Molecular Evolution of Transition Metal Bioavailability at the Host-Pathogen Interface.

The molecular evolution of the adaptive response at the host-pathogen interface has been frequently referred to as an 'arms race' between the host and bacterial pathogens. The innate immune system employs multiple strategies to starve microbes of metals. Pathogens, in turn, develop successful strategies to maintain access to bioavailable metal ions under conditions of extreme restriction of transition metals, or nutritional immunity. However, the processes by which evolution repurposes or re-engineers host and pathogen proteins to perform or refine new functions have been explored only recently. Here we review the molecular evolution of several human metalloproteins charged with restricting bacterial access to transition metals. These include the transition metal-chelating S100 proteins, natural resistance-associated macrophage protein-1 (NRAMP-1), transferrin, lactoferrin, and heme-binding proteins. We examine their coevolution with bacterial transition metal acquisition systems, involving siderophores and membrane-spanning metal importers, and the biological specificity of allosteric transcriptional regulatory proteins tasked with maintaining bacterial metallostasis. We also discuss the evolution of metallo-ß-lactamases; this illustrates how rapid antibiotic-mediated evolution of a zinc metalloenzyme obligatorily occurs in the context of host-imposed nutritional immunity.

Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface.

Among the biologically required first row, late d-block metals from MnII to ZnII, the catalytic and structural reach of ZnII ensures that this essential micronutrient touches nearly every major metabolic process or pathway in the cell. Zn is also toxic in excess, primarily because it is a highly competitive divalent metal and will displace more weakly bound transition metals in the active sites of metalloenzymes if left unregulated. The vertebrate innate immune system uses several strategies to exploit this "Achilles heel" of microbial physiology, but bacterial evolution has responded in kind. This review highlights recent insights into transcriptional, transport, and trafficking mechanisms that pathogens use to "win the fight" over zinc and thrive in an otherwise hostile environment.