Abstract
Calprotectin, the most abundant cytoplasmic protein in neutrophils, suppresses the growth of Staphylococcus aureus by sequestering the nutrient metal ions Zn and Mn. Here we show that calprotectin can also enhance the activity of the SaeRS two component system (TCS), a signaling system essential for production of over 20 virulence factors in S. aureus. The activity of the SaeRS TCS is repressed by certain divalent ions found in blood or neutrophil granules; however, the Zn bound-form of calprotectin relieves this repression. During staphylococcal encounter with murine neutrophils or staphylococcal infection of the murine peritoneal cavity, calprotectin increases the activity of the SaeRS TCS as well as the production of proinflammatory cytokines such as IL-1β and TNF-α, resulting in higher murine mortality. These results suggest that, under certain conditions, calprotectin can be exploited by S. aureus to increase bacterial virulence and host mortality.
Highlights
S. aureus is an important Gram-positive human pathogen colonizing the skin, anterior nares and other mucosal surfaces in approximately 30% of the human populations, causing a wide variety of diseases [1]
Previous study showed that the growth of S. aureus in abscesses is suppressed by the host antimicrobial protein calprotectin, which sequesters Zn and Mn from bacterial usage
We found that the Zn-binding property of calprotectin increases the pathogenic potential of S. aureus by enhancing the activity of the SaeRS two component system in S. aureus
Summary
S. aureus is an important Gram-positive human pathogen colonizing the skin, anterior nares and other mucosal surfaces in approximately 30% of the human populations, causing a wide variety of diseases [1]. The pathogenesis of S. aureus requires multiple virulence factors, and the expression of those virulence factors is controlled by multiple regulatory systems such as SarA family transcription factors, the agr quorum sensing system, and the SaeRS two component system (TCS) [2,3]. The SaeRS TCS is composed of the sensor kinase SaeS and the response regulator SaeR along with two auxiliary proteins SaeP and SaeQ [4,5,6]. Conserved in all clinical isolates of S. aureus, the SaeRS TCS controls the production of more than 20 virulence factors (e.g., hemolysins, leukocidins, coagulases and immune evasion molecules) and plays an essential role in staphylococcal survival and pathogenesis [7,8,9]. S. aureus appears to use the SaeRS TCS to adapt to hostile host environments such as innate immune responses. Several sae-regulated gene products show anti-neutrophil properties [11,12,13,14]
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