br Secreted enzymes Only two secreted S

Secreted enzymes Only two secreted S. aureus enzymes reportedly induce apoptosis, namely, staphylococcal staphopain B (SspB) and coagulase. SspB selectively cleaved CD11b/CD18 integrin and induced an apoptosis-like cell death in neutrophils and monocytes (Smagur et al., 2009). Neutrophils or monocytes expressed phosphatidylserine and annexin I upon treatment with SspB, thereby becoming more permeable to propidium iodide and demonstrating distinct apoptotic and necrotic features. The apoptotic-like cell death caused by SspB seemingly relied on the lower expression of surface CD11b/CD18 and altered cytoskeleton but not on caspase activities (Smagur et al., 2009). Coagulase activates prothrombin to generate fibrin, and the activity of the former is essential in the formation of bacteria–fibrin–platelet microaggregates during S. aureus infection (Peetermans et al., 2015). Interestingly, the coagulase overexpressed by S. aureus enhanced the apoptosis in the MC3T3-E1 pre-osteoblastic cell line compared with the original S. aureus or S. aureus silencing the enzyme (Jin et al., 2013). Further study revealed that MC3T3-E1 beta lactamase incubated with S. aureus strains that overexpress coagulase showed increased levels of cleaved-caspases 3 and 9 in comparison with that incubated with the control strain, thereby suggesting that staphylocoagulase can trigger the mitochondrial death pathway. However, the mechanism on how staphylocoagulase promotes the accumulation of cleaved-caspases 3 and 9 in cells is totally unclear, and more cell-types treated with purified staphylocoagulase are suggested.
Apoptosis prevention therapy With increasing research on S. aureus toxin-induced apoptosis, pharmacological interventions of apoptosis, including prevention of caspase activation, overexpression of anti-apoptotic molecules, and inhibition of Fas/FasL interaction, have significantly demonstrated protection in murine sepsis models (Hotchkiss et al., 1999, Chung et al., 2001, Coopersmith et al., 2002, Chung et al., 2003, Bommhardt et al., 2004, Ayala et al., 2007). Moreover, the intervention of some cytokines closely related to cell apoptosis, such as TNFα, is also effective in sepsis treatment (Jacobi et al., 2005, Aziz et al., 2014). Even though anti-apoptosis therapy showed promising results, prevention of sepsis is usually incomplete, and this disease is manifested as multiple processes, making this task challenging.
Cancer therapy In addition to fighting against apoptosis for the sake of improving the outcome of certain diseases, S. aureus toxin-activated apoptosis could also serve as a potential tool for cancer treatment. Given the T cell-stimulating and proapoptotic abilities of S. aureus toxins, SEs were tested for their ability to trigger apoptosis in various kinds of cancer cell lines with the help of toxin-activated immunocytes. PBMC activation by SEB was able to promote apoptosis in human transitional carcinoma cell lines RT112 and RT4 through Fas-FasL interaction (Perabo et al., 2005). SEA could result in Ehrlich ascite tumor cell apoptosis in a Swiss albino murine model by coordinating with SPA to exert more effect (Mondal et al., 2002). PBMC stimulated by egcSEs (five genetically linked staphylococcal enterotoxins, SEG, SEI, SELM, SELN, and SELO and two pseudotoxins) were shown to induce apoptosis in bladder, lung, and breast carcinoma, melanoma, neuroblastoma, and osteogenic sarcoma cells (Terman et al., 2013). Besides the indirect utilization of SEs in stimulating PBMC to kill cancer cells, the PVL-binding component, LukS-PV, is an adequate candidate for new anti-cancer therapy development (Bu et al., 2013, Shan et al., 2015, Shan et al., 2017). The bi-component nature makes non-hemolytic PVL a safer instrument for triggering apoptosis in cancer, because the pore can only form in the presence of two components. However, this project certainly needs further studies (Shan et al., 2017).