Date Published: December 26, 2013
Publisher: Public Library of Science
Author(s): Kavitha Subramanian Vignesh, Julio A. Landero Figueroa, Aleksey Porollo, Joseph A. Caruso, George S. Deepe, Joseph Heitman.
The innate immune system employs various defense mechanisms to combat invading microbes. From a pathogen perspective, access to adequate nutrition is one of the fundamental requirements for survival within the host. The ability to counter microbial survival by restricting basic elements of growth, extending from amino acids to sugars and metals, is referred to as nutritional immunity . The mechanisms of Zn acquisition, transport, and storage have been investigated in both prokaryotic and eukaryotic systems. In this review, the total amount of zinc regardless of its chemical form will be referred to as Zn, and the labile fraction as Zn2+. From an immunological perspective, the primary focus has been on the impact of Zn regulation on the numbers and function of lymphocytes and phagocytes and their correlation with susceptibility to infections, but a dissection of the molecular details in these processes has been lacking. More recently, understanding the Zn modulatory mechanisms and how they drive host-pathogen interactions at the molecular level has been a subject of intense scrutiny. This review will accentuate existing and novel insights into the roles of Zn in nutritional immunity and in phagocyte defenses against fungi.
Regulation of Zn homeostasis is essential for several host functions at multiple levels: i) for cellular processes including, but not limited to, transcription, translation, catalysis, and cell division; ii) for countering Zn2+ deficiency or excess; and iii) for immunomodulatory responses in host-pathogen interactions. An estimated 10% or 2,800 proteins in the human genome are Zn-dependent, implying a critical role for this metal in biological functions . In the immune system, Zn regulation is of paramount importance as the development and function of innate and adaptive arms of immunity are influenced by this metal . Zn homeostasis established by a balance in Zn2+ flux, intracellular distribution, and storage impacts phagocytosis, leukocyte recruitment, cytokine production, glycolysis, and oxidation triggered in response to immune signals. Aberrant Zn regulation in the circulation or in cells mitigates robust immune activation and leads to suboptimal host defenses. For example, Zn deficiency in humans with the genetic disorder acrodermatitis enteropathica is caused by Zn malabsorption and characterized by increased susceptibility to infections. An excess of Zn2+ diminishes T cell mitogenic responses . Thus, an intact immune response requires strict Zn2+ regulation.
The immune system maintains Zn equilibrium via transporters, storage, and binding mechanisms (Figure 1). While lower eukaryotes such as fungi possess fewer Zn2+ transporters , mammals have 24 transporters, called ZIPs (Slc39a, importers) and ZNTs (Slc30a, exporters). Some transporters manifest a ubiquitous expression pattern in several host cells, and others exhibit tissue specificity and function irreplaceably in Zn2+ transport. For example, Slc30a1is widely expressed in >12 organs, while Slc39a4 expression is restricted to the small intestine and kidney and is absolutely essential for dietary Zn absorption . Spatial organization of the transporters regulates Zn2+ in the cytosol and intracellular compartments including Golgi, mitochondria, and zincosomes that are a source of exchangeable metal during deficiency . The remarkable complexity in Zn2+ transporters reflects the need for strict homeostasis and a regulatory system that responds to different biological stimuli in an organelle-, cell-, and tissue-specific manner. For example, interleukin-6 induces Zn2+ import via ZIP14 in hepatocytes , while granulocyte macrophage-colony stimulating factor (GM-CSF) triggers Zn2+ uptake via ZIP2 in macrophages . The dependence of mammals on dietary sources for the metal implies the need for mechanisms that efficiently acquire Zn2+ and maintain regulated distribution in organ systems. Metallothioneins (MTs) comprise a class of metal binding proteins that regulate Zn2+ and prevent intoxication. MTs bind Zn2+ with picomolar affinity through seven binding sites, one of which is more readily exchangeable, and interactions with glutathione, ATP, or GTP mediate Zn2+ release . These properties facilitate a controlled exchange mechanism in infected phagocytes, where Zn2+ access to the microorganism needs to be restricted. Thus, phagocytes possess manifold mechanisms to manipulate Zn resources during infection.
Microbes are extremely sensitive to metal availability, and phagocytes have mastered mechanisms to curtail pathogen access to Zn2+. Despite our knowledge of Zn homeostasis, the manner in which the innate system modulates Zn2+ regulatory proteins in the context of fungal interactions and its influence on survival has been sparingly investigated.
Regulation of Zn2+ shapes the functional attributes of innate defense, impacting phagocyte function beyond nutritional immunity. GM-CSF–activated macrophages counter pathogen attack by eliciting a dual defense strategy comprising Zn2+ restriction to H. capsulatum, while concurrently enhancing phagocyte effector function. Zn2+ abates superoxide production by NADPH oxidase (Nox) by inhibiting hydrogen voltage-gated channel HV1. Fungi scavenge superoxide radicals via Zn and Cu or Mn dependent SODs , . In activated macrophages, MTs bind Zn2+ and create an environment deficient in Zn2+ ions, in effect, sustaining HV1 and Nox function (Figure 2). In this milieu, H. capsulatum is susceptible to ROS , presumably due to an ineffectual Zn and Cu dependent SOD response. The extent of Zn2+ deprivation by MTs results in effective superoxide production, and may simultaneously compromise fungal SOD-mediated defenses.