Dissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet

Area of Science:

• Bacterial pathogenesis
• Molecular microbiology
• Structural biology

Background:

• The multifunctional autoprocessing repeats-in-toxin (MARTX) is a key virulence factor used by bacteria like Vibrio vulnificus to invade host cells.
• Vibrio vulnificus causes severe infections, including sepsis, but the precise molecular mechanisms of MARTX-mediated pathogenesis are not fully understood.

Purpose of the Study:

• To elucidate the structural and mechanistic basis of how the MARTX toxin effector duet (DUF1/RID) functions in bacterial invasion and sepsis.
• To reveal the molecular interactions of the DUF1/RID complex with host targets, specifically calmodulin and Rac1.

Main Methods:

• Crystal structure determination of the DUF1/RID complex.
• Cryo-electron microscopy (cryo-EM) to resolve the structure of the RDTND-RID duet complexed with calmodulin and Rac1.
• In vitro and in vivo immunological analyses in mice.

Main Results:

• The DUF1 domain functions as a RID-dependent transforming NADase domain (RDTND), disrupting NAD+ homeostasis by hijacking calmodulin.
• The RDTND-RID duet complex modifies Rac1 and depletes NAD(P)+, suppressing reactive oxygen species (ROS) generation.
• These actions lead to the paralysis of immune responses, bacterial dissemination, and the induction of sepsis.

Conclusions:

• The study reveals the intricate molecular mechanism by which Vibrio vulnificus employs the MARTX toxin effector duet to subvert host immunity and cause sepsis.
• These findings provide a foundation for developing novel therapeutic strategies targeting MARTX toxin-related human diseases.