Zinc sequestration by human calprotectin facilitates manganese binding to the bacterial solute-binding proteins PsaA and MntC Original paper

What was studied?

This study investigated the role of the human immune protein calprotectin (CP) in the competition between Streptococcus pneumoniae and Staphylococcus aureus for metal ions, particularly zinc (Zn²⁺) and manganese (Mn²⁺), during infection. The focus was on how CP’s ability to sequester zinc facilitates manganese binding to bacterial solute-binding proteins (SBPs) like PsaA and MntC, which are essential for bacterial metal acquisition. The study employed X-ray absorption spectroscopy (XAS) and electron paramagnetic resonance (EPR) spectroscopy to elucidate the mechanisms behind CP-mediated metal exchange in the context of bacterial virulence.

Who was studied?

The study primarily examined two Gram-positive pathogens, Streptococcus pneumoniae and Staphylococcus aureus. The research focused on the solute-binding proteins (SBPs) PsaA and MntC from these bacteria, which are involved in manganese acquisition. Additionally, the study explored the interaction between these bacterial proteins and CP, a key host-defense protein, in the context of zinc sequestration and manganese uptake.

What were the most important findings?

The study demonstrated that CP’s zinc sequestration abilities significantly affect the microbial acquisition of essential metals. Zinc ions, when bound to PsaA or MntC, prevent the uptake of manganese, which is crucial for bacterial survival and virulence. CP effectively competes with both PsaA and MntC for zinc, sequestering zinc from these proteins and allowing manganese to bind instead. This metal exchange was facilitated by CP’s dual metal-binding sites, which preferentially sequester zinc and promote manganese binding in bacterial solute-binding proteins. Additionally, the study found that both PsaA (from S. pneumoniae) and MntC (from S. aureus) exhibited a strong thermodynamic preference for zinc over manganese, but CP’s metal-withholding strategy prevents zinc toxicity and allows manganese to be utilized for bacterial growth. These findings suggest that CP plays a crucial role in modulating metal ion availability during infection, influencing the pathogenesis of bacterial diseases.

What are the greatest implications of this study?

The study’s findings provide new insights into the intricate interplay between host metal-withholding mechanisms and bacterial metal acquisition systems. By showing how CP facilitates manganese binding to bacterial proteins while preventing zinc poisoning, the research contributes to a better understanding of the host-pathogen battle for essential metals. These insights open up new avenues for therapeutic strategies aimed at manipulating metal availability to hinder bacterial survival, especially in the treatment of S. pneumoniae and S. aureus infections. Moreover, this study highlights the role of CP in the broader context of nutritional immunity, where metal sequestration not only limits pathogen growth but may also influence microbial community dynamics and infection outcomes.