Research Article: Conflicting Interests in the Pathogen–Host Tug of War: Fungal Micronutrient Scavenging Versus Mammalian Nutritional Immunity

Date Published: March 13, 2014

Publisher: Public Library of Science

Author(s): Joanna Potrykus, Elizabeth R. Ballou, Delma S. Childers, Alistair J. P. Brown, Joseph Heitman.


Partial Text

Strife concerning the accessibility of essential trace elements, such as transition metals, represents an important aspect of the dynamic interaction between a pathogenic fungus and its mammalian host. The host defends itself against infection by sequestering these essential micronutrients away from the invading pathogen via a phenomenon termed “nutritional immunity” [1]. In turn, the fungus employs an array of tactics (scavenging and storage) to hoard micronutrients and support growth when these resources are scarce. In addition, micronutrient limitation triggers the expression of virulence determinants that can aggravate disease [2]–[4].

The mammalian host exploits both “constitutive” and “inducible” nutritional immunity to sequester transition metals away from microbial pathogens. The host regulates its interchangeable metal pools by sequestering metals via protein carriers or by partitioning them between intracellular stores [1], [9]. This essentially imposes constitutive nutritional immunity by depleting the extracellular milieu of essential metals and creating a micronutrient-limiting environment for the pathogen. For example, the estimated serum concentration of free ferric iron is 10−24 M, many orders of magnitude lower than that expected based on its solubility (10−9 M) [17]. Likewise, the intracellular “free pool” of copper is less than one copper atom per cell [18]. Pathological disruption of this constitutively low metal ion environment is one factor that predisposes patients to fungal infection [10], [18].

Fungi exploit many mechanisms to scavenge metal ions from different substrates, adjusting their metal acquisition machinery as required [26]. The molecular mechanics that underlie metal sensing remain unclear [5], and the regulatory networks that control metal acquisition systems are complex, responding not just to micronutrient availability but also to environmental cues such as carbon source, hypoxia, and pH. These are reviewed elsewhere (e.g., [2], [3], [14]). Here, we summarise the fungal micronutrient acquisition pathways themselves and discuss how they respond to nutritional immunity.

The metal tug of war between pathogen and host is a complex and dynamic process, with each party striving to procure and retain essential micronutrients. The great complexity of this interaction is only now being realised. It is becoming apparent that the host responds to infection by redirecting micronutrients via niche- and perhaps infection-stage–specific mechanisms to various ends, e.g., micronutrient limitation versus micronutrient poisoning. On the other hand, the apparent redundancy of some fungal metal acquisition mechanisms needs to be explored, and their essentiality to the different stages of pathogenesis remains to be established. Also, before we can start drawing global comparisons of metal homeostasis in fungal and bacterial infectious agents, more information is required about micronutrient warfare in fungal pathogens outside the small handful of established model organisms. The ultimate challenge will be to integrate the responses of host and pathogen into a holistic model that describes how the host modulates micronutrient homeostasis during infection and how the pathogen responds to these changes, spatially and temporally. New technologies, such as live-animal imaging of fungal gene expression [16], MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging of proteins, and 2-D element mapping directly from biological specimens [22], are beginning to illuminate the pathogen–host tug-of-war over micronutrients. We are confident that the future holds many exciting discoveries in this field.




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