Metal ions are required by all organisms for the chemical processes that support life. However, in excess they can also exert toxicity within biological systems. During
infection, bacterial pathogens such as Streptococcus pneumoniae are exposed to host-imposed
metal intoxication, where the toxic properties of metals, such as
copper, are exploited to aid in microbial clearance. However, previous studies investigating the antimicrobial efficacy of
copper in vivo have reported variable findings. Here, we use a highly
copper-sensitive strain of S. pneumoniae, lacking both
copper efflux and intracellular
copper buffering by
glutathione, to investigate how
copper stress is managed and where it is encountered during
infection. We show that this strain exhibits highly dysregulated
copper homeostasis, leading to the attenuation of growth and hyperaccumulation of
copper in vitro. In a murine
infection model, whole-tissue
copper quantitation and elemental bioimaging of the murine lung revealed that
infection with S. pneumoniae resulted in increased
copper abundance in specific tissues, with the formation of spatially discrete
copper hot spots throughout the lung. While the increased
copper was able to reduce the viability of the highly
copper-sensitive strain in a
pneumonia model,
copper levels in professional phagocytes and in a bacteremic model were insufficient to prosecute bacterial clearance. Collectively, this study reveals that host
copper is redistributed to sites of
infection and can impact bacterial viability in a hypersusceptible strain. However, in wild-type S. pneumoniae, the concerted actions of the
copper homeostatic mechanisms are sufficient to facilitate continued viability and virulence of the pathogen. IMPORTANCE Streptococcus pneumoniae (the pneumococcus) is one of the world's foremost bacterial pathogens. Treatment of both localized and systemic
pneumococcal infection is becoming complicated by increasing rates of multidrug resistance globally.
Copper is a potent
antimicrobial agent used by the mammalian immune system in the defense against bacterial pathogens. However, unlike other bacterial species, this
copper stress is unable to prosecute pneumococcal clearance. This study determines how the mammalian host inflicts
copper stress on S. pneumoniae and the bacterial
copper tolerance mechanisms that contribute to maintenance of viability and virulence in vitro and in vivo. This work has provided insight into the chemical biology of the host-pneumococcal interaction and identified a potential avenue for novel antimicrobial development.