Giuseppe
Emeritus
[Source: mBio, full text: (LINK). Abstract, edited.]
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Vitamin D and the Human Antimicrobial Peptide LL-37 Enhance Group A Streptococcus Resistance to Killing by Human Cells
John F. Love<SUP>a,b</SUP>*, Hien J. Tran-Winkler<SUP>a</SUP>, and Michael R. Wessels<SUP>a</SUP>
<SUP></SUP>
Author Affiliations: Division of Infectious Diseases, Boston Children?s Hospital, Boston, Massachusetts, USA,<SUP>a</SUP> and Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA<SUP>b</SUP>
Address correspondence to Michael R. Wessels, michael.wessels@childrens.harvard.edu. Editor R. John Collier, Harvard Medical School
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.
Footnotes
* Present address: John F. Love, Section of Infectious Diseases, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA
Citation Love JF, Tran-Winkler HJ, and Wessels MR. 2012. Vitamin D and the human antimicrobial peptide LL-37 enhance group A Streptococcus resistance to killing by human cells. mBio 3(5):e00394-12. doi:10.1128/mBio.00394-12.
Received 25 September 2012 - Accepted 2 October 2012 - Published 23 October 2012
Copyright ? 2012 Love et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
-<SUP></SUP>
Author Affiliations: Division of Infectious Diseases, Boston Children?s Hospital, Boston, Massachusetts, USA,<SUP>a</SUP> and Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA<SUP>b</SUP>
Address correspondence to Michael R. Wessels, michael.wessels@childrens.harvard.edu. Editor R. John Collier, Harvard Medical School
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.
Footnotes
* Present address: John F. Love, Section of Infectious Diseases, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA
Citation Love JF, Tran-Winkler HJ, and Wessels MR. 2012. Vitamin D and the human antimicrobial peptide LL-37 enhance group A Streptococcus resistance to killing by human cells. mBio 3(5):e00394-12. doi:10.1128/mBio.00394-12.
Received 25 September 2012 - Accepted 2 October 2012 - Published 23 October 2012
Copyright ? 2012 Love et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
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