A role for zinc in the mitigation of zoonotic disease attributable to RNA viruses—a review with application to One Health perspective

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One Health is a concept that serves as a common foundation for connecting human and animal populations, primarily those of domestic livestock, poultry, wildlife, and companion animals, with environmental and socioeconomic factors, as it relates to the understanding, prevention, and treatment of multiple zoonotic diseases that can afflict all groups on a global basis. Numerous zoonotic diseases affecting both human and animal populations are attributable to various families of RNA viruses as the primary etiologic agent. A growing body of research is providing evidence to support the concept that dietary zinc can potentially have a role in the prevention and mitigation of zoonotic diseases attributable to RNA viruses. The increasing risk to One Health from an increased prevalence of RNA viral diseases requires a better understanding of the role nutritional immunity may have for prevention and mitigation. The concept of One Health may be associated with many diverse interpretations in both scope and practice as viewed from a particular frame of reference or perspective. From a general perspective of human and veterinary medicine, One Health is based on the general premise that human and veterinary medicine are connected at multiple levels, with environmental and socioeconomic factors often providing a common denominator. The interdisciplinary One Health High-Level Expert Panel (OHHELP; Adisasmito et al., 2022) has broadly defined One Health as an integrated, unifying approach that aims to sustainably balance and optimize the health of people, animals, and ecosystems. The OHHELP definition also recognizes health of humans, domestic and wild animals, plants, and the wider environment (including ecosystems) constitutes an often-diverse set of factors that are intimately connected, integrated, and interdependent at multiple points and levels. Multiple events are occurring to converge many disparate effects into a generalized synergism affecting the health of global human and animal populations. These effects may include growing numbers of human populations that are expanding into new geographic areas, either through population growth, conflict-induced migration, or ecosystem disruption as affected by climate change. These factors along with increased international trade and global travel may result in a closer proximity between people and animals (wild and domestic) that allows for increased passage of pathogens that may facilitate the potential dissemination and emergence of existing and novel zoonotic diseases (Keusch et al., 2022). The recent occurrence of global pandemics, including severe acute respiratory syndrome-associated coronavirus infection (SARS-COVID) in 2019 and the increasing prevalence of the H5N1 strain of highly pathogenic avian influenza A (HPAI-A) have required increased attention to the role of viral pathogens and specifically RNA viruses may have and their implications on One Health. A recent review by Ameni et al. (2024) documented seven major zoonotic outbreaks attributable to RNA viruses from 1997 to 2021 indicating three primary causative groups of RNA viruses associated with these outbreaks were: (1) HPAI-A and swine-origin influenza (H1N1); (2) SARS-COVID-19, Middle East respiratory syndrome (MERS-COVID), and other Coronavirus borne diseases; and (3) Zika virus infections. RNA viruses are also responsible for causing rabies, foot and mouth disease (FMD), and a myriad of other diseases affecting both human and/or animal populations. In general, viral diseases, including those attributable to RNA viruses, have had profound impacts on human and veterinary morbidity, mortality, and socioeconomic loss (Ameni et al., 2024). Given the potential for RNA viruses to rapidly mutate, enabling them to spread from a primary host to other species, consideration needs to be focused on alternative methods to restrict further cross-species transmission and potential alternative methods for prophylaxis and therapy. Similarly, because of the difficulty, time, and cost associated with developing antiviral pharmacologic interventions, consideration for nutritionally based or other alternatives is required. Recently, this has become more urgent with the documented presence of the HPAI-A virus being found in dairy cows with several confirmed cases of this virus being transmitted to humans as well as 400 other avian and mammalian species (Center for Disease Control [CDC], 2025). Similarly, the specter of potential future pandemics being caused by novel and yet unrecognized RNA viruses remains on the horizon. An in-depth discussion of RNA virology and the research concerning basic or mechanistic aspects of zinc on viral physiology and associated immunology is beyond the scope of this paper. The research in this area has been extensive and globally based and the subject for several excellent reviews, which will be highlighted throughout this paper. Rather, our objective is to provide an overview of how the general concept of nutritional immunity may have application with particular attention on published research investigating the effects of zinc on RNA viral biology and its potential application for mitigating the risk that RNA viral diseases pose to both human and animal populations from a One Health perspective. Trace elements (TE) are those provided in the diet at rates of mg or ng/kg of dry matter (DM) intake and include metals such as iron, zinc, manganese, copper, selenium, and chromium, among others, and have numerous biological and physiological roles essential for all recognized life forms, including bacteria (Shenkin, 2006). The critical requirement for TE by bacteria thereby underscores the basic premise of nutritional immunity as it is presently understood. The concept of nutritional immunity has classically referred to the ability of an animal host to restrict access of nutrient metals from bacteria as a means of helping to mitigate pathogenesis. Murdoch and Skaar (2022) discussed the concept of nutritional immunity as the battle for TE at the host–pathogen interface. The traditional