A new-born Salmonella in Africa

Although Salmonella is well known as a cause of mostly annoying gastro-intestinal infections, the situation in Africa is very different. Through this study I have realised how Salmonella is a dominant cause of death among young children in Africa.
A new-born Salmonella in Africa

At the beginning of this century, the complete genomes of Salmonella bacteria were sequenced for the very first time (McClelland et al., 2001, Nature - Parkhill et al., 2001, Nature). We have all heard of Salmonella as a cause of gastro-intestinal infections across the world and its genetic similarity with E. coli makes it an attractive pathogenic model organism for molecular biologists.

However, meanwhile 'in the wild', a new variant of this Salmonella Typhimurium debranched and evolved in Africa to become a specialist in infecting human bloodstreams. This specific branch was called ST313. Together with Salmonella Enteritidis, also known to cause gastro-intestinal infections globally, Salmonella Typhimurium is now predicted to account for more than 600,000 deaths per year by causing bloodstream infections in sub-Saharan Africa. These are mostly young children under five. That is a lot of people. That is actually more than there are inhabitants of my own city, Antwerp. Or Atlanta, Edinburg or Zürich. I wasn't fully aware of that before I started this study. These high numbers are the result of a staggering fatality rate, predicted to be around 20 %. I can think of few diseases with such fatality rates.

So the next question is: What happened that a rather harmless Salmonella became so efficient at infecting and killing humans?

Well, there are two things:

1. This disease affects a vulnerable human population, often suffering also from malnutrition, co-infection with malaria and/or HIV.

2. Salmonella itself changed and evolved to cause severe bloodstream infections.

Since the completion of that first Salmonella Typhimurium genome in 2001, genome sequencing has truly revolutionised molecular bacteriology, making this an exciting research field. A large collaborative effort in which sequences from invasive Salmonella Typhimurium across Africa were analysed (Okoro et al., 2012, Nature Genetics, https://www.nature.com/articles/ng.2423?proof=true) made clear that Salmonella Typhimurium evolved to form two distinct ST313 lineages which subsequently spread over Africa. These two lineages are genetically different from the global clades and are specifically associated with bloodstream infections in sub-Saharan Africa.

Our study shows that evolution of Salmonella Typhimurium ST313 in Africa is not at its end point. For the first time, we observed a substructure in the population, a sublineage emerging from the Democratic Republic of the Congo (DRC). Ongoing evolution might indicate that the bacteria is further adapting. We observed for example a different multicellular behaviour in this sublineage, but it remains unsure what the effect might be on the actual disease.

The onset of this study was triggered by a striking observation made by the researchers in the DRC. For the very first time, they noticed resistance to the reserve antibiotic azithromycin. In addition, this was linked to resistance to ceftriaxone, an antibiotic of choice for the treatment of Salmonella bloodstream infections. Such 'extensively drug resistant' has not been seen before, and is worrying. The treatment options are then becoming very limited. There is one last drug that can be used to cure these patients in the DRC. But this is probably a race against the clock. Across the world antibiotic resistance is increasing and we have already observed one Salmonella Typhimurium isolate in DRC showing decreased susceptibility to that last antibiotic as well.

In this study (https://www.nature.com/articles/s41467-019-11844-z), we wanted to understand what was happening and hereto this study is truly a result from a collaboration between clinicians, biologists and bioinformaticians. This collaboration was pivotal throughout the study and bridge the different research fields. I was able to work with authorities within these different fields and also personally this has been an enriching journey for me. Literally, as this study took me from the Institute of Tropical Medicine in Antwerp to the hospitals and laboratories in the DRC in Africa to discuss with the local teams, but also to Cambridge in the UK, where bioinformatics and infection experiments were set up. I worked in different inspiring environments and many people in these different places contributed to this study. To me this collaboration itself is one of the major results.

In the end, this study also made me realise that we aren't there yet. We have given a new view on invasive Salmonella Typhimurium in Africa, but our view on the population structure of Salmonella Typhimurium in Africa is still scattered. More surveillance is needed. Better, faster and cheaper diagnostics are needed. New strategies are also needed to intervene with the disease, to treat patients with highly resistant infections and to prevent people from infections. More research on the biology and transmission is needed, which are still barely understood. I am wondering, what makes this Salmonella cause bloodstream infections instead of gastrointestinal infections. But probably also more attention to this disease is needed. It strikes me how such a large disease is known by so few.

So I'll end with this number: these 600,000 predominantly young children, every single year, more than the inhabitants of Antwerp. I didn't realise that. I believe that our observations urge for action. They indicate that Salmonella is evolving, and at the same time the bacterium is becoming extremely resistant to treatment.

Blood culture bottles. This is the first step where strains are identified - or not. Blood samples are taken and grown in culture bottles as shown in the picture. They are incubated and in a few days there is growth or not, which might be a Salmonella bacterium that caused a bloodstream infection.

Visit of a local lab at the INRB national reference labs in Kinshasa, DRC.

DNA sequencing and genomics are big in Cambridge. This is where individuals lived like Charles Darwin, who elucidated the fundamentals of evolution, Watson and Crick who announced the DNA structure and Fred Sanger who developed the first DNA sequencing methodology. On this DNA cycling path you can cycle along the gene sequence of BRCA2, a gene with an important role in cancer, also found in Cambridge.