Researchers Uncover How Gut Bacteria Disarm Host Immune Defenses Through a Network of Effectors

Singapore, March 2025 — A new international study has revealed how harmful gut bacteria use a coordinated arsenal of molecular weapons to disable the body’s immune defenses, ensuring their own survival and persistence. Published in The EMBO Journal, the research led by LSI Investigator Chen Kaiwen and PhD student Yeap Hui Wen, unravels how Citrobacter rodentium—a model organism for human diarrheal pathogens such as enteropathogenic and enterohemorrhagic E. coli—deploys a trio of proteins through its type III secretion system (T3SS) to manipulate cell death pathways and block inflammation.

The immune system relies on tightly regulated cell death programs—apoptosis, pyroptosis, and necroptosis—to eliminate infected cells and alert surrounding tissues. Central to this defense is caspase-8, an enzyme activated by RIPK1 that drives both inflammatory signaling and controlled cell death. The new study demonstrates that when C. rodentium injects the effector NleE to suppress pro-inflammatory responses, host macrophages and colonic epithelial cells retaliate by activating caspase-8. To counter this, the bacteria deploy another effector, NleB, which blocks caspase-8, inadvertently priming the cells for RIPK3-dependent necroptosis—a highly inflammatory form of death. To prevent this outcome, the pathogen introduces EspL, a protease that cleaves RIPK1 and RIPK3, shutting down necroptosis entirely.

Together, NleE, NleB, and EspL form a layered network that suppresses apoptosis, necroptosis, and inflammasome activation, tilting the balance in favour of bacterial persistence. “Our findings highlight the sophistication of bacterial survival strategies,” said Dr. Kaiwen Chen of the National University of Singapore, senior author of the study. “C. rodentium has evolved a fail-safe system where if one effector’s action triggers a host response, another effector is ready to block that response. This reflects an evolutionary arms race between host immunity and pathogen evasion.”

The work also revealed that removing EspL sensitized macrophages to necroptosis and boosted inflammasome activity, reducing bacterial persistence in the colon. This suggests that targeting these effectors—or mimicking the host’s ability to bypass them—could provide new strategies to fight enteric infections. By illuminating the interplay between bacterial proteins and host cell death pathways, the study underscores how pathogens exploit molecular redundancies to maintain infection. These insights not only advance understanding of host–pathogen interactions but may also inform the development of therapies for infectious and inflammatory diseases.

Reference: Yeap HW, Goh GR, Rosli SN, et al. “A bacterial network of T3SS effectors counteracts host pro-inflammatory responses and cell death to promote infection.” The EMBO Journal. 2025. DOI: 10.1038/s44318-025-00412-5