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Cracking bacterial tactics for infection

Researchers at ITQB NOVA uncovered a new way in which bacteria hijack host behavior to promote infection. The discovery could contribute to the development of new drugs for diarrheal diseases.

Oeiras, 22 March 2024

Escherichia coli (E. coli) bacteria live peacefully in our gut and very rarely causes disease. However, some specific strains can lead to diarrheal diseases, the third leading cause of death in children under five years old, and other complications. This is the case for enteropathogenic E. coli (EPEC), which is mainly endemic in low-income countries, and enterohemorrhagic E. coli (EHEC), which affects more industrialized countries not only with diarrheal disease but also hemolytic uremic syndrome (HUS), an acute form of renal failure.

Despite presenting differently in terms of epidemiology and clinical disease, these bacteria share the same mechanism of colonization: they attach to the gut mucosa and cause distinctive lesions. Since they do not have a way to directly attach to the mucosa, bacteria create their own receptor, secrete it and then translocate it to the host cells. This receptor, called Tir (translocated intimin receptor), then binds a component on the pathogen’s surface. But its role in infection goes beyond anchoring bacteria to host cells; it also shapes host behavior, assuring their survival.

In a new study, published in Communications Biology, researchers revealed that Tir is a disordered protein, with not so well-defined structures and host-like binding motifs. “This conformational flexibility allows for versatile interactions with human cell components, interfering with normal cellular function, promoting infection and mediating host cell death”, explains Marta F. M. Vieira, first author of the paper.

The work led by ITQB NOVA in collaboration with the Imperial College London, FMP-Berlin, and the Aix Marseille University is the first to show that pathogenic bacteria use host-like disordered protein features as a strategy to evade the host immune system and facilitate infection. “This intrinsic disorder is quite common in more complex organisms, which require more plasticity, but is not very usual in bacteria”, explains Tiago Cordeiro, leader of the Dynamic Structural Biology Lab. “What is really impressive is that these bacteria create their own disordered protein to mimic the regulatory stratagem of the host and fine-tune signaling to their benefit”, he adds.

The resulting findings will pave the way to future treatments and strategies selectively targeting this bacterial receptor, providing alternatives to tackling enteropathogenic and enterohemorrhagic E. coli infection. In the future, the knowledge arising from this study may help us handle global outbreaks of foodborne diseases more effectively, benefiting global health, food safety, and farming, and lessening the economic impact of bacterial infections on low-income countries.

This work was funded by Fundação para a Ciência e a Tecnologia (PTDC/BIA-BFS/0391/2021) and the Agence Nationale de la Recherche (French National Research Agency).


The pathogen-encoded signalling receptor Tir exploits host-like intrinsic disorder for infection

Vieira, M.F.M., Hernandez, G., Zhong, Q. et al. T. Commun Biol 7, 179 (2024).

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