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

Abstract

Staphylococcus aureus can survive within phagocytes. Indeed, we confirm in this study that approximately 10% of population persists in macrophages during S. aureus 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 S. aureus 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 S. aureus infection. Finally, we establish in vivo that increased bacteriolysis significantly enhances S. aureus 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 S. aureus 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.

The dance of macrophage death: the interplay between the inevitable and the microenvironment

“…challenged the classical model stating that cell death accompanying inflammasome activation should always be pyroptosis. They demonstrated that the bacteriolysis of Staphylococcus aureus USA300 strain in infected macrophages induces AIM2-mediated necroptosis ( 117 ).…”

Necroptosis in bacterial infections

“…After S. aureus is phagocytosed by macrophages, approximately 10% of the S. aureus population will persist in macrophages, with the remaining bacteria eliminated by bacteriolysis. However, excessive bacteriolysis can cause cell death ( 67 ). Further studies confirmed that this type of cell death is not apoptosis or pyroptosis (It is characterized by dependence on inflammatory caspase enzymes, mainly caspase-1, 4, 5, 11, accompanied by the release of a large number of pro-inflammatory cytokines) but rather AIM2-mediated necroptosis ( 67 ).…”

“…However, excessive bacteriolysis can cause cell death ( 67 ). Further studies confirmed that this type of cell death is not apoptosis or pyroptosis (It is characterized by dependence on inflammatory caspase enzymes, mainly caspase-1, 4, 5, 11, accompanied by the release of a large number of pro-inflammatory cytokines) but rather AIM2-mediated necroptosis ( 67 ). Apoptosis is known to be important for clearing pathogens ( 68 ), and the authors propose a potential immune manipulation strategy by which S. aureus 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 ( 67 ).…”

Inflammasome activation by Gram-positive bacteria: Mechanisms of activation and regulation

“…The CARD domain of ASC subsequently recruits procaspase-1 to the complex allowing for autocleavage of caspase-1, processing of pro-IL-1β, pro-IL18 and gasdermin D, resulting in cytokine secretion and pyroptosis. Gram-positive bacteria, including but not limited to Staphylococcus aureus and Listeria monocytogenes release dsDNA in the cytosol after escaping the phagolysosome that activates the AIM2 inflammasome ( 64 , 65 ).…”

“…Additionally, phagocytosis and bacterial degradation were related to the activation of NLRP3 inflammasomes and IL-1β secretion in response to both live S. aureus and S. aureus peptidoglycan. Interestingly, IL-1β production was mediated by the NLRP3 activation, and the secretion of IL-6, KC and CCL2 was AIM2-dependent ( 120 ). Together, the NLRP3/AIM2 inflammasomes played a critical role in S. aureus infection and could be a therapeutic target to control unwanted inflammation.…”