Host Responses to Group A Streptococcus: Cell Death and Inflammation (original) (raw)
Figure 2
Epithelial cellular responses to GAS infection.
A GAS-induced apoptosis of epithelial cells is triggered via intrinsic and extrinsic pathways. SpeB binding to epithelial αvβ3 integrins or the Fas receptor (FasR) triggers upregulation of caspase-8 (casp-8) via JAK2, p38, p53, and STAT1 signalling [62]–[64]. Procaspase-8 (pro-casp-8) is also activated directly due to FasR signalling, leading to truncation of cytosolic Bid (tBid) and translocation of tBid to the mitochondria. Extracellular GAS binding to host integrins is enabled via bridging molecules such as fibronectin (Fn), and enables Rac1-mediated internalization of GAS into host epithelial cells. GAS internalization and Rac1 activation facilitates production of ROS, leading to increased p38 phosphorylation [65], [66]. Encapsulated extracellular GAS are not internalized by epithelial cells, and secrete the pore-forming toxin SLO. Integration of SLO into host cell membranes triggers net calcium (Ca++) flux into the cytosol and endoplasmic reticulum (ER) stress [67]. All three pathways elicit loss of mitochondrial outer membrane potential (ψm) and release of cytochrome C from the mitochondria, which precedes activation of caspase-9 (casp-9), caspase-3 (casp-3), and apoptosis. Overexpression of the anti-apoptotic factor Bcl-2 by the host can inhibit epithelial cell apoptosis. B GAS evades xenophagic killing by epithelial cells. GAS binding to the CD46 receptor is an early signal to activate autophagic responses [72], and GAS are uptaken into early endosomes in a Rab5-dependent manner [74]; however, SLO expression allows GAS to escape from endosomes into the cytosol. GAS exposure to the cytosol is recognized via ubiquitin (Ub) adapter proteins that, in conjunction with Rab7 and Rab23, facilitate shuttling of GAS into GcAVs bearing the classic autophagy LC3 marker [71], [73]. In the absence of SLO, streptolysin S is sufficient to damage endosomal vacuoles for targeting to GcAVs by Ub-independent, galectin-8-mediated autophagy [76]. Lysosomal fusion with GcAVs, via Rab7 and Rab9a, effects xenophagic destruction of intracellular GAS. Expression of SpeB by cytosolic GAS degrades Ub adapter proteins and prevents targeting of bacteria to GcAVs, enhancing intracellular GAS survival [77]. Secretion of GAS NADase also protects GAS from xenophagic killing by inhibiting fusion of GcAVs with lysosomes [76].