in the replication of many viruses, however, antiviral action of zinc has also been demonstrated in in vitro infection models most likely through induction of host antiviral responses. Therefore, depending on the host machinery that the virus employs at different stages of infection, zinc may either facilitate, or inhibit virus infection. In this study, we show that zinc plays divergent roles in rotavirus and dengue virus infections in epithelial cells. Dengue virus infection did not perturb the epithelial barrier functions despite the release of virus from the basolateral surface whereas rotavirus infection led to disruption of epithelial junctions. In rotavirus infection, zinc supplementation post-infection did not block barrier disruption suggesting that zinc does not affect rotavirus life-cycle or protects epithelial barriers post-infection suggesting the involvement of cellular pathways in the beneficial effect of zinc supplementation in enteric infections. Zinc depletion by N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) inhibited dengue virus and Japanese encephalitis virus (JEV) infection but had no effect on rotavirus. Time-of-addition experiments suggested that zinc chelation affected both early and late stages of dengue virus infectious cycle and zinc chelation abrogated dengue virus RNA replication. We show that transient zinc chelation induces ER stress and antiviral response by activating NF-kappaB leading to induction of interferon signaling. These results suggest that modulation of zinc homeostasis during virus infection could be a component of host antiviral response and altering zinc homeostasis may act as a potent antiviral strategy against flaviviruses.

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

“…It is puzzling that Zn 2+ both promotes and inhibits virus replication, while its deficiency is associated with increased viral load, suggesting that there are major gaps in our understanding of how this metal influences viruses. While Zn 2+ is required for virus replication, its chelation inhibits viral proteins (HPV E6 protein, flavivirus NS5A protein) and virus replication (HPV, dengue virus (DENV), and Japanese encephalitis virus (JEV)) [ 207 , 208 , 209 , 210 ]. Despite severe toxicities associated with experimental Zn 2+ chelators, such as TPEN (N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine) and 1,6-hexanediol, other drug classes with better safety profiles, including bananins, may be effective against HIV-1 and other viruses, including coronaviruses [ 211 , 212 ].…”

“…Despite severe toxicities associated with experimental Zn 2+ chelators, such as TPEN (N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine) and 1,6-hexanediol, other drug classes with better safety profiles, including bananins, may be effective against HIV-1 and other viruses, including coronaviruses [ 211 , 212 ]. Zn 2+ ionophores, such as pyrithione and chloroquine derivatives, among others, have also recently been shown to inhibit diverse groups of viruses, such as HSV, DENV, and SARS-CoV-2 [ 210 , 213 , 214 ].…”

The Role of Micronutrients in Support of the Immune Response against Viral Infections

“…[ 242 , 243 , 244 ]. Zinc supplementation is also effective in decreasing oxidative stress [ 245 , 246 ], in shortening the duration of cold symptoms in adults [ 247 ], and was found to have a direct antiviral effect on RSV [ 248 ], Dengue virus [ 249 ], and coronaviruses [ 250 ]. Lastly, some authors suggested that a combination of chloroquine with zinc might enhance chloroquine’s toxicity on viruses [ 249 , 250 , 251 , 252 ].…”

“…Zinc supplementation is also effective in decreasing oxidative stress [ 245 , 246 ], in shortening the duration of cold symptoms in adults [ 247 ], and was found to have a direct antiviral effect on RSV [ 248 ], Dengue virus [ 249 ], and coronaviruses [ 250 ]. Lastly, some authors suggested that a combination of chloroquine with zinc might enhance chloroquine’s toxicity on viruses [ 249 , 250 , 251 , 252 ]. Te Velthius et al [ 249 ] reported that the combination of Zn2+ and zinc-ionophores like pyrithione can increase the intracellular Zn2+ concentration, and thus inhibits the replication of SARS-coronavirus (SARS-CoV) and equine arteritis virus in cell culture.…”

“…Lastly, some authors suggested that a combination of chloroquine with zinc might enhance chloroquine’s toxicity on viruses [ 249 , 250 , 251 , 252 ]. Te Velthius et al [ 249 ] reported that the combination of Zn2+ and zinc-ionophores like pyrithione can increase the intracellular Zn2+ concentration, and thus inhibits the replication of SARS-coronavirus (SARS-CoV) and equine arteritis virus in cell culture.…”