Intracellular bacteriolysis contributes to pathogenicity of <i>Staphylococcus aureus</i> by exacerbating AIM2-mediated inflammation and necroptosis

<i>Staphylococcus aureus</i> can survive within phagocytes. Indeed, we confirm in this study that approximately 10% of population persists in macrophages during <i>S. aureus</i> infection, while the rest are eliminated due to bacteriolysis, which is of particular interest to us. Herein, we observe that the bacteriolysis is an early event accompanied by macrophage death during <i>S. aureus</i> infection. Furthermore, the cell death is significantly accelerated following increased intracellular bacteriolysis, indicating that intracellular bacteriolysis induces cell death. Subsequently, we establish that the cell death is not apoptosis or pyroptosis, but AIM2-mediated necroptosis, accompanied by AIM2 inflammasome activation. This finding challenges the classical model that the cell death that accompanies inflammasome activation is always pyroptosis. In addition, we observe that the apoptosis-associated genes are highly inhibited during <i>S. aureus</i> infection. Finally, we establish in vivo that increased bacteriolysis significantly enhances <i>S. aureus</i> pathogenicity by promoting its dissemination to kidney and leading to an inflammatory cytokine storm in AIM2-mediated manner. Collectively, our data demonstrate that bacteriolysis is detrimental when triggered in excess and its side effect is mediated by AIM2. Meanwhile, we propose a potential immune manipulation strategy by which <i>S. aureus</i> sacrifices the minority to trigger a limited necroptosis, thereby releasing signals from dead cells to inhibit apoptosis and other anti-inflammatory cascades of live cells, eventually surviving within host cells and establishing infection.