Group A <b><i>Streptococcus</i></b> Modulates Host Inflammation by Manipulating Polymorphonuclear Leukocyte Cell Death Responses

Abstract

Polymorphonuclear leukocyte (PMN) cell death strongly influences the resolution of inflammatory episodes, and may exacerbate adverse pathologies in response to infection. We investigated PMN cell death mechanisms following infection by virulent group A Streptococcus (GAS). Human PMNs were infected in vitro with a clinical, virulent GAS isolate and an avirulent derivative strain, and compared for phagocytosis, the production of reactive oxygen species (ROS), mitochondrial membrane depolarization and apoptotic markers. C57BL/6J mice were then infected, in order to observe the effects on murine PMNs in vivo. Human PMNs phagocytosed virulent GAS less efficiently, produced less ROS and underwent reduced mitochondrial membrane depolarization compared with phagocytosis of avirulent GAS. Morphological and biochemical analyses revealed that PMNs infected with avirulent GAS exhibited nuclear fragmentation and caspase-3 activation consistent with an anti-inflammatory apoptotic phenotype. Conversely, virulent GAS induced PMN vacuolization and plasma membrane permeabilization, leading to a necrotic form of cell death. Infection of the mice with virulent GAS engendered significantly higher systemic pro-inflammatory cytokine release and localized infiltration of murine PMNs, with cells associated with virulent GAS infection exhibiting reduced apoptotic potential. Avirulent GAS infection was associated with lower levels of proinflammatory cytokines and tissue PMN apoptosis. We propose that the differences in PMN cell death mechanisms influence the inflammatory responses to infection by GAS.

Streptococcus pyogenes M1T1 Variants Induce an Inflammatory Neutrophil Phenotype Including Activation of Inflammatory Caspases

“…GAS can induce death of human neutrophils ( Kobayashi et al., 2003 ; Tsatsaronis et al., 2015 ), however the mechanism remains poorly described. Phosphatidylserine (PS) exposure is a hallmark of the induction of multiple death pathways including apoptosis and pyroptosis ( Wang et al., 2013 ; Man and Kanneganti, 2016 ).…”

Group B Streptococcus Induces Neutrophil Recruitment to Gestational Tissues and Elaboration of Extracellular Traps and Nutritional Immunity

“…This neutrophil response likely initiates an antimicrobial response, through phagocytosis and bacterial killing, as well as through the deposition of antimicrobial molecules at the site of infection. Furthermore, it is likely that neutrophil presence results in the stimulation of pro-inflammatory signaling cascades which initiates further inflammation pathways leading to perturbed maternal-fetal tolerance and tissue destruction (Marzano et al, 2010 ; Simard et al, 2011 ; PrabhuDas et al, 2015 ; Tsatsaronis et al, 2015 ).…”

Superoxide anions produced by Streptococcus pyogenes group A-stimulated keratinocytes are responsible for cellular necrosis and bacterial growth inhibition

“…35 Recently, it has also been shown that virulent GAS strains are able to modulate the PMN inflammatory response by reducing their apoptotic potential leading to a necrotic form of cell death. 36 However, although the production of high levels of ROS is responsible of the death of keratinocytes, we show that this ROS production also contributes to eliminating the pathogen. This was demonstrated by the growth rates of GAS strains co-cultured with keratinocytes.…”