Anthrax lethal toxin disrupts intestinal barrier function and causes systemic infections with enteric bacteria

Area of Science:

• Microbiology
• Immunology
• Cell Biology

Background:

• Intestinal pathogens often target host signaling pathways like mitogen-activated protein kinase (MAPK).
• Bacillus anthracis utilizes lethal toxin (LT) to interfere with MAPK signaling by cleaving MAPK kinases (MKKs).

Purpose of the Study:

• To investigate the effects of anthrax lethal toxin (LT) on intestinal epithelial integrity and barrier function.
• To elucidate the role of LT's proteolytic activity in intestinal pathology and systemic infection.

Main Methods:

• Intoxication of C57BL/6J mice with varying doses of intravenous LT.
• Assessment of intestinal epithelial integrity, crypt cell proliferation, and apoptosis.
• Evaluation of systemic infection development and the impact of antibiotics.

Main Results:

• LT caused dose-dependent intestinal erosion, ulceration, and bleeding.
• LT blocked intestinal crypt cell proliferation and induced apoptosis in villus tips.
• Intravenous LT administration led to systemic infections with enteric organisms within 72 hours.
• Antibiotics partially attenuated LT-induced intestinal pathology, suggesting a dual role in infection.

Conclusions:

• Anthrax LT compromises intestinal barrier integrity by targeting MAPK pathways, weakening mucosal defenses.
• Disruption of the intestinal barrier, coupled with LT's immunosuppressive effects, facilitates host invasion via the enteric route.
• These findings offer a mechanism for Bacillus anthracis pathogenesis during natural infection.