Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Pathogens like Yersinia target innate immune responses.
• Yersinia's YopJ virulence factor inhibits NF-κB and MAPK signaling, suppressing cytokine production and inducing cell death.
• While RIPK1 kinase, caspase-8, TLR4, and TRIF are implicated in Yersinia-induced cell death, TLR4/TRIF-independent pathways also contribute.

Purpose of the Study:

• To investigate the mechanisms of Yersinia-induced cell death in murine macrophages.
• To elucidate the role of TNF/TNFR1 signaling in Yersinia infection.
• To understand the impact of virulence factor injection heterogeneity on immune response.

Main Methods:

• Analysis of Yersinia-infected murine macrophages.
• Investigation of TNF/TNFR1 signaling pathways.
• Assessment of cell death (apoptosis) in Yersinia-infected cells.
• Use of TNFR-deficient mice to study Yersinia susceptibility.

Main Results:

• TNF/TNFR1 signaling plays a critical role in Yersinia-induced macrophage apoptosis, independent of NF-κB and MAPK blockade.
• Yersinia infection leads to heterogeneous YopJ injection, with TNF production originating from low-injection cells.
• TNF from low-injection cells is crucial for maximal apoptosis in high-injection cells.
• TNFR-deficient mice show increased susceptibility to Yersinia infection.

Conclusions:

• TNF and pattern recognition receptor signals collaborate to promote maximal apoptosis during Yersinia infection.
• Heterogeneity in Yersinia virulence factor injection and cellular responses is vital for effective anti-bacterial defense.