CD44 Promotes intoxication by the clostridial iota-family toxins

Area of Science:

• Microbiology
• Cell Biology
• Toxicology

Background:

• Pathogenic clostridia produce binary protein toxins involved in human and animal enteric diseases.
• These toxins utilize binding/translocation (B) components to interact with cell surface receptors, facilitating the entry of enzymatic (A) components into the host cell cytosol.
• The internalized toxin components disrupt the actin cytoskeleton, leading to cellular damage and disease.

Purpose of the Study:

• To investigate the role of the mammalian cell surface protein CD44 in mediating cellular intoxication by clostridial binary toxins, specifically the iota toxin family.
• To determine if CD44 acts as a receptor for iota toxins and if its absence confers resistance to intoxication.

Main Methods:

• Utilized cell-based assays with CD44-positive and CD44-deficient cells to assess toxin binding and cytotoxicity.
• Employed specific antibodies against CD44 to block toxin activity.
• Performed in vitro binding assays with purified CD44 and various clostridial toxins.
• Assessed toxin lethality in CD44 knockout mice.

Main Results:

• CD44 was identified as a key facilitator of intoxication by the iota family of clostridial binary toxins.
• Antibodies targeting CD44 inhibited the cytotoxic effects of Clostridium perfringens iota toxin.
• Cells lacking CD44 exhibited reduced toxin binding and dose-dependent resistance to iota, iota-like, and related toxins.
• Purified CD44 demonstrated specific in vitro interaction with iota and iota-like toxins.
• CD44 knockout mice showed resistance to iota toxin-induced lethality.

Conclusions:

• CD44 functions as a critical receptor for clostridial binary toxins, including the iota toxin family.
• Targeting CD44 presents a potential therapeutic strategy to counteract intoxication by these pathogenic binary toxins.
• The findings elucidate a significant host-pathogen interaction mechanism in clostridial enteric diseases.