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- Title
Pathogen-driven nucleotide overload triggers mitochondria-centered cell death in phagocytes.
- Authors
Schwermann, Nicoletta; Haller, Rita; Koch, Sebastian; Grassl, Guntram A.; Winstel, Volker
- Abstract
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. Author summary: Staphylococcus aureus is a high-priority pathogen which converts antimicrobial neutrophil extracellular DNA traps into death-effector deoxyribonucleosides to trigger a genotoxic buildup of nucleotides in phagocytes. However, the exact signaling events and pathological consequences that S. aureus-driven manipulation of immune cell nucleotide homeostasis may initiate remain undefined. By profiling the apoptotic response of phagocytes along with the exploration of the allelic repertoire of human CASP9, we show that staphylococcal death-effector deoxyribonucleosides and coupled alterations in intracellular nucleotide pools provoke mitochondrial damage and subsequent ignition of the intrinsic pathway of apoptosis, an immunological silent event that helps S. aureus to establish abscesses in host tissues. Given that S. aureus-derived effector-nucleosides substantially contribute to staphylococcal immune evasion and disease pathogenesis, our discoveries and the identification of human factors that increase the susceptibility of the host to S. aureus will aid in the design of new anti-infective agents and may further help to answer the question why certain single nucleotide polymorphisms in host genes targeted by staphylococcal products are maintained in human populations.
- Subjects
CELL death; PHAGOCYTES; SINGLE nucleotide polymorphisms; DEOXYRIBONUCLEOSIDES; DEOXYRIBONUCLEOTIDES; HOMEOSTASIS; INSECT nematodes
- Publication
PLoS Pathogens, 2023, Vol 19, Issue 12, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1011892