Affiliation:
1. Division of Infectious Diseases, Boston Children’s Hospital, Boston, Massachusetts, USA
2. Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Abstract
ABSTRACT
The CsrRS two-component regulatory system of group A
Streptococcus
(GAS;
Streptococcus pyogenes
) responds to subinhibitory concentrations of the human antimicrobial peptide LL-37. LL-37 signaling through CsrRS results in upregulation of genes that direct synthesis of virulence factors, including the hyaluronic acid capsule and streptolysin O (SLO). Here, we demonstrate that a consequence of this response is augmented GAS resistance to killing by human oropharyngeal keratinocytes, neutrophils, and macrophages. LL-37-induced upregulation of SLO and hyaluronic acid capsule significantly reduced internalization of GAS by keratinocytes and phagocytic killing by neutrophils and macrophages. Because vitamin D induces LL-37 production by macrophages, we tested its effect on macrophage killing of GAS. In contrast to the reported enhancement of macrophage function in relation to other pathogens, treatment of macrophages with 1α,25-dihydroxy-vitamin D3 paradoxically reduced the ability of macrophages to control GAS infection. These observations demonstrate that LL-37 signals through CsrRS to induce a virulence phenotype in GAS characterized by heightened resistance to ingestion and killing by both epithelial cells and phagocytes. By inducing LL-37 production in macrophages, vitamin D may contribute to this paradoxical exacerbation of GAS infection.
IMPORTANCE
It remains poorly understood why group A
Streptococcus
(GAS) causes asymptomatic colonization or localized throat inflammation in most individuals but rarely progresses to invasive infection. The human antimicrobial peptide LL-37, which is produced as part of the innate immune response to GAS infection, signals through the GAS CsrRS two-component regulatory system to upregulate expression of multiple virulence factors. This study reports that two CsrRS-regulated GAS virulence factors—streptolysin O and the hyaluronic acid capsule—are critical in LL-37-induced resistance of GAS to killing by human throat epithelial cells and by neutrophils and macrophages. Vitamin D, which increases LL-37 production in macrophages, has the paradoxical effect of increasing GAS resistance to macrophage-mediated killing. In this way, the human innate immune response may promote the transition from GAS colonization to invasive infection.
Publisher
American Society for Microbiology
Reference49 articles.
1. Pathogenesis of Group A Streptococcal Infections
2. StevensDL . 2000. Group A beta-hemolytic streptococci: virulence factors, pathogenesis, and spectrum of clinical infections, p 19–36. In StevensDL KaplanEL , Streptococcal infections. Clinical aspects, microbiology, and molecular pathogenesis. Oxford University Press, New York, NY.
3. An Outbreak of Invasive Group A Streptococcal Disease Associated With High Carriage Rates of the Invasive Clone Among School-aged Children
4. Group A Streptococcus Carriage among Close Contacts of Patients with Invasive Infections
5. RscA, a Member of the MDR1 Family of Transporters, Is Repressed by CovR and Required for Growth of
Streptococcus pyogenes
under Heat Stress
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