Deciphering the cellular and molecular rationale for the success of combined beta-lactam and macrolide therapy in community acquired pneumonia

Qualification: PhD

Department: Genetics

Application deadline: 15 March 2021

Start date: September 2021

Overview

Supervisors:

Project description:

Community acquired pneumonia has for the last 15 years been the leading cause of in-hospital mortality from communicable disease and Streptococcus pneumoniae is the most frequent etiological agent of pneumonia. There is a general consensus in treatment guidelines worldwide that first line beta-lactam treatment of community acquired pneumonia benefits from association with macrolides which have been shown to reduce mortality. However, the precise mechanism for this beneficial synergy is not known. Recently, we have shown in experimental infection, that intravenously induced sepsis is preceded by a concomitant, intracellular replication of pneumococci within a subset of splenic macrophages and that macrolides efficiently sterilise these intracellular foci of infection (Ercoli et al. Nature Microbiology 2018). In light of these findings, we aimed to test the hypothesis that pneumococcal bacteraemia (invasive pneumococcal disease, IPD) does not derive form a passive shedding of bacteria from the lung, but derives from intracellular replication in splenic macrophages and subsequent shedding from the spleen.

The aim is to understand the underlying molecular mechanisms responsible for better treatment outcome for high severity pneumonia. This would eventually have to be tested in a prospective trial for adoption into guidelines and acceptance as treatment standard.

The objectives will be to define the (i) cellular and (ii) molecular parameters both in (iii) bacteria and (iv) in the host cells which associate with progression of community acquired pneumonia to invasive disease using the model organism Streptococcus pneumoniae. 

The work will address bacterial replication within the host, using experimental infections and cell culture models (Ercoli et al., Nature Microbiology 2018; Chung et al., Alternatives to Animal Experimentation 2018). The student will have an important and unique opportunity at Leicester, to test the project hypotheses in a trial (ClinicalTrials gov Identifier NCT04620824), utilising ex vivo perfusion of human spleens to study the early phases of infection. This cutting-edge work on whole organs will be integrated with work on tissue cultures and primary cell cultures to investigate the stepwise progression of host cell infection by bacteria and quantify the beneficial impact of drugs with high and low penetration into host cells. The analyses will include confocal fluorescent microscopy, flow cytometry, and molecular methodologies including gene expression profiling. These approaches will require interdisciplinary training spanning from cell biology, microbiology, to next generation sequence analysis. In addition to laboratory work the student will have access to clinical community acquired pneumonia data under supervision of Dr. Woltmann, the Head of Service Respiratory Medicine, at University Hospitals of Leicester. This will allow interrogation of the extensive pneumonia database with the aim to correlate clinical data to the mechanistic experimental findings. 

This project is based on recent high impact scientific insight by the proposing academics into the pathophysiology of invasive disease and, importantly, represents a continuation of a collaboration between academia and hospital-based pneumonia clinicians. The student will be integrated in a vibrant research group and we anticipate that the work will provide the student with a set of significant publications and a strong interdisciplinary training which could lead to further academic work and employability. Being part of a multidisciplinary academic and clinical group will allow the student to get strong biomedical laboratory training, but also insight into clinical practice as a prerequisite for translation of laboratory findings into improved treatment of respiratory infections. These domains are central to the LeMID focus on respiratory infections of and the BRC theme proposal. 

References:

  • Chung, W., Wanford, J., Kumar, R., Isherwood, J., Haigh, R., Oggioni, M., Dennison, A. and Ercoli, G. 2019. An ex vivo porcine spleen perfusion as a model of bacterial sepsis. ALTEX. 2019;36(1):29-38.
  • Ercoli G, VE Fernandes, WY Chung, JJ Wanford, S Thomson, CD Bayliss, K Straatman, PR Crocker, A Dennison, L Martinez-Pomares, PW Andrew, ER Moxon, MR Oggioni. 2018. Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia. Nature Microbiology, 3(5):600-610.
  • Mitsi E, B Carniel, J Reiné, J Rylance, S Zaidi, A Soares-Schanoski, V Connor, AM Collins, A Schlitzer, E Nikolaou, C Solórzano, S Pojar, H Hill, AD Hyder-Wright, KC Jambo, MR Oggioni, M De Ste Croix,  SB Gordon, SP Jochems, DM Ferreira. Nasal pneumococcal density is associated with microaspiration and heightened human alveolar macrophage responsiveness to bacterial pathogens. Am J Respir Crit Care Med. 2020 Feb 1;201(3):335-347.
  • Olaru ID, Van Den Broucke S, Rosser AJ, Salzer HJF, Woltmann G, Bottieau E, Lange C. Pulmonary Diseases in Refugees and Migrants in Europe. Respiration. 2018;95(4):273-286.
  • Pareek M, Bangash MN, Pareek N, Pan D, Sze S, Minhas JS, Hanif W, Khunti K. Ethnicity and COVID-19: an urgent public health research priority. Lancet. 2020 May 2;395(10234):1421-1422.
  • Rosser A, Richardson M, Wiselka MJ, Free RC, Woltmann G, Mukamolova GV, Pareek M. A nested case-control study of predictors for tuberculosis recurrence in a large UK Centre. BMC Infect Dis. 2018 Feb 27;18(1):94.

Funding

Funding

This 3-year PhD studentship provides:

  • UK/EU tuition fee waiver
  • Annual stipend at UKRI rates (£15,609 for 2021/22)
  • Research Training Support Grant of £5,000 per annum

Entry requirements

Entry requirements

Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better, or overseas equivalent in a relevant subject.  

The University of Leicester English language requirements apply where applicable.

Informal enquiries

Informal enquiries

Project enquiries:

Application enquiries:

How to apply

How to apply

To submit your application, please use the 'Apply' button at the bottom of the page and select September 2021 from the dropdown menu.

With your application, please include:

  • CV
  • Personal statement explaining your interest in the project, your experience and why we should consider you
  • Degree Certificates and Transcripts of study already completed and if possible transcript to date of study currently being undertaken
  • Evidence of English language proficiency if applicable
  • In the reference section please enter the contact details of your two academic referees in the boxes provided or upload letters of reference if already available
  • In the funding section please specify that you wish to be considered for a LeMID 2021 studentship
  • In the research proposal section please provide the names of the project supervisors and project title (a research proposal is not required)
     

Eligibility

Eligibility

UK/EU candidates only