Acidic and alkaline conditions enhance Staphylococcus aureus α-toxin pore formation and cytotoxicity
- 1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
- 2Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, Karnataka, India
Abstract
Staphylococcus aureus α-toxin (AT) is a potent pore-forming toxin that causes cell damage during infection. The structure and activity of AT have been studied extensively, but the environmental factors that modulate its toxicity remain unclear. Here, we demonstrate that the extracellular pH modulates AT cytotoxicity through two independent mechanisms in human cells. First, we show that acidic conditions enhance AT pore maturation, causing a toxin-intrinsic and ADAM10 independent increase in cytotoxicity after prolonged exposure to AT. Second, we demonstrate that both acidic and alkaline conditions impair the cellular capacity to internalize AT pores, resulting in toxin retention at the cell surface and increased cytotoxicity after pulse intoxication. The cell-intrinsic, pH-dependent sensitization to AT is observed in various human cell types but not for other pore forming toxins. Together, our findings indicate that the extracellular pH modulates AT activity and host cell susceptibility. Author summary: Staphylococcus aureus is a bacterium that can cause severe invasive infections. S. aureus produces many toxins during infection, of which α-toxin (AT) is clinically relevant. AT is a pore-forming toxin that damages host cells by assembling into ring-shaped complexes that insert into the cell membrane to form transmembrane pores. During infection, S. aureus may encounter environments with different acidity, such as the skin, inflamed tissues, and the lungs. The impact of the local acidity on AT function is unclear. Here, we show that pH alters AT cytotoxicity through two separate mechanisms. First, acidic conditions enhance AT pore formation, causing an increase in its toxicity. Second, both acidic and alkaline conditions impair a host cell defence pathway that removes AT from the cell membrane. This leads to increased membrane damage after even brief toxin exposure. We observed this pH-dependent sensitization in multiple human cell types, but not with other pore-forming toxins. Together, our findings indicate that local tissue conditions, including the environmental acidity, modulate AT activity and host cell susceptibility.
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BibTeX
@article{linden2026acidic,
title = {{Acidic and alkaline conditions enhance Staphylococcus aureus α-toxin pore formation and cytotoxicity}},
author = {Tristan J. van der Linden and Arnab Chatterjee and Lisette M. Scheepmaker and Debajyoti Chakraborty and Somnath Dutta and Bart W. Bardoel and András N. Spaan},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014568},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014568},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Acidic and alkaline conditions enhance Staphylococcus aureus α-toxin pore formation and cytotoxicity
AU - Tristan J. van der Linden
AU - Arnab Chatterjee
AU - Lisette M. Scheepmaker
AU - Debajyoti Chakraborty
AU - Somnath Dutta
AU - Bart W. Bardoel
AU - András N. Spaan
PY - 2026
DA - 2026/09/01
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014568
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014568
AB - Staphylococcus aureus α-toxin (AT) is a potent pore-forming toxin that causes cell damage during infection. The structure and activity of AT have been studied extensively, but the environmental factors that modulate its toxicity remain unclear. Here, we demonstrate that the extracellular pH modulates AT cytotoxicity through two independent mechanisms in human cells. First, we show that acidic conditions enhance AT pore maturation, causing a toxin-intrinsic and ADAM10 independent increase in cytotoxicity after prolonged exposure to AT. Second, we demonstrate that both acidic and alkaline conditions impair the cellular capacity to internalize AT pores, resulting in toxin retention at the cell surface and increased cytotoxicity after pulse intoxication. The cell-intrinsic, pH-dependent sensitization to AT is observed in various human cell types but not for other pore forming toxins. Together, our findings indicate that the extracellular pH modulates AT activity and host cell susceptibility. Author summary: Staphylococcus aureus is a bacterium that can cause severe invasive infections. S. aureus produces many toxins during infection, of which α-toxin (AT) is clinically relevant. AT is a pore-forming toxin that damages host cells by assembling into ring-shaped complexes that insert into the cell membrane to form transmembrane pores. During infection, S. aureus may encounter environments with different acidity, such as the skin, inflamed tissues, and the lungs. The impact of the local acidity on AT function is unclear. Here, we show that pH alters AT cytotoxicity through two separate mechanisms. First, acidic conditions enhance AT pore formation, causing an increase in its toxicity. Second, both acidic and alkaline conditions impair a host cell defence pathway that removes AT from the cell membrane. This leads to increased membrane damage after even brief toxin exposure. We observed this pH-dependent sensitization in multiple human cell types, but not with other pore-forming toxins. Together, our findings indicate that local tissue conditions, including the environmental acidity, modulate AT activity and host cell susceptibility.
SN - 1553-7374
ER -