Group A Streptococcus Prevents Mast Cell Degranulation to Promote Extracellular Trap Formation.

Mary Clark,Cheryl Y M Okumura,Jacqueline Shimamoto,Jessica Kim,Neelou Etesami,Ryan V Whalen,Gary Martin

doi:10.3389/fimmu.2018.00327

Abstract

The resurgence of Group A Streptococcus (GAS) infections in the past two decades has been a rising major public health concern. Due to a large number of GAS infections occurring in the skin, mast cells (MCs), innate immune cells known to localize to the dermis, could play an important role in controlling infection. MCs can exert their antimicrobial activities either early during infection, by degranulation and release of antimicrobial proteases and the cathelicidin-derived antimicrobial peptide LL-37, or by forming antibacterial MC extracellular traps (MCETs) in later stages of infection. We demonstrate that MCs do not directly degranulate in response to GAS, reducing their ability to control bacterial growth in early stages of infection. However, MC granule components are highly cytotoxic to GAS due to the pore-forming activity of LL-37, while MC granule proteases do not significantly affect GAS viability. We therefore confirmed the importance of MCETs by demonstrating their capacity to reduce GAS survival. The data therefore suggests that LL-37 from MC granules become embedded in MCETs, and are the primary effector molecule by which MCs control GAS infection. Our work underscores the importance of a non-traditional immune effector cell, utilizing a non-conventional mechanism, in the defense against an important human pathogen.

Highlights

Group A Streptococcus (GAS) causes a diverse spectrum of clinical manifestations in humans
HMC-1 cells could not control the growth of M1T1 subclone of GAS (M1 GAS) at longer time points, whereas L. lactis growth continued to be restricted throughout the time course (Figure 1B)
We found that M1 GAS grew less well in the presence of both HMC-1 and bone marrow-derived mast cells (BMMCs) mast cell extracellular trap (MCET) compared with MCETs treated with micrococcal nuclease (MNase), an exonuclease used to dismantle the DNA backbone, and MPO to degrade tryptase (Figures 4A,B) [13]

Summary

Introduction

Group A Streptococcus (GAS) causes a diverse spectrum of clinical manifestations in humans. Infections range from mild diseases, such as impetigo at the outer keratin layer, to severe invasive diseases, such as necrotizing fasciitis in the deep fascia [1]. GAS is conservatively estimated to be responsible for over 140 million cases of impetigo globally each year [2]. The globally disseminated serotype M1T1 subclone of GAS (M1 GAS) has been the most frequently isolated serotype from patients with either non-invasive or invasive disease [3]. An important consequence of GAS infection is the increased propensity for developing post-streptococcal diseases, such as rheumatic heart disease (RHD). RHD poses a substantial worldwide health burden, resulting in significant morbidity and mortality [2, 4]

Methods

Results

Conclusion