A Critical Role of Zinc Importer AdcABC in Group A Streptococcus-Host Interactions During Infection and Its Implications for Vaccine Development

Abstract

Bacterial pathogens must overcome host immune mechanisms to acquire micronutrients for successful replication and infection. Streptococcus pyogenes, also known as group A streptococcus (GAS), is a human pathogen that causes a variety of clinical manifestations, and disease prevention is hampered by lack of a human GAS vaccine. Herein, we report that the mammalian host recruits calprotectin (CP) to GAS infection sites and retards bacterial growth by zinc limitation. However, a GAS-encoded zinc importer and a nuanced zinc sensor aid bacterial defense against CP-mediated growth inhibition and contribute to GAS virulence. Immunization of mice with the extracellular component of the zinc importer confers protection against systemic GAS challenge. Together, we identified a key early stage host-GAS interaction and translated that knowledge into a novel vaccine strategy against GAS infection. Furthermore, we provided evidence that a similar struggle for zinc may occur during other streptococcal infections, which raises the possibility of a broad-spectrum prophylactic strategy against multiple streptococcal pathogens.

Zinc’ing it out: zinc homeostasis mechanisms and their impact on the pathogenesis of human pathogen group A streptococcus

“…49 CP was present in sub milligram quantities at GAS colonization surfaces in two different mouse models of invasive infection, indicating that CP participates in host defense against GAS infection (Fig. 1).…”

“…When grown in the presence of CP, GAS senses CP-mediated zinc sequestration and responds by upregulating expression of the genes involved in GAS adaptive responses to zinc limitation (discussed below). 49 Although CP inhibits GAS growth at higher concentrations, GAS outcompetes CP and sustains growth at concentrations comparable to CP levels observed at infection sites. These observations indicate that GAS possesses molecular arsenals to overcome CP-mediated zinc sequestration and survives in the host.…”

“…43–47 CP is a heterodimer of S100A8 and S100A9 proteins, which is present abundantly at various bacterial colonization surfaces in the host. 45,47–49 CP is produced primarily by myeloid cells, which include neutrophils, monocytes, and macrophages. 50 CP constitutes approximately 50% of the cytosolic protein content of neutrophils and it is recruited to the infection sites as part of the first line of host innate defenses.…”

“…1). 49 During in vitro growth, CP chelates transition metals including zinc from the growth medium (Fig. 1).…”

“…Interestingly, growth of several streptococcal pathogens was similarly inhibited by CP during growth in vitro , suggesting that other streptococcal pathogens may also engage in battle against CP during infection. 49 However, S. pneumoniae was a notable exception as pneumococci displayed higher levels of resistance against CP compared to other streptococcal pathogens. 49 Intriguingly, two different studies investigating the interactions between pneumococci and CP proposed conflicting roles for CP.…”