Abstract
Transition row metal ions are both essential and toxic to microorganisms. Zinc in excess has significant toxicity to bacteria, and host release of Zn(II) at mucosal surfaces is an important innate defence mechanism. However, the molecular mechanisms by which Zn(II) affords protection have not been defined. We show that in Streptococcus pneumoniae extracellular Zn(II) inhibits the acquisition of the essential metal Mn(II) by competing for binding to the solute binding protein PsaA. We show that, although Mn(II) is the high-affinity substrate for PsaA, Zn(II) can still bind, albeit with a difference in affinity of nearly two orders of magnitude. Despite the difference in metal ion affinities, high-resolution structures of PsaA in complex with Mn(II) or Zn(II) showed almost no difference. However, Zn(II)-PsaA is significantly more thermally stable than Mn(II)-PsaA, suggesting that Zn(II) binding may be irreversible. In vitro growth analyses show that extracellular Zn(II) is able to inhibit Mn(II) intracellular accumulation with little effect on intracellular Zn(II). The phenotype of S. pneumoniae grown at high Zn(II):Mn(II) ratios, i.e. induced Mn(II) starvation, closely mimicked a ΔpsaA mutant, which is unable to accumulate Mn(II). S. pneumoniae infection in vivo elicits massive elevation of the Zn(II):Mn(II) ratio and, in vitro, these Zn(II):Mn(II) ratios inhibited growth due to Mn(II) starvation, resulting in heightened sensitivity to oxidative stress and polymorphonuclear leucocyte killing. These results demonstrate that microbial susceptibility to Zn(II) toxicity is mediated by extracellular cation competition and that this can be harnessed by the innate immune response.
Highlights
S. pneumoniae is the world’s foremost bacterial pathogen and a leading cause of death in young children in developing countries [1,2,3]
Infectious diseases associated with zinc deficiency include respiratory infections caused by bacteria, and notably, Streptococcus pneumoniae, which is responsible for more than 1 million deaths annually
We sought to determine if zinc could inhibit manganese transport, and to observe what the effects would be on S. pneumoniae
Summary
S. pneumoniae is the world’s foremost bacterial pathogen and a leading cause of death in young children in developing countries [1,2,3]. One of the major factors associated with the incidence and severity of S. pneumoniae infections in these children is dietary zinc deficiency (a significant ongoing problem in developing countries [4,5]). Zn(II) concentrations are elevated in response to inflammation and bacterial infection as a consequence of Zn(II) release from damaged or apoptotic cells, and from sequestering proteins such as metallothionein. Despite the requirement of Zn(II) for optimal immune function, diseases in developing countries associated with Zn(II)-poor status are predominantly acute respiratory infections, otitis media and diarrhea [7]. In recent years clinical trials of Zn supplementation have been undertaken in developing countries and meta-analyses of multiple trials [11,12] have shown a clear association between Zn(II) supplementation and a reduction in the incidence and severity of pneumonia and diarrhea. To date no clear mechanism for the protective effect of Zn(II) has been identified
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