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How typhoid toxin drives cell ageing decoded

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Scientists have decoded how the toxin produced by the deadly typhoid bacterium hijacks an infected cell’s natural DNA repair mechanism, and accelerates its ageing — an advance that may help develop strategies to combat the killer disease. As part of the study, published in the journal Nature Communications, researchers infected human cells cultured in a lab with the bacterial pathogen that causes typhoid – Salmonella typhi.

To cause typhoid, the researchers noted that the pathogen releases the typhoid toxin, which damages DNA in the cells.

According to the study, the DNA in our cells is constantly under threat by environmental factors such as smoking and ultraviolet (UV) light, but cells usually have robust DNA repair machines to combat these threats.

Using fluorescent microscopes to study how the toxin damaged the DNA at the molecular level, they discovered that it induces a peculiar form of DNA damage.

The toxin takes over DNA repair machines, and accelerates cellular ageing, rendering them more susceptible to infection, the study noted.

According to the authors, the secretions from the infected cells gradually cause ageing in neighbouring cells, leading to faster ageing at a cellular level.

“Our findings have shown that pathogenic bacteria can speed up cellular ageing through a toxin and take advantage of this to establish infections” said Daniel Humphreys, lead author of the study from the University of Sheffield in the UK.

“This makes sense as infections are often harder to combat and recover from as we get old, which is partly due to cellular ageing, but the fact that bacterial pathogens target this phenomenon is unexpected,” said Humphreys.

Angela Ibler, who made the discovery, dubbed the DNA damage response RING — Response induced by a Genotoxin — in reference to the single-strand breaks in the double helix of DNA that accumulate in a signature ring-like pattern.

“Until now, how the typhoid toxin of Salmonella Typhi contributed to infection had been a mystery,” Professor Sherif El-Khamisy, who co-led the study, said.

“If we are to combat typhoid, understanding how the toxin causes breaks in the DNA of human cells and promotes infection is key and we hope this find will be the first step in developing new strategies to control typhoid, which affects some of the world’s most vulnerable communities,” El-Khamisy said.

According to a 2018 World Health Organization (WHO) report, typhoid fever is a major killer in low and middle-income countries, affecting 21 million people annually, and causing 168,000 deaths.

The infectious disease is a particular problem in South Asia where it is compounded by antimicrobial resistance and a lack of effective vaccines and diagnostics.

The researchers now hope to further investigate how this discovery can be exploited to help us diagnose and treat typhoid, and also determine whether the RING phenotype is a signature of other diseases associated with DNA damage, such as cancer.

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