Group A Streptococcus (GAS, also known as Streptococcus pyogenes) is a common human pathogen, most frequently causing pharyngitis or """"""""strep throat."""""""" However, severe invasive infections like necrotizing fasciitis and toxic shock syndrome are also caused by this organism, leading to its nickname in the lay press - """"""""flesh-eating bacteria."""""""" This work will help explain the process by which a microbe in the throat can invade and cause life-threatening illness. Previous studies found that GAS alter transcription of multiple virulence factors in response to the human cathelicidin, LL-37, an antimicrobial peptide. A membrane-bound sensor kinase (CsrS) and its cytoplasmic response regulator (CsrR) appear to drive this reaction. This application aims to examine the role of LL-37 in stimulating an invasive phenotype in GAS. We will focus on the interaction of GAS with two host cell types commonly encountered early in infection: keratinocytes and macrophages. We will examine the role that LL-37 and CsrRS play in GAS's ability to avoid internalization and killing. Overall, these studies will examine a fascinating evolutionary interaction between a human pathogen and the innate immune system, offering new insights into the pathogenesis of GAS infections.

Public Health Relevance

The public health burden of GAS infection remains high. Sequelae of infection, including rheumatic heart disease, continue to plague especially developing areas, where prompt antibiotic therapy is unavailable. Additionally, there has been a rise in invasive GAS infections as a new, more virulent strain has spread around the globe. For these reasons, improving our understanding of the earliest stages of human infection will be essential to battling this common yet evolving pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI085965-02
Application #
8109214
Study Section
Special Emphasis Panel (ZRG1-F13-C (20))
Program Officer
GU, Xin-Xing
Project Start
2010-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$58,682
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Love, John F; Tran-Winkler, Hien J; Wessels, Michael R (2012) Vitamin D and the human antimicrobial peptide LL-37 enhance group a streptococcus resistance to killing by human cells. MBio 3:
Tran-Winkler, Hien J; Love, John F; Gryllos, Ioannis et al. (2011) Signal transduction through CsrRS confers an invasive phenotype in group A Streptococcus. PLoS Pathog 7:e1002361