2025-26 Project (Reljic & Wasserman & Jarvis & Lai)

Characterising infection immunity and pharmacokinetics in HIV-associated pneumocystis pneumonia

SUPERVISORY TEAM

Supervisor

Professor Rajko Reljic at City St George’s
Email: rreljic@sgul.ac.uk

Co-Supervisor

Dr Sean Wasserman at City St George’s
Email: swasserm@sgul.ac.uk

Co-Supervisor

Professor Joe Jarvis at LSHTM
Email: joseph.jarvis@lshtm.ac.uk

Co-Supervisor

Dr Rachel Lai at Imperial College London
Email: rachel.lai@imperial.ac.uk

PROJECT SUMMARY

Project Summary

P. jirovecii is an opportunistic pathogen causing pneumocystis pneumonia (PCP) in immunocompromised individuals, a severe illness frequently leading to life-threatening respiratory failure. PCP contributes substantial burden of disease in high HIV-prevalence settings, but there are important knowledge gaps on disease mechanisms and treatment in this population.  

A cohort study conducted among patients with HIV-associated PCP in South Africa will generate clinical material for translational laboratory studies of host immune responses that drive immunopathogenesis and disease severity. In addition, drug concentration data will be available to investigate sources of pharmacokinetic (PK) variability and explore relationship with treatment response. 

For this project, the successful candidate will perform multi-omics (transcriptomic, proteomic and metabolomic) analyses to comprehensively investigate molecular mechanisms that underlie PCP pathologies and use PK data to inform treatment optimisation.

Project Key Words

Pneumocystis pneumonia, HIV, multi-omics, immunopathogenesis, pathway

MRC LID Themes

  1. Infectious Disease
  2. Global Health
  3. Translational and Implementation Research

Skills

MRC Core Skills

  1. Quantitative skills
  2. Interdisciplinary skills
  3. Whole organism physiology

Skills we expect a student to develop/acquire whilst pursuing this project

The successful student will acquire skills in RNA-sequencing and liquid chromatography mass spectrometry (LC-MS), analysis and interpretation of multi-omics and PK data, manuscript and grant writing, and ability to interact within a multidisciplinary scientific 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 George’s – MRes Biomedical Science – Infection and Immunity
  • City St George’s – MSc Genomic Medicine
  • City St George’s – MRes/MSc Translational Medicine
  • LSHTM – MSc Immunology of Infectious Diseases
  • LSHTM – MSc Medical Statistics

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? No

Location & Travel

Students funded through MRC LID are expected to work on site at their primary institution, meeting – at the minimum – the institutional research degree regulations and expectations. 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). Other travel expectations and opportunities highlighted by the supervisory team are noted below.

Primary location for duration of this research degree: City St George’s, London

Travel requirements for this project: Conference and training visits

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

  • Minimum City St George’s institutional eligibility criteria for doctoral study.
  • The successful student should have analytical skills and research experience, either from BSc or MSc research project, or work experience, in at least one of the following areas:  Infection immunity, biochemistry or analytical chemistry, or bioinformatics

Other useful information

  • Potential Industrial CASE (iCASE) conversion? = No
  • Following upgrading, the project supervisory team will change (pending approval from City St George’s RD Committee). It is envisaged that Dr Wasserman will become Primary Supervisor, with Professor Jarvis and Dr Lai as Co-Supervisors.

PROJECT IN MORE DETAIL

Scientific description of this research project

Rationale and objectives   
P. jirovecii is an opportunistic pathogen causing pneumocystis pneumonia (PCP) in immunocompromised individuals, a severe illness frequently leading to life-threatening respiratory failure. PCP contributes substantial burden of disease in high HIV-prevalence settings, with important challenges and knowledge gaps in diagnosis and treatment.    

Disease severity is thought to be driven by host inflammatory response, evidenced by correlation with crude markers of lung inflammation (neutrophils and lactate dehydrogenase) and clinical response to glucocorticoids. However, knowledge of PCP pathophysiology is derived almost exclusively from murine P. carinii infection models, and there are limited data on disease mechanisms in patients with HIV-associated PCP. Cellular pathways for fungal clearance are not completely understood but there appears to be complex interplay between fungal burden and host immune responses that drive immunopathogenesis and disease severity.    

Additionally, the optimal dose and duration of first-line PCP treatment, trimethoprim-sulfamethoxazole (TMP-SMX), is not established. Sources of variability in TMP-SMX pharmacokinetics (PK), which could influence treatment response, have not been described in patients with HIV-associated PCP but are needed to inform dose optimisation.    

Research priorities in PCP include
(1) identification of potentially modifiable outcome predictors for risk stratification and to design interventions for improved care;
(2) identification of biomarkers of treatment response, which do not currently exist for PCP, for future trial design and treatment optimisation;
(3) understanding host immune pathways to identify targets for development of novel therapeutic strategies; and
(4) dose optimisation of TMP-SMX to reduce toxicity and improve outcomes.   

We are undertaking an NIHR-funded cohort study (part of the IMPRINT NIHR Global Health Group, including LSHTM and SGUL; https://witsmycology.co.za/projects/IMPRINT/index.html) among inpatients with suspected HIV-associated PCP in Cape Town, South Africa, to characterise clinical phenotype and medium-term functional outcomes. Participants will undergo bronchoscopy, longitudinal blood sampling, including rich PK sampling, and detailed clinical metadata collection during hospital admission. Clinical data and materials generated from this study will enable PK and laboratory-based translational studies.     

For this Studentship, the successful candidate will undergo training to perform conventional immunoassays, microscopy and multi-omics (transcriptomic, proteomic and metabolomic) analyses to comprehensively investigate molecular mechanisms that underlie PCP pathologies and identify potential diagnostic and treatment targets. The student will also perform non-compartmental analysis of drug concentration data to describe the PK of TMP-SMX in patients with HIV-associated PCP.   

Specific scientific objectives include: 
1. Identify biomarker(s) that can differentiate confirmed PCP infection in suspected cases using human clinical specimens 
2. Investigate mechanisms underlying disease pathogenesis at the site of infection using specimens from animal models  
3. Characterise the plasma and bronchoalveolar fluid PK of TMP-SMX    

Techniques to be used and lab environment 
During the MPhil year, the student will undertake training courses in RNA sequencing, metabolomics, and analytical methods. They will also perform initial laboratory-based work in the Lai Lab (Imperial College London) which has an established laboratory and bioinformatic pipeline for multi-omics analyses. The student will learn to extract RNA, prepare sequencing libraries and start to analyse RNA-Sequencing data from patient BALf samples. In parallel, the student will also learn to extract metabolites, perform LC-MS to generate metabolomic data from the same BALf samples. These preliminary analyses will form the basis if the MPhil dissertation.    

After transferring to the PhD the student will learn bioinformatic pipelines

Further reading

Relevant preprints and/or open access articles:
(DOI = Digital Object Identifier)

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.

Reljic-Wasserman-Jarvis-Lai recording

MRC LID LINKS

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