2026-27 Project (Groppelli & Jarvis & Harrison)
Investigating the immunological interplay in CMV, HIV and cryptococcus meningitis co-infections and its link to disease severity
SUPERVISORY TEAM
Supervisor
Dr Elisabetta Groppelli at City St George’s
School of Health & Medical Sciences, Department of Medicine
Email: e.groppelli@sgul.ac.uk
Co-Supervisor
Professor Joe Jarvis at LSHTM
Faculty of Infectious & Tropical Diseases, Department of Clinical Research
Email: joseph.jarvis@lshtm.ac.uk
Co-Supervisor
Professor Tom Harrison at City St George’s
School of Health & Medical Sciences, Department of Medicine
Email: tharriso@citystgeorges.ac.uk
PROJECT SUMMARY
Project Summary
The case fatality rate of HIV-associated cryptococcal meningitis remains high (>25%), with co-prevalent viral infections contributing to poor outcomes. This is particularly evident in the case of Cytomegalovirus (CMV) co-infections, but a causal relationship has not been established. This project aims to elucidate the underlying immunological mechanisms of opportunistic CMV infection and the potential role of the virally-encoded IL-10. We hypothesise that viral IL-10 acts as a super-agonist of human IL-10 in amplifying immunosuppressive pathways and further dampens inflammatory responses that drive worse disease outcomes. The project will establish a high throughput assay to quantify viral IL-10 in plasma, serum and CSF samples from ongoing studies, and investigate the correlation with clinical data and disease outcome. The project is particularly well-suited to candidates with a strong interest in co-infections, viral immunology, and global health, who wish to undertake novel investigations at the interface of clinical and mechanistic research.
Project Key Words
viral immunology, co-infections; IL-10, CMV
MRC LID Themes
- Infectious Disease
- Global Health
- Translational and Implementation Research
Skills
MRC Core Skills
- Quantitative skills
- Interdisciplinary skills
- Whole organism physiology
Skills we expect a student to develop/acquire whilst pursuing this project:
The student will gain expertise in immune-assay development, viral immunology, scientific writing and communication (manuscript and grant writing; oral presentations) and develop the ability to interact within a multidisciplinary environment.
Routes
Which route/s are available with this project?
- 1+4 = Yes
- +4 = Yes
Possible Master’s programme options identified by supervisory team for 1+4 applicants:
- City St Georges – MRes Biomedical Science – Infection and Immunity
Full-time/Part-time Study
Is this project available for full-time study? Yes
Is this project available for part-time study? Yes
Location & Travel
Students funded through MRC LID are expected to work on site at their primary institution. At a minimum, all students must meet the institutional research degree regulations and expectations about onsite working and under this scheme they may be expected to work onsite (in-person) more frequently. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training for research degree study and training. Other travel expectations and opportunities highlighted by the supervisory team are noted below.
Day-to-day work (primary location) for the duration of this research degree project will be at: City St George’s – Tooting campus, London
Travel requirements for this project: Funding from professional societies (MicroSoc; British Society for Immunology) will be sought to support visits to trial sites in sub-Saharan Africa, to support a deeper understanding of the research and its real-world challenges and impact
Eligibility/Requirements
Particular prior educational requirements for a student undertaking this project
- Minimum standard institutional eligibility criteria for doctoral study at City St George’s
- Previous research experience or professional equivalent in viral immunology would be an advantage.
Other useful information
- Potential Industrial CASE (iCASE) conversion? = No
PROJECT IN MORE DETAIL
Scientific description of this research project
The case fatality rate of HIV-associated cryptococcal meningitis remains high (>25%), with co-prevalent viral infections contributing to poor outcomes. Yet, the epidemiology of opportunistic viral infections-particularly those affecting the central nervous system (CNS)-is poorly defined. Recently, the supervisory team published a study in Lancet HIV on the prevalence and clinical significance of Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) co-infections in patients with cryptococcal meningitis in five African countries. EBV and CMV co-infections were found to be highly prevalent: approximately half of participants showed CMV viraemia, and 5% CMV CNS co-infection; 73% had EBV viraemia, and 27% EBV CNS co-infection. Crucially, CMV co-infections were associated with a pauci-inflammatory response, higher fungal burdens and increased mortality. High-level CMV viraemia was significantly and independently associated with greater than double the odds of 2-, and 10-week mortality; CMV CNS co-infection was similarly associated with higher mortality. These findings suggest that CMV viraemia represent a modifiable risk factor to improve survival in cryptococcal meningitis. Although these results highlight therapeutic opportunities, elucidating the underlying immunological mechanisms of opportunistic viral infections remains essential. Indeed, whether the relationship between CMV infection and poor outcomes in the context of HIV is causal remains to be established. CMV infection and reactivation are known to be highly immunogenic and to upregulate type 1 interferons. However, type 1 interferons cause downregulation of type 3 interferons that act against intracellular pathogens like Cryptococcus. Additionally, CMV encodes a functional homolog of human interleukin-10 (IL-10) that acts as a super-agonist that amplifies immunosuppressive pathways and further dampens inflammatory responses. We therefore hypothesise that CMV reactivation and CMV IL-10 expression in advanced HIV disease may further compromise the immune response driving worse outcomes.
To elucidate the interplay between viral and fungal infections and immunomodulation, this project aims to:
- Establish a high-throughput immunological assay to specifically quantify CMV-encoded IL-10 in plasma, serum and CSF samples and quantify human- and CMV- IL10 in samples from previous, ongoing and future studies and investigate their correlation with clinical data. Extensive expertise within the supervisory team and reagents available commercially and from repositories will guide the establishment of an ELISA (sandwich) to detect CMV-IL10 with high specificity.
- Investigate the CMV-mediated impairment of the type 1 helper T cell response using a combination of laboratory approaches (immunoassays, including ELISA and flow cytometry; virus and cell culture; isolation of Peripheral Blood Mononuclear Cells, activation and differentiation of T cells), type 1 T helper)
This project builds on a high-impact publication and is supported by an experienced supervisory team, with the aim of advancing our understanding of a complex disease and informing both clinical practice and therapeutic development. Although expertise, reagents and samples are available through the supervisory team, an extensive global network of collaborators and studies provide both risk mitigation and further opportunities.
The project is particularly well-suited to candidates with a strong interest in co-infections, viral immunology, and global health, who wish to undertake novel investigations at the interface of clinical and mechanistic research.
Further reading
Relevant preprints and/or open access articles:
(DOI = Digital Object Identifier)
Other pre-application materials: None
Additional information from the supervisory team
The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.
Groppelli & Jarvis & Harrison Recording
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