Diphtheria toxin entry into cells is facilitated by low pH

Area of Science:

• Cell Biology
• Toxicology
• Molecular Biology

Background:

• Diphtheria toxin (DT) poses a significant threat to cellular function.
• Cellular protection mechanisms against DT are crucial for understanding its toxicity.
• Previous studies suggest pH influences DT's cellular interactions.

Purpose of the Study:

• To investigate the role of pH in cellular protection against diphtheria toxin.
• To elucidate the mechanism of diphtheria toxin entry into cells.
• To compare the effect of low pH on DT with related toxins.

Main Methods:

• Cell cultures were exposed to diphtheria toxin at neutral and low pH (4.5-5.5).
• Protective agents (NH4Cl, chloroquine) and antibodies were used to assess protection.
• Protein synthesis rates were measured to quantify DT's toxic effect.
• Related toxins (abrin, ricin, modeccin) were tested under similar low pH conditions.

Main Results:

• NH4Cl and chloroquine protection against DT was abolished at low pH.
• Low pH exposure accelerated the decrease in protein synthesis, indicating enhanced DT toxicity.
• Antibody addition before low pH incubation partially reduced DT toxicity, while addition after low pH showed stronger toxicity.
• Low pH did not enhance the entry of abrin, ricin, or modeccin.

Conclusions:

• Low pH facilitates direct penetration of diphtheria toxin (or its A fragment) through the cell surface membrane.
• At neutral pH, DT entry likely involves adsorptive endocytosis and vesicle acidification.
• The mechanism of DT entry at low pH differs from that of related toxins like abrin, ricin, and modeccin.