Deciphering interactions between bacterial species in chronic and persisting infections





1. Please give a summary of your research.

Chronic