The latest effort from my former PhD supervisor Teresa Frisan, from the Karolinska Institute in Stockholm, was published today April 7th in PLoS Pathogen. And it rocks!
I am proud of two things: first, to have co-authored this work with Lisa Del Bel Luz, a PostDoc in Frisan’s lab, who made critical contributions to the manuscript. But I am also very proud to publish this work in a good Open-Access journal, that expressively encouraged me to spread the word about our results.
So here we go.
“is ‘toxin’ the appropriate designation”?
We talk about genotoxins, a special bacterial product that damage (-toxin) the DNA (geno-) of cells.
Although we know how genotoxins look and do in vitro, their function during a normal bacterial infection is surprisingly understudied. Studies have consistently showed that genotoxin are ugly beasts, causing cell death and inflammation. So we were surprised to find that one of these genotoxins – typhoid toxin – actually increases survival of the host during bacterial infection. As Teresa says: this work “poses the semantic question of whether ‘toxin’ is the appropriate designation”.
The Frisan’s lab has focused on typhoid toxin from Salmonella enterica Typhi (S. Typhi), and specifically looked at chronic asymptomatic infections, a medically overlooked condition. But S. Typhi infects only humans, making it difficult to perform study in mice. So we turned to the cousin Salmonella enterica Typhimurium (S. Typhimurium), a strain that can infect mice, but don’t naturally harbor typhoid toxin.
In what turned out to be the “epic cloning adventure” of 2011 (for which Teresa gets all the credit) we managed to engineer two S. Typhimurium strains to produce natural levels of either an active or an inactive version of the toxin, and to compare their behaviour during an infection.
You live and I stay
The two strains behaved identically in the body, but to most of our surprise, mice infected with the strain carrying the active toxin survived better the infection. These surviving mice were also more likely to become ‘chronic carriers’, with Salmonella hiding in them for up to 6 months.
When we looked closely at the intestines of these mice – the first organ hit by the bacterium – we found that mice infected with the toxigenic strain mounted a weaker immune response, as if the bacterium went undetected in the body. On the contrary, in strains lacking typhoid toxin caused enteritis in the mice, with infiltration of inflammatory white blood cells.
An analysis of the intestinal microbiota (the kilogram or so of bugs that naturally reside inside mammal’s intestine) from these mice also revealed that the presence of the toxin caused special changes compared controls. In summary, typhoid toxin is used by Salmonella to colonise longer the host, helping the host to live longer.
Typhoid Toxin damages the liver DNA
Salmonella doesn’t stay in the gut for long. The bacteria quickly spread form the intestine to other parts of the body, causing a systemic – often lethal – infection in humans. Salmonella ultimate target is the liver, where it can quietly reside for decades.
In our study, we found that typhoid toxin can accumulate in the cells of the liver, causing DNA damage as early as 10 days post-infection. Differently then in the intestine, mice infected with toxigenic bacteria had more liver pathology compared to controls. Among many other products, these livers produce more IL-6, a cytokine associated with liver cancer.
Published work from us and others has showed that – due to its DNA-damage activity – genotoxins cause cellular abnormalities that may promote cancer. Whether they do so in vivo is not clear. What is better understood – however – is that human chronically infected with Salmonella have higher chances to develop liver and gallbladder cancer. Although in our experimental conditions chronic infection was not associated with dysplasia or pre-carcinogenic lesions, our evidence cannot rule out completely typhoid toxin as possible cancer promoter.
Our results, however, revealed an undiscovered function of genotoxin in suppressing the immune response of the host organism, during the course of intestinal infections, for the benefit of both the host and the pathogen.