Pathogen-driven nucleotide overload triggers mitochondria-centered cell death in phagocytes.
Nicoletta SchwermannRita HallerSebastian KochGuntram A GrasslVolker WinstelPublished in: PLoS pathogens (2023)
Staphylococcus aureus is a dangerous pathogen that evolved refined immuno-evasive strategies to antagonize host immune responses. This involves the biogenesis of death-effector deoxyribonucleosides, which kill infectious foci-penetrating macrophages. However, the exact mechanisms whereby staphylococcal death-effector deoxyribonucleosides and coupled imbalances of intracellular deoxyribonucleotide species provoke immune cell death remain elusive. Here, we report that S. aureus systematically promotes an overload of deoxyribonucleotides to trigger mitochondrial rupture in macrophages, a fatal event that induces assembly of the caspase-9-processing apoptosome and subsequent activation of the intrinsic pathway of apoptosis. Remarkably, genetic disruption of this cascade not only helps macrophages coping with death-effector deoxyribonucleoside-mediated cytotoxicity but also enhances their infiltration into abscesses thereby ameliorating pathogen control and infectious disease outcomes in laboratory animals. Combined with the discovery of protective alleles in human CASP9, these data highlight the role of mitochondria-centered apoptosis during S. aureus infection and suggest that gene polymorphisms may shape human susceptibility toward a predominant pathogen.
Keyphrases
- cell death
- cell cycle arrest
- staphylococcus aureus
- endothelial cells
- dendritic cells
- candida albicans
- immune response
- regulatory t cells
- oxidative stress
- infectious diseases
- pluripotent stem cells
- induced pluripotent stem cells
- type iii
- small molecule
- depressive symptoms
- machine learning
- endoplasmic reticulum stress
- adipose tissue
- gene expression
- toll like receptor
- escherichia coli
- methicillin resistant staphylococcus aureus
- reactive oxygen species
- biofilm formation
- inflammatory response
- dna methylation
- skeletal muscle
- insulin resistance
- metabolic syndrome
- molecular dynamics