Scientists have revealed how the typhoid toxin works to hijack DNA repair machines and accelerate the aging of cells; a breakthrough that could pave the way for new strategies to combat the killer disease. Using fluorescent microscopes to study how the toxin damaging the DNA at the molecular level, they discovered 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.
In time, secretions from the infected cells can also cause aging in neighbouring cells, leading to faster aging at a cellular level. 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.
Typhoid toxin working
To cause typhoid, the bacterial pathogen Salmonella typhi releases the typhoid toxin, which damages cellular DNA. Our DNA is constantly under threat 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 attacking our cells, it is this repair machine function that gets hijacked; 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 human cell DNA that accumulate in a signature ring-like pattern.
The findings, published in Nature Communications today (6 September 2019); could potentially enable the toxin-associating cellular aging to be using as a biomarker to help with earlier diagnosis; and faster treatment for typhoid sufferers. Our findings have shown that pathogenic bacteria can speed up cellular aging through a toxin and take advantage of this to establish infections.
Bacterial pathogens target
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 unexpecting. Until now, how the typhoid toxin of Salmonella typhi contributed to infection had been a mystery. 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.
But currently, no routine diagnostics exist for typhoid; which is often confusing in the clinic with deadly fevers such as Malaria and Dengue. But as a consequence, patients receive delayed antibiotic therapy, which causes clinical complications. Better diagnostics will improve clinical diagnoses and enable faster treatment; while also helping researchers quantify the extent of typhoid in endemic settings; which is need to convince governments to implement public health/vaccine programmes.