The study reveals that the typhoid toxin accelerates cellular aging to improve killer infection

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• New research has shown that a Salmonella Typhi toxin causes typhoid fever to take over from DNA repair machines to age cells and increase the aggressiveness of the infection

• The discovery could pave the way for the development of new diagnoses and previous treatments for typhoid

• Typhus currently affects 21 million people each year and causes 168,000 deaths

• The results mark the first study involving the Healthy Lifespan Institute of the University of Sheffield, which aims to slow the aging process and address the global multimorbidity epidemic

RINGS of DNA damage in human cells caused by typhoid toxin at the base of typhoid fever

Scientists have revealed how the typhoid toxin works to hijack machines for DNA repair and accelerate cell aging, a breakthrough that could pave the way for new strategies to combat the killer disease.

Within the scope of the study, experts from the Department of Biomedical Sciences, with the support of the new Healthy Lifespan Institute at the University of Sheffield, infected human cells in a laboratory with the bacterial typhoid pathogen – Salmonella Typhi.

Using fluorescent microscopes to study how the toxin damaged DNA at the molecular level, they found that it induces a peculiar form of DNA damage; the toxin takes control of the DNA repair machines and accelerates cellular aging, making them more susceptible to infection. Over time, secretions from infected cells can also cause aging in neighboring cells, leading to faster cellular aging.

Typhoid fever is a major killer in low and middle income countries, affecting 21 million people each year and causing 168,000 deaths. Infectious disease is a particular problem in South Asia, where it is aggravated by antimicrobial resistance and lack of effective vaccines and diagnostic systems.

To cause typhoid, the bacterial pathogen Salmonella Typhi releases the typhoid toxin, which damages cellular DNA. Our DNA is constantly threatened by environmental factors such as smoking and UV light, but cells usually have robust DNA repair machines to combat these threats. In the case of the typhoid toxin that attacks our cells, it is this function of repairing the machine that is hijacked. Dr. Angela Ibler, who made the discovery, nicknamed the answer to DNA damage. RING – A response induced by a genotoxin – in reference to single-strand breaks in the double helix of DNA of human cells that accumulate in a model typical ring.

The results, published in Nature Communications, could potentially allow cellular aging associated with toxins to be used as a biomarker to help with early diagnosis and faster treatment for typhoid sufferers.

The dott. Daniel Humphreys, who led the study of the Department of Biomedical Sciences at the University of Sheffield, said: "Our results showed that pathogenic bacteria can accelerate cell aging through a toxin and take advantage of it to establish infections. This makes sense since infections are often more difficult to fight and age, partly due to cellular aging, but the fact that bacterial pathogens affect this phenomenon is unexpected. "

Professor Sherif El-Khamisy, deputy director of the Healthy Lifespan Institute of Sheffield University and a professor in the Department of Molecular Biology and Biotechnology, who co-led the work, said: "So far, how did the Typhoid Typhoid Typhoid Toxin Infection had been a mystery. If we want to fight typhus, understand how the toxin breaks the DNA of human cells and promotes infection is the key and we hope that this discovery is the first step in developing new strategies to control typhoid, which affects some of the most vulnerable in the community world “.

Currently there is no routine diagnosis of typhus, which is often confused in the clinic with deadly fevers such as malaria and dengue. As a result, patients receive delayed antibiotic therapy, which causes clinical complications. Better diagnostics will improve clinical diagnoses and enable faster treatment, while helping researchers quantify the extent of typhus in endemic contexts, necessary to convince governments to implement public health / vaccine programs.

The work marks the first study that involves the Healthy Lifespan Institute at the University of Sheffield. The Institute brings together 120 world-class researchers from a wide range of disciplines with the goal of slowing the aging process and tackling the global multimorbidity epidemic – the presence of two or more chronic conditions – in an attempt to help everyone live healthier, independent lives longer and reduce the cost of care.

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

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