Pete Johnston is a PhD student and infectious diseases doctor funded through the Wellcome Trust Liverpool Clinical PhD Programme for Health Priorities in the Global South. He conducts his research at the Malawi Liverpool Wellcome Programme in Blantyre, where he also practices as a physician at Queen Elizabeth Central Hospital.
How I became a global health researcher focused on Salmonella disease
As a medical student I worked in a hospital in rural Zambia. I was profoundly affected by tragedies that could have been prevented with more resources. I returned as a qualified doctor a few years later, but realised quickly that my individual efforts had a narrow reach. Evidence-based interventions delivered at scale were needed, such as the protocolised treatment of HIV. This sparked my passion for global health research.
I returned to the UK for specialist training in infectious diseases combined with an Academic Clinical Fellowship. This dual clinical and academic role allowed me to pursue projects related to typhoid fever. Typhoid is caused by Salmonella, and is one of several human illnesses caused by this ‘family’ of bacteria. For my PhD fellowship I developed an interest in invasive non-typhoidal Salmonella disease (iNTS), a devastating and common cause of bloodstream infection amongst vulnerable children in Africa. Having gained a place on the Wellcome-funded Liverpool Clinical PhD Programme for Health Priorities in the Global South, I moved to Malawi to study this disease in an endemic setting.
Why study invasive non-typhoidal Salmonella?
Non-typhoidal Salmonella (NTS) bacteria are the most frequent cause of community-onset bloodstream infection in Africa. Young children are most commonly afflicted, and one in five of those who develop an invasive infection will die.
Outside of Africa, infection with NTS bacteria most often leads to a stomach upset – not a case of sepsis. The difference in Africa is that NTS have developed ways of escaping gut immune defences. Additionally, many people in Africa have weakened immune defences due to malaria, HIV, malnutrition, and sickle cell disease.
What do I aim to find out and why does it matter?
To cause invasive disease, NTS bacteria must find their way into the gut of a susceptible person. When this occurs it is called enteric NTS disease (eNTS). It is likely that exposure to NTS bacteria (through repeated eNTS episodes) leads to natural protection from invasive disease. It is therefore evident that the deployment of iNTS control strategies, such as vaccines and sanitary measures, must be underpinned by an understanding of the transmission of NTS bacteria and resulting eNTS episodes.
My study seeks to define key aspects of NTS transmission and immunity: the frequency of eNTS episodes and their resulting secondary infections; the duration that NTS bacteria are shed in stool; whether people with eNTS experience symptoms; and what risk factors predispose to infection. I’m also investigating the impact of eNTS episodes on the immune system, including whether Salmonella bacteria not usually associated with invasive disease might be important in generating natural protection through their similar surface proteins.
How will I find this out?
My study recruited randomly selected households within an informal settlement called Ndirande. My study team followed every member of each household over time. We collected blood, stool, and nose swabs from these participants. We tested stool and nose swabs for NTS bacteria, and tested blood samples for antibodies directed against NTS bacteria. We went back to households every other day for at least four weeks. This allowed us to track the incidence of eNTS episodes (and the development of immune responses) in real time.
The next step is to sequence the DNA from the bacteria that we have grown. This will tell us whether the same isolates are being passed around within each household, and to predict what proteins the bug has on its surface (which might affect the antibody response a participant has). We are also using a highly sensitive PCR test to check whether there were additional Salmonella positive individuals that were not picked up through culture alone. Excitingly, we can then piece together the DNA sequences of PCR-positive but culture-negative samples using low-diversity metagenomic sequencing. Through integrating this data with clinical symptoms and immune responses, we will provide unprecedented insights into how NTS spread and – ultimately, how to prevent invasive infection.
What next?
The data from this study will provide work and insights for years to come, but already I am dreaming up the next project. Being the Principal Investigator on a study of my own design has been an indescribably rewarding experience, with each obstacle and achievement offering an opportunity for growth. In the next few years I will seek to leverage my knowledge in genomics and transmission modelling to lead studies that will uncover more about how antimicrobial resistant organisms spread, and how we can control them.