Abstract
Ricin, Shiga toxin, exotoxin A, and diphtheria toxin are AB-type protein toxins that act within the host cytosol and kill the host cell through pathways involving the inhibition of protein synthesis. It is thought that a single molecule of cytosolic toxin is sufficient to kill the host cell. Intoxication is therefore viewed as an irreversible process. Using flow cytometry and a fluorescent reporter system to monitor protein synthesis, we show a single molecule of cytosolic toxin is not sufficient for complete inhibition of protein synthesis or cell death. Furthermore, cells can recover from intoxication: cells with a partial loss of protein synthesis will, upon removal of the toxin, increase the level of protein production and survive the toxin challenge. Thus, in contrast to the prevailing model, ongoing toxin delivery to the cytosol appears to be required for the death of cells exposed to sub-optimal toxin concentrations.
Highlights
AB-type protein toxins are released into the extracellular environment but attack targets within the host cytoplasm[1,2]
The oxidative stress resulting from a 20 h exposure to 1 mM H2O2 lowered cell viability to 56 ± 3% (n = 3, ± std. dev.) of the untreated control value. These results indicated substantial cell death did not occur after a 20 h toxin challenge despite the reduction in protein synthesis
Our results demonstrated a single molecule of cytosolic toxin is not sufficient to completely inhibit protein synthesis and kill the target cell after a 20 h incubation
Summary
AB-type protein toxins are released into the extracellular environment but attack targets within the host cytoplasm[1,2]. An alternative interpretation for toxin ED50 values would be based on proportionality rather than probability: at the ED50 for protein synthesis inhibition, it is possible all cells in the exposed population contain an amount of cytosolic toxin that only reduces protein synthesis by 50%. With this proportionality model, limiting but not eliminating the quantity of cytosolic toxin could protect a cell from the lethal outcome of intoxication. Our work presents the first evidence with quantifiable data to challenge the “single molecule” paradigm of intoxication
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