Malaria and the Intestinal Immune Response

Project offered for Ker Memorial PhD Studentship in Infectious Diseases

Half of the world’s population is at risk of malaria, with over 247 million cases in 2021. One under-appreciated impact that malaria has on global health is that it creates an environment for secondary pathogens to thrive. In particular, children with Plasmodium falciparum infection are at increased risk of bacterial sepsis, particularly to Salmonella – contributing to the >100,000 deaths per year of invasive Salmonellosis. However, it remains unclear how underlying malaria increases this risk of secondary bacterial infections, particularly at the intestinal interface. Bloodstream bacterial infections are difficult to detect in hospital, often requiring culturing. Further, prophylactic antibiotic treatment in suspected sepsis cases has contributed to the rise in antimicrobial resistance. Therefore, it would be prudent to improve resilience to Salmonella infection by restoring intestinal health. If we can understand and prevent infection at the site of Salmonella entry during malaria, the intestine, this would reduce the need for antibiotics, reduce sepsis and ultimately save lives. In this project, the student will investigate this important co-infection using a mix of human and animal models of malaria infection performed in parallel. 

In humans with P. falciparum infection, diarrhoea is a well-established symptom. However, our understanding of how this occurs remains difficult to unpick, as gut tissue sampling is often limited to severe disease at autopsy. Therefore, we use a rodent model of malaria to investigate the consequences of the gastroenteritis seen in human infection. In mice, we have found that malaria infection alone induces mild intestinal inflammation and promotes the colonization of Salmonella. In addition, malaria alters the intestinal barrier, leading to a “leaky gut”. Moreover, the intestine plays a crucial role maintaining overall health, particularly through nutrient absorption and supporting the gut microbiome – features perturbed during malaria. The overarching aim of the project is to investigate the mechanisms of intestinal inflammation seen in rodent malaria models in vivo, and translate the relevance of these findings to malaria infection in humans.

Aims:

1. In mice, characterise cellular influx in the intestine to pinpoint the source of inflammation, including myeloid cell activation.
2. In mice, unpick the pathological consequences of malaria-induced gastroenteritis by investigating intestinal crypt microarchitecture and barrier function – including using intestinal organoid cultures.
3. In children with P. falciparum, evaluate faecal samples for intestinal inflammation, building evidence for future fieldwork using these non-invasive methods.

Approaches:

• Performing in vivo malaria experiments in rodents.
• Analysing human samples, with complex datasets.
• Flow cytometry and immune cell phenotyping.
• Microscopy of the intestine including; immunohistochemistry, immunofluorescence, and two-photon microscopy.
• Intestinal organoid cultures.
• Microbiome sequencing and analysis.

The aims and approaches outlined are optional, as the student should work in partnership with the supervisors to decide the direction of their PhD research.

Training and skills

The PhD is a career training opportunity, expanding on existing skills and gaining new transferrable skills to widen future career options. The transferable skills in this project includes; parasitology, immunology, organoid cultures, bioimaging (microscopy & FACS), in vivo animal studies, and working with human field trial samples and resulting complex datasets.

Professional and practical skills are equally as important to what we learn in the lab. These ‘soft skills’ include; (1) Engagement (e.g. academic communication, public engagement, etc.), (2) Personal Development (e.g. networking, project management, resource management, etc.), (3) Research Governance (e.g. ethics and data management, funding bid experience, etc.), and (4) Knowledge Abilities (e.g. problem solving, application of knowledge, etc.). Obtaining these transferrable skills are essential for a well-rounded PhD and we will promote opportunities to develop these career skills outwith the research environment. At the start of the degree, the mentors will work with the student to develop a personalised training plan.

For attendance of scientific meetings, the student will be encouraged to present their findings both locally and domestically, at meetings such as the Scottish Parasitology, Edinburgh Infectious Diseases, and the British Society of Immunology annual congress and local meetings.

This PhD project will build upon our established knowledge, whilst also providing flexibility in the questions asked by the student. As an Edinburgh Infectious Diseases Ker Memorial PhD student, the individual will take a leading role in driving the scientific trajectory. Curiosity will be highly encouraged.

Mooney lab

Mabbott lab