Group A Streptococcus encounters with host macrophages

Abstract

Group A Streptococcus (GAS) is a leading human bacterial pathogen with diverse clinical manifestations. Macrophages constitute a critical first line of host defense against GAS infection, using numerous surface and intracellular receptors such as Toll-like receptors and inflammasomes for pathogen recognition and activation of inflammatory signaling pathways. Depending on the intensity of the GAS infection, activation of these signaling cascades may provide a beneficial early alarm for effective immune clearance, or conversely, may cause hyperinflammation and tissue injury during severe invasive infection. Although traditionally considered an extracellular pathogen, GAS can invade and replicate within macrophages using specific molecular mechanisms to resist phagolysosomal and xenophagic killing. Unraveling GAS-macrophage encounters may reveal new treatment options for this leading agent of infection-associated mortality. [Formula: see text].

Keywords: Group A Streptococcus (GAS); IL-1β signaling; NLRP3 inflammasome; Toll-like receptors; intracellular survival; macrophage; phagocytosis; xenophagy.

Figure 1.. Group A Streptococcus-induced phagocytosis and xenophagy in macrophages.

The phagocytic process is initiated by the recognition of group A Streptococcus (GAS) by macrophage (MΦ) surface pattern recognition receptors. Receptor recognition activates signaling pathways that induce remodeling of the actin cytoskeleton to form a phagosome in a process that involves fusion and fission events with vesicles of the endocytic compartment. The formed phagosome interacts with different types of endosomes and lysosomes, leading to development of phagolysosomes. GAS survival within the MΦ is mediated by streptolysin O-induced pore formation, which prevents acidification of the GAS-containing phagolysosome and allows the delivery of its co-toxin NAD–glycohydrolase (NADase) from the phagosome into the MΦ cytosol, increasing streptolysin O cytotoxicity and promoting GAS replication. Intracellular GAS can then be targeted by the autophagy machinery in a process called xenophagy, and ultimately delivered to the autophagosome, although the GAS-derived specific molecules recognized during xenophagy remain unknown (?). PRRs: Pattern recognition receptors.

Figure 2.. Toll-like receptor-mediated group A Streptococcus recognition in macrophages.

Macrophages express all Toll-like receptors (TLRs), which are responsible for sensing invading pathogens, including group A Streptococcus (GAS), both from the cell surface and in intracellular endosomes and lysosomes. Specific GAS-derived molecules activate the TLR-mediated signaling cascades, which require the adaptor MyD88, although some TLRs such as TLR4 use both MyD88 and TRIF adaptors. MyD88 and TRIF mediate the activation of IRF3 and NFκB transcriptional factors and subsequent induction of IFN-β and proinflammatory cytokines, such as TNF-α and IL-6. TLR2 recognizes GAS lipoteichoic acid and peptidoglycan. TLR4, a receptor for lipopolysaccharide of Gram-negative bacteria, has also been shown to have an effect in the recognition of the GAS pore-forming toxin streptolysin O. TLR9 recognizes unmethylated CpG-rich DNA motifs and plays an important role in host defense against GAS by stimulating the production of reactive oxygen species and nitric oxide (NO). Bacterial 23S RNA, including GAS rRNA, is also recognized by TLR signaling, specifically by murine TLR13. Recognition of GAS RNA by TLR13 is dependent on phagocytosis and endosomal GAS recognition.

Figure 3.. Comparison between group A Streptococcus-induced noncanonical and NLRP3 canonical IL-1β signaling activation.

During early stages of group A Streptococcus (GAS) infection, the proteolytic activity of the GAS cysteine protease SpeB hastens degradation of all known GAS canonical NLRP3 activators: streptolysin O (SLO), SpyA and M protein. SpeB also elicits the maturation of the proinflammatory cytokine pro-IL-1β by direct cleavage to its mature form IL-1β, overriding the contribution of the NLRP3 inflammasome. During the progress from mild to severe invasive GAS infections, mutations of covR/S take place, inactivating SpeB, while accelerating the expression and release of SLO, SpyA and M protein. Canonical NLRP3 inflammasome activation depends on two signals. Pathogen-associated molecular patterns are recognized by specific pattern recognition receptors, to induce the transcriptional activation of il-1β and other inflammasome components (signal 1). SLO pore formation, uptake of soluble M protein by clathrin-mediated endocytosis (CME) and SpyA make an independent contribution to the activation and assembly of the NLRP3 inflammasome and trigger potassium efflux (K [+] efflux) through an unknown mechanism (?). The assembly of the inflammasome leads to the caspase-1-dependent processing of pro-IL-1β to IL-1β, and resulting in DNA damage and pyroptotic cell death in macrophages. PAMPs: Pathogen-associated molecular patterns; PRRs: Pattern recognition receptors.