Leptospira interrogans induces apoptosis in macrophages via caspase-8- and caspase-3-dependent pathways

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Host cell apoptosis is crucial in infectious disease pathogenesis.
• Leptospira interrogans, the cause of leptospirosis, induces apoptosis in macrophages and hepatocytes.
• The precise molecular mechanisms of L. interrogans-induced host cell death were unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which L. interrogans induces apoptosis in macrophages.
• To identify the key signaling pathways and proteases involved in L. interrogans-mediated host cell death.

Main Methods:

• Utilized a macrophage-like cell line (J774A.1) and primary murine macrophages.
• Assessed apoptosis markers, including caspase activation (caspase-3, -6, -8, -9), FADD expression, PARP and lamin cleavage, and cytochrome c release.
• Investigated the role of caspase-8 and caspase-3 using specific inhibitors.

Main Results:

• L. interrogans induced apoptosis in macrophages in a time- and dose-dependent manner.
• Apoptosis involved activation of caspase-3, -6, and -8, increased FADD expression, and cleavage of PARP and lamin A/C.
• Caspase-8 activation initiated the apoptotic cascade, while caspase-3 played a role in caspase-6 activation and potentially caspase-9 activation via feedback.
• Mitochondrial cytochrome c release and caspase-9 activation were minimal.

Conclusions:

• L. interrogans induces apoptosis in macrophages via a pathway dependent on Fas-associated death domain (FADD) and caspase-8.
• The primary apoptotic signaling involves caspase-3 and caspase-6 activation, independent of the mitochondrial pathway.
• Understanding these mechanisms is vital for developing therapeutic strategies against leptospirosis.