model (Kehl-Fie and Skaar, 2010; Hennigar and McClung, 2016; Murdoch and Skaar, 2022) for nutritional immunity has been where a host employs various metabolic strategies to limit the access of iron to a bacterial pathogen infecting the body. As described by Murdoch and Skaar (2022) in addition to other immunological responses following infection by a bacterial pathogen, the affected host restricts the amount of iron potentially available to the bacterial pathogen through a systemic reprogramming of iron homeostasis sequestering iron into many cells, such as macrophages, hepatocytes, and enterocytes. Concurrently, iron absorption from the gut is reduced with the combined effects being an overall reduction in available iron to support bacterial growth. In addition to iron, similar nutritional immunity mechanisms for limiting bacterial access to manganese and zinc are also activated in response to invasion by a bacterial pathogen (Kehl-Fie and Skaar, 2010). Like the role of TE in the overall defense against bacterial infection, whether through nutritional immunity or a generalized systemic immune response, TE has also played a therapeutic role in medicine throughout history. Lemire et al. (2013) have reviewed the critical role of various TE as metallopharmaceutics in the treatment of numerous diseases, especially prior to the discovery of antibiotics. The discovery and development of Salvarsan, an organo-metallic complex of arsenic, for the treatment of syphilis by Paul Erlich and coworkers in 1910 ushered in the age of chemotherapy as a vital component in both human and veterinary medicine. However, the general concepts of both nutritional immunity and metallopharmaceutics to this point have primarily involved their application to bacterial pathogens and not viral-genic disease. As will be discussed in the remainder of this paper, the concepts of nutritional immunity and metallopharmaceutics as applicable to viral-based disease, while valid, may need to be approached from a different perspective than that generally applied to bacterial pathogens. For this purpose, the discussion will focus on zinc as a potential intervention for aiding in the mitigation of zoonotic disease caused by RNA viruses. Zinc was first identified as essential for human nutrition in the 1960s (Prasad, 2012). Research studies conducted throughout the intervening years have documented the numerous roles zinc has in many metabolic, physiological, structural, and immunological processes (Maret, 2025). As a transition metal, zinc has several intrinsic properties that make it a vital component or cofactor in over 3,000 known metabolic processes and is second only to calcium in this regard (Singh and Prasad, 2023; Maret, 2025). A dietary supply of zinc is required daily since little is stored in a form that can be readily used to support physiological or immune functions (Huang et al., 2025). Unfortunately, it has been estimated that approximately two billion people, primarily those living in less developed countries may be deficient in zinc; although, other groups in more developed countries such as the elderly or those with lesser socioeconomic status may similarly have inadequate or marginal daily dietary zinc intake (Prasad, 2012; Wessels and Brown, 2012). A similar situation may exist for domestic food animal populations, where adequacy of zinc status and dietary sufficiency remains difficult to assess in many circumstances and likely contingent on dietary levels as affected by geographic, environmental, and economic factors. This may be especially relevant for non-supplemented livestock grazing pasture or rangeland where zinc and other nutrient concentrations in the plants and forage may be marginal and vary across the year (Brummer et al., 2019; Spears et al., 2022). Similarly, monogastric livestock and poultry may be at greater risk for lower zinc absorption due to the presence of dietary phytates (Herdt and Hoff, 2011). Assessing functional zinc status in both humans and animals, however, remains problematic as its measurement is subject to multiple factors and lack of validated methods (Franco et al., 2024; Maret, 2025); however, general categories based on serum levels and(or) dietary intake concentration are used for assessing adequate, deficient, or marginal status in human and animal populations (Herdt and Hoff, 2011; Maret, 2025). Numerous chemical sources of zinc are typically available for dietary supplementation. Inorganic as well as organic sources can vary significantly in their overall bioavailability. Inorganic zinc sources such as zinc oxide are generally less bioavailable than sulfate or chloride forms. Organic forms such as those where zinc is complexed to an organic ligand such as amino acid may be regarded as generally more available for absorption (Wedekind et al., 1992). Developing nutritionally based strategies for potential mitigation of RNA viral disease will require consideration of both dietary zinc source and level across both at-risk human and animal populations. The application of molecular modeling described by Choudhury et al. (2021) may be a potential avenue for facilitating further research. Gombart et al. (2020) reviewed the role of micronutrients in immune function. Specifically, zinc has a key role in over 100 metabolic systems and is integral to all aspects of immune function including those related to viral diseases, and especially those attributable to RNA viruses. An abridged summary of the role of zinc in various immune functions is shown in Table 1 (Gombart et al., 2020). Zinc has a wide diversity of roles through its involvement in many different biological processes including cell proliferation and differentiation, cell cycle activities, reactive oxygen species (ROS) homeostasis, and immune response (Read et al., 2019; Gombert et al., 2020). Zinc is involved in improving response of immune cells to a virus, as well as being involved in zinc-dependent protein production that kill viruses, directly preventing RNA viruses from replicating (Ibs and Rink, 2003; Gao et al., 2018). Zinc reduces inflammatory cytokines and chemokines such as tumor necrosis factor (TNF-α), interleukins (IL-1β, IL-6), monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule (VCAM), and C-reactive protein (CRP) as well as oxidative stress markers such as lipid peroxidation products and DNA intermittent oxidation products (Daskou et al., 2023). Other research has shown that zinc is crucial in regulating inflammatory cytokines by reducing IL-6 concentrations and proinflammatory responses via kappa-light-chain-enhancement of activated B cells (NF-kB), alleviating redox-induced cellular injury controlling oxidative stress, and avoiding host-tissue damage by inflammation (Jarosz et al., 2017; Wu et al., 2019). Summary of zinc in immune functiona,b Maintains/enhances natural killer cell activity Role in immune cell growth and differentiation Enhance phagocytic activity of macrophages Improves phagocytic activity of monocytes Anti-inflammatory agent Modulation of cytokine release development of proinflammatory and cells of cytokine from activity of proliferation of cytokine production and response for differentiation, and of cells and of immune with production with response to in immune Maintains/enhances natural killer cell activity Role in immune cell growth and differentiation Enhance phagocytic activity of macrophages Improves phagocytic activity of monocytes Anti-inflammatory agent Modulation of cytokine release development of proinflammatory and cells of cytokine from activity of proliferation of cytokine production and response for differentiation, and of cells and of immune with production with response to in immune from Gombart et al. reactive oxygen necrosis factor Summary of zinc in immune functiona,b Maintains/enhances natural killer cell activity Role in immune cell growth and differentiation Enhance phagocytic activity of macrophages Improves phagocytic activity of monocytes Anti-inflammatory agent Modulation of cytokine release development of proinflammatory and cells of cytokine from activity of proliferation of cytokine production and response for differentiation, and of cells and of immune with production with response to in immune Maintains/enhances natural killer cell activity Role in immune cell growth and differentiation Enhance phagocytic activity of macrophages Improves phagocytic activity of monocytes Anti-inflammatory agent Modulation of cytokine release development of proinflammatory and cells of cytokine from activity of proliferation of cytokine production and response for differentiation, and of cells and of immune with production with response to in immune from Gombart et al. reactive oxygen necrosis factor of the immune response to viral infection the response of natural killer cells This population of immune cells are a of cells that an of on their cell and in the immune response an essential role in immunity against with the ability to kill cells (Daskou et al., 2023). These cells viruses or cells by three (1) the of an antiviral (2) of and and (3) through of (Read et al., 2019; et al., 2022). is known that of cell functions is in by an activated cytokine a virus which is highly to the of et al., of function provide a on viral in the body. et al. zinc zinc reduced an that was zinc was to Zinc has the of through a of the major molecule Zinc activity of cells and the infection (Daskou et al., 2023). RNA is an required for RNA from the viral RNA of this of viruses. This is a protein required for the viral life cycle and of infection the DNA In research has shown effects of zinc on virus by its to the acid and other that can or with the et al., effects of zinc by viral RNA and protein processes in several diverse viral including human virus, and virus have been (Read et al., 2019; et al., 2022). recent have provided to zinc status is a affecting the of and that dietary zinc may be for mitigation and/or treatment of this disease et al., et al., Wessels et al., et al., et al., 2024). In their summary of multiple research et al. have the potential role of zinc as an antiviral agent may be into two (1) zinc to the antiviral response and systemic immunity in with zinc and (2) zinc treatment to specifically viral or have research investigating potential mechanisms for antiviral effects of zinc et al., 2017; et al., 2019; et al., et al., et al., et al., et al., 2023; et al., 2023). functional RNA is to RNA viruses as from all other which DNA as the for of allows for a and for RNA viruses with DNA viruses. provide a potential therapeutic for treatment of and other RNA viruses as this is to the RNA to et al., 2017; et al., Zinc may the viral cycle of coronavirus in by with this response being more to a greater concentration of dietary zinc et al., et al., a zinc has been shown to the cycle of in in the presence of zinc zinc can the viral and the viral cycle by viral RNA et al., Other potential from zinc are reduction of concentration the response to human activity and of on Other research has with infection have a reduced concentration of serum zinc with as and Brown, 2012; et al., 2024). that have a significantly serum concentration of zinc with a Wessels et al., 2020). zinc concentrations of or less have been zinc deficient, while or more is zinc or in the human body et al., 2020). zinc has been found to be to the of infection as by rates of such as acute respiratory the need for of and These may elderly populations, are more to zinc have a significantly risk of and et al., 2020). As reviewed an increasing body of and research studies are providing evidence that zinc has an role in antiviral immunity and has antiviral The antiviral effects of zinc to be with a diversity of RNA viral families that different and species being et al., 2019). The of HPAI-A an of how this virus has spread from wild populations to domestic of and to many other avian species, and mammalian species (including in and 2025). In Table common human and animal RNA viruses as etiologic in zoonotic disease are et al., 2020). of RNA viral zoonotic from et al. of RNA viral zoonotic from et al. The research discussed to this point has been related to more basic aspects of zinc as an antiviral with an human medicine. However, the zoonotic potential for many RNA viruses to multiple species remains a et al. (2022) have influenza viruses, respiratory virus, and are among the respiratory viruses to both human and animal populations. 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