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Pathogen colonisation and microbiota interactions in the ageing airway

Principal Supervisor: Dr David William Cleary

Secondary Supervisor(s): Dr Kylie Belchamber (University of Birmingham), Prof. Stuart C. Clarke (University of Southampton)

University of Registration: University of Birmingham

BBSRC Research Themes:

  • Understanding the Rules of Life (Microbiology)
  • Integrated Understanding of Health (Ageing)

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Deadline: 4 January, 2024


Project Outline

Bacterial colonisation of the upper respiratory tract (URT) is pre-requisite of multiple respiratory tract diseases including pneumonia, otitis media, sinusitis, exacerbations of chronic obstructive pulmonary disease (COPD), and, less commonly, diseases resulting from bacteraemia such as meningitis. Preventing bacterial colonisation would significantly reduce global morbidity and mortality due to these infections. An estimated 4 million deaths are attributed to these infections annually (1) and escalating levels of antimicrobial resistance (AMR) will increase this burden. Even in the UK, recent analysis has shown that the burden of non-SARS-CoV2 infections in adults remains a significant problem (2).

In addition, there are significant gaps in knowledge regarding pathogen colonisation and intra-microbiota interactions which impact disease outcomes in the ageing airway. Not only is there growing consensus that a reliance on pathogen isolation has led to an underestimation of adult carriage of important respiratory pathogens e.g., Streptococcus pneumoniae (3), but there is also no data regarding the prevalence and/or function in older adult populations of commensal species such as Corynebacterium (4) and Dolosigranulum (5) that are considered beneficial to human health and in some cases have been shown to impact pathogen colonisation (6).

Understanding these interactions between pathogens and commensals in the ageing airway not only underpins our understanding of disease risk, but will reveal novel interventions, such as microbiome modification using said commensals, that reduce the requirement for antimicrobial use in already susceptible populations.

In this innovative project we propose the following aims:

1. Determine the carriage prevalence of respiratory pathogens in adult populations using molecular approaches, with a focus on differences between healthy and those with co-morbidities and underlying respiratory health conditions e.g., COPD and asthma.

2. Using a combination of culture, genomic and culture-enriched metagenomics approaches, the student will generate an inventory of important pathogen-commensal interactions. This will focus initially on commensals with known co-exclusion interactions such as Corynebacterium sp. or Dolosigranulum sp.

3. Examine interactions using in vitro models. Using strains identified in Aims 1 and 2, interactions will be examined using solid and liquid media growth inhibition assays and mixed species biofilm models. Host interactions will be examined using air-liquid-interface (ALI) epithelial models.

The student will be exposed a broad range of areas including infectious disease epidemiology, analysis of bacterial genomes, metagenomics and microbiome analysis, cell-culture, and host-bacterial responses.

References

  1. T. Ferkol, D. Schraufnagel, The Global Burden of Respiratory Disease. Annals of the American Thoracic Society 11, 404-406 (2014)
  2. Hyams C et al. Incidence of community acquired lower respiratory tract disease in Bristol, UK during the COVID-19 pandemic: a prospective cohort study. The Lancet Regional Health Europe 21:100473 (2022) DOI: https://doi.org/10.1016/j.lanepe.2022.100473
  3. Miellet WR et al. Streptococcus pneumoniae carriage studies in adults: Importance, challenges, and key issues to consider when using quantitative PCR-based approaches. Front. Microbiol. 14:1122276. doi:10.3389/fmicb.2023.1122276 (2023)
  4. Tran et al. Metabolic capabilities are highly conserved among human nasal-associated Corynebacterium species in pangenomic analyses bioRxiv doi: https://doi.org/10.1101/2023.06.05.543719
  5. Ramos SF et al. Genomic Stability and Genetic Defense Systems in Dolosigranulum pigrum, a Candidate Beneficial Bacterium from the Human Microbiome mSystems Vol. 6, No. 5 DOI:https://doi.org/10.1128/msystems.00425-21
  6. Brugger SD et al. (2016) Commensal–Pathogen Interactions along the Human Nasal Passages. PLoS Pathog 12(7): e1005633. https://doi.org/10.1371/journal.ppat.1005633

Techniques

Bacterial culture; DNA extraction; bioinformatics; bacterial genomics; metagenomics; 16S and microbiome analysis; co-culture and bacterial competition assays; cell culture; host-responses (immunology, transcriptomics)