A Red Blood Cell Membrane-Camouflaged Nanoparticle Counteracts Streptolysin O-Mediated Virulence Phenotypes of Invasive Group A Streptococcus

Tamara Escajadillo,Joshua Olson,Liangfang Zhang,Victor Nizet,Brian T Luk

doi:10.3389/fphar.2017.00477

Tamara Escajadillo, Joshua Olson + Show 3 more

Open Access

https://doi.org/10.3389/fphar.2017.00477

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Abstract

Group A Streptococcus (GAS), an important human-specific Gram-positive bacterial pathogen, is associated with a broad spectrum of disease, ranging from mild superficial infections such as pharyngitis and impetigo, to serious invasive infections including necrotizing fasciitis and streptococcal toxic shock syndrome. The GAS pore-forming streptolysin O (SLO) is a well characterized virulence factor produced by nearly all GAS clinical isolates. High level expression of SLO is epidemiologically linked to intercontinental dissemination of hypervirulent clonotypes and poor clinical outcomes. SLO can trigger macrophage and neutrophil cell death and/or the inactivation of immune cell functions, and promotes tissue injury and bacterial survival in animal models of infection. In the present work, we describe how the pharmacological presentation of red blood cell (RBC) derived biomimetic nanoparticles (“nanosponges”) can sequester SLO and block the ability of GAS to damage host cells, thereby preserving innate immune function and increasing bacterial clearance in vitro and in vivo. Nanosponge administration protected human neutrophils, macrophages, and keratinocytes against SLO-mediated cytotoxicity. This therapeutic intervention prevented SLO-induced macrophage apoptosis and increased neutrophil extracellular trap formation, allowing increased GAS killing by the respective phagocytic cell types. In a murine model of GAS necrotizing skin infection, local administration of the biomimetic nanosponges was associated with decreased lesion size and reduced bacterial colony-forming unit recovery. Utilization of a toxin decoy and capture platform that inactivates the secreted SLO before it contacts the host cell membrane, presents a novel virulence factor targeted strategy that could be a powerful adjunctive therapy in severe GAS infections where morbidity and mortality are high despite antibiotic treatment.

Highlights

Streptococcus pyogenes, known as group A Streptococcus (GAS), is a leading human-specific Gram-positive bacterial pathogen (Walker et al, 2014)
The RBCderived nanoparticles, hereafter termed “nanosponges,” have an approximate particle size of 80 nm, right side out orientation, and other physical characteristics and physiochemical properties that lead to favorable pharmacokinetics and biodistribution (Hu et al, 2011)
streptolysin O (SLO) can trigger membrane damage and cytolytic cell death in keratinocytes, which may play a role in the severe tissue injury of invasive Group A Streptococcus (GAS) necrotizing skin infection (Ruiz et al, 1998; Sierig et al, 2003)

Summary

Introduction

Streptococcus pyogenes, known as group A Streptococcus (GAS), is a leading human-specific Gram-positive bacterial pathogen (Walker et al, 2014). The capacity of GAS to produce invasive human disease is the byproduct of a diverse array of bacterial virulence determinants that coordinately promote tissue invasion and resistance to innate immune clearance by host phagocytic cells including neutrophils and macrophages (Cole et al, 2011; Walker et al, 2014; Hamada et al, 2015; Dohrmann et al, 2016). These include the anti-opsonophagocytic surface-anchored M protein (Oehmcke et al, 2010) and hyaluronic acid capsule (Dale et al, 1996), resistant mechanisms against host defense peptides (LaRock and Nizet, 2015) and reactive oxygen species (Henningham et al, 2015), and secreted toxins capable of lysing phagocytes and/or disrupting their critical antimicrobial functions (Barnett et al, 2015)

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