How bacteria that cause inflammatory colitis outmaneuver our body’s defenses

Bacteria uses multiple defense mechanisms to survive in the host body. Shigella bacteria, that causes colitis, disable multiple host defense pathways using three specialized effector proteins, as reported by researchers from Japan. They found that these effectors suppress inflammation, block apoptosis, and prevent necroptosis in human cells, allowing the pathogen to replicate. This study offers new insights that could help develop vaccines and targeted therapies to manage inflammatory colitis.

Shigellosis, an acute intestinal infection that manifests as severe inflammatory colitis (inflammation of the colon), is a significant public health challenge. Caused by Shigella bacteria, it is especially prevalent in developing countries and areas with poor sanitation, affecting millions of adults and children alike. The resulting illness, which can range from mild to life-threatening, puts a substantial strain on healthcare systems and remains a leading cause of diarrheal mortality globally.

Shigella flexneri, the species responsible for most cases of shigellosis, possesses unique evolutionary adaptations that allow it to thrive within the human intestine. The body’s first response to harmful bacteria is inflammation—a rapid defensive action to recruit immune cells and wall off the infection. If that fails, host cells deploy a second, drastic measure: intentional cell death (apoptosis and necroptosis). Recent research has shown that Shigella can actively counteract both of these strategies using proteins called effectors. However, the precise mechanisms these bacteria use to achieve this feat are not fully understood.

In a new study, a research team led by Associate Professor Hiroshi Ashida and Professor Toshihiko Suzuki from the Department of Bacterial Infection and Host Response of the Graduate School of Medical and Dental Sciences at Institute of Science Tokyo (Science Tokyo), Japan, sought to tackle this knowledge gap. Their latest paper, published online in The EMBO Journal on September 10, 2025, describes in great detail, the highly specialized effectors S. flexneri uses to circumvent our body’s defenses.

“We wanted to understand how a common bacteria like Shigella employs different strategies to enhance its survival in the host body,” says Ashida, as the motivation behind the study.

Through several experiments involving human cell cultures, the researchers identified three key effectors and demonstrated how each targets a different host defensive response. First, they found that Shigella releases an effector OspI, which deactivates the protein Ubc13. This has two main consequences: it suppresses the NF-κB inflammatory pathway, thus preventing early inflammation, but also induces apoptosis through the caspase-8 (casp-8) pathway.

To counteract this form of cell death, Shigella then releases OspC1, an effector that modifies casp-8 via ADP-riboxanation and prevents apoptosis. Host cells detect this disturbance of casp-8, resulting in the induction of necroptosis as a backup defense. Finally, Shigella also blocks necroptosis using the OspD3 effector, which degrades the key proteins, receptor-interacting serine/threonine-protein kinase (RIPK) 1 and RIPK3. Together, these three effectors neutralize a big part of the early strategies our bodies rely on to limit the extent of bacterial invasions. “These findings highlight a clever multilayered manipulation that pathogenic bacteria use to evade and exploit the host’s defense mechanisms,” remarks Ashida.

By clarifying these intricate bacterial–host interactions, this study will help scientists come up with effective ways to combat shigellosis, reducing the burden of this dangerous condition. “Our findings shed new light on the infection mechanisms of intestinal pathogens and are expected to contribute to the development of vaccines and novel therapeutic strategies,” concludes Ashida, hopeful about the future. 

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About Institute of Science Tokyo (Science Tokyo)
Institute of Science Tokyo (Science Tokyo) was established on October 1, 2024, following the merger between Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech), with the mission of “Advancing science and human wellbeing to create value for and with society.”