132. The Human Cathelicidin LL-37 Induces Group A Streptococcus Resistance to Killing by Multiple Human Cell Types
Session: Oral Abstract Session: Bacterial Pathogenesis and Virulence
Friday, October 21, 2011: 8:45 AM
Room: 151AB
Background: Group A Streptococcus (GAS) is a common human pathogen responsible for a spectrum of clinical illnesses, ranging from pharyngitis to life-threatening invasive infections.  Numerous virulence factors play a role in GAS infection, including hyaluronic acid capsule, M protein, cytotoxins, and proteases; expression of several of these factors is regulated by a two-component regulatory system, CsrRS (also called CovRS).   Recent work has demonstrated that the human cathelicidin LL-37, an antimicrobial peptide, is specifically recognized by the sensor kinase CsrS, leading to upregulation of many GAS virulence determinants.  

Methods: This study explored how the response of an M type 1 GAS strain to host LL-37 alters the interaction between the bacteria and human cell types encountered early in infection, oropharyngeal keratinocytes, macrophages, and neutrophils.

Results: When grown in the presence of subinhibitory yet physiologic concentrations of LL-37, GAS exhibited a 5-fold increase in resistance to killing by human neutrophils compared to GAS grown in its absence.  Similarly, GAS exposure to LL-37 reduced the efficiency of GAS internalization and intracellular killing by oropharyngeal keratinocytes. Upregulation of  LL-37 expression in THP-1 macrophages was associated with reduced phagocytosis of GAS.  The ability of LL-37 to confer resistance to killing by all three cell types was dependent on CsrRS, as uptake and intracellular killing of a CsrR-deletion mutant were unaffected by LL-37.  In addition, by constructing isogenic mutants deficient in individual virulence factors, we showed that both the hyaluronic acid capsule and streptolysin O are essential for enhanced GAS intracellular survival.

Conclusion: These studies demonstrate the critical role of host-pathogen signaling through the CsrRS system in determining the outcome of early interactions between GAS and its human host.


Subject Category: B. Bacterial pathogenesis, studies in animal models, molecular pathogenicity

John Love, MD, PhD1,2, Jessica Hein Tran-Winkler, PhD2 and Michael Wessels, MD2, (1)Beth Israel Deaconess Medical Center, Boston, MA, (2)Children's Hospital Boston, Boston, MA

Disclosures:

J. Love, None

J. H. Tran-Winkler, None

M. Wessels, None

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