A Tale of Two Salmonellas
Thoughts of Salmonella are more likely to get your stomach churning than stimulate your interest. However Salmonella is more than a bacterium that causes a bad stomach ache: certain types of the bacteria can cause serious damage. Professor Jay Hinton, a professor in IIB’s research theme, is finding out how different types of Salmonella cause such a wide range of symptom severity. His group uses gene expression to find out what factors differ between Salmonella subtypes in order to identify new treatments for the nastier types of Salmonella.
Jay has been working on microbial diseases for the past 30 years. In that time, he’s kept a sharp focus on studying Salmonella ever since he finished his PhD. “Salmonella bacteria are great to work with since you can do just about any experiment you want with them. There are also a lot of scientific resources available, including 50 years of research on their genetics and biochemistry. Anytime you work with Salmonella, you’re really standing on the shoulders of giants.” Jay commented.
For over 20 years, Jay has researched the type of Salmonella which is found all over the world, the one you’d likely run into if you happen to eat a bit of undercooked chicken (we’ll refer to it here as ‘Global Salmonella’). He first focused on the role of global gene expression in the ability of Salmonella to make people ill. Jay’s work demonstrates that the more potent types Salmonella express higher levels of certain genes in order to make more of the proteins required to infect their host.
Global Salmonella is a rather innocent subtype. It’s tough enough to survive on dry surfaces and is responsible for severe gastroenteritis in healthy individuals—but there are other far more potent strains. One strain now in focus at Jay’s lab belongs to the ST313 sequence type—the numbering system simply means that it’s the 313th Salmonella type to be discovered. ST313 was first discovered in 2002 in sub-Saharan Africa. Global Salmonella is usually responsible for stomach upsets while ST313 causes a much nastier infection. ST313 kills 20% of the people it infects and the disease is also resistant to 9 antibiotics. ST313 also causes an especially dangerous disease if the patient is immunocompromised by malaria, HIV, or malnutrition. When these patients are infected with ST313, the Salmonella can spread to the liver and spleen and cause severe fever and diarrhoea.
“To find ways to cure the disease, we must understand how the infection works. There have been very few new antibiotics made against Salmonella in recent years, so our group is using tools to learn why some Salmonella strains are much more dangerous than others” said Jay. His group’s approach is to look for differences in virulence factors by comparing Salmonella strains at both the genomic and the gene expression levels. “Looking at the genome alone isn’t enough. The gene content of an organism does suggest potential phenotypes, but if a gene’s not expressed then it can’t cause a change in virulence. The approach we use is to consider both what genes are available and what genes are actually being expressed.” Jay commented.
When looking at the genome itself, researchers focus on natural genetic differences known as single nucleotide polymorphisms (SNPs). A SNP occurs when a single letter in a gene’s code is different between two individuals. Even in organisms of the same species, there are many SNPs that exist between individuals. Due to this diversity, it’s not always easy to interpret the biological role of particular SNPs. For example, when comparing Global Salmonella and the ST313, there are 1000 different SNPs and over 300 genes which distinguish the two types. “It’s difficult to get information that helps us understand the actual biological differences when just looking at SNPs and genes. So we are using gene expression patterns to map functional information onto these two genomes” says Jay.
Key protein discovery
When comparing gene expression between Global Salmonella and the African ST313 types, Jay’s group came across a protein which was much more highly expressed in ST313. As this protein helps bacteria to survive in human serum, Jay believes that an increase in the amount of this protein allows ST313 to grow and live in the bloodstream. Jay’s group then wanted to understand the mechanism of the increased expression of this key protein, and focused on the nucleotide sequence differences between the two types of Salmonella. They were able to find a key SNP difference in the regulatory region of the gene that actually controls the level of expression.
This work is the culmination of a 4 year project by Jay and his group which was recently been completed, and his group is now getting ready to submit a manuscript for publication. The paper will include experimental work done by several post-docs and PhD students and will include data from infection models that show the role of this protein in causing disease. Jay hopes that the approach of using both genomics and gene expression will be applied by other researchers to identify and validate how other types of bacteria cause disease. “You need to study more strains to gain a broader understanding of how the extremely dangerous Salmonella infections happen” said Jay.
Jay greatly enjoys sharing his work outside of his scientific community. He finds it easy to connect to others since most people he meets will have some form of a ‘Salmonella’ story. He also thinks that scientists as a whole need to be more proactive at communicating research. “Scientists don’t do enough to talk about the good we are doing. I’m lucky because my field is one that’s easy for people to understand, since everyone agrees that this research on Salmonella is worthwhile. As scientists, it is good to be outward facing with our research. The way we interact with people influences the way they see our work.” said Jay. Jay always strives to be collaborative and open to new ideas, whether it’s working with clinicians in Malawi or sharing techniques with colleagues. “The key for scientists is not to compete with one another but to work together” Jay emphasised.
Jay started his career by earning his bachelor’s degree in microbiology. “I love microbiology because your experiments will yield results quite quickly—I’m not patient enough for really long experiments!” said Jay. He completed his PhD in plant pathogenesis by identifying virulence genes of Erwinia, the bacterium that causes potato rot. Jay then became more interested in gene regulation and identified Salmonella as the best available model system to study microbe-host interactions. This combination of a great model system and its impact on human health gives Jay his “get out of bed in the morning” factor.
Jay’s day-to-day job involves research, grant writing, and mentoring a group of 6 post-docs, 3 PhD students, and 1 MSc student. He also lectures first-year biology students on topics including “Infections in the 21st century.” When asked about a normal day at work, Jay motioned to his desk piled with papers and books and replied casually “A bit messy!” While Jay did make it a summer goal to clean his desk (which, by the autumn, was halfway finished), he admitted that it was hard to find the time within his endless to-do list. “There’s always more papers to read, another grant to write, or just rushing around from office to office between meetings” said Jay. Jay also strives to leave time to step back from his to-do list and make time to reflect on ideas, concepts, and to gain new perspectives.
Jay’s group will be kept busy in the coming months with a new research project just funded by the Global Challenges Research Fund. This “10,000 Salmonella Genome Project” involves sequencing Salmonella isolates from thousands of patients in Africa and South America. “By discovering the types of Salmonella that are causing disease across the developing world, we hope our research will lead to new interventions that will improve the lives of people affected by these diseases” said Jay about the impact of this newly-funded research.
Jay’s group is itself a reflection of the global nature of his work, with researchers from Chile, Spain, Wales, Switzerland, Malawi, Colombia, and the UK. Jay’s research and his group truly embody what it means to be an ‘outward facing’ scientist, including the stuffed microbes that greet you with a friendly smile as you enter his office. Want to see the Salmonella group in action? Check out their video: