Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity

Area of Science:

• Microbiology
• Immunology
• Lipid Biochemistry

Background:

• Pathogenic mycobacteria possess virulence lipids in their outer cell wall.
• Phthiocerol dimycocerosate (PDIM) is a crucial outer membrane lipid involved in evading host defenses.
• PDIM is essential for evading Myd88-dependent monocyte recruitment early in infection.

Purpose of the Study:

• To investigate the role of PDIM in mycobacterial infection using a chemical tracking approach.
• To understand how PDIM interacts with host tissues and influences immune evasion.
• To explore potential therapeutic strategies targeting PDIM function.

Main Methods:

• Development of a chemical approach to track PDIM during *Mycobacterium marinum* infection in zebrafish.
• Observation of PDIM spread into host epithelial membranes.
• Assessment of the impact of cholesterol synthesis inhibition on PDIM spread and infection outcome.

Main Results:

• PDIM's methyl-branched lipid tails facilitate its spread into host epithelial membranes, preventing immune activation.
• PDIM exhibits an affinity for cholesterol, which promotes its membrane-spreading phenotype.
• Statin treatment, a cholesterol synthesis inhibitor, reduced PDIM spread and conferred protection against *M. marinum* infection in zebrafish.

Conclusions:

• Host-pathogen lipid interactions significantly impact mycobacterial infectivity.
• PDIM spread into host membranes is a critical mechanism for immune evasion.
• Statins show potential as a preventive therapy for tuberculosis by inhibiting PDIM spread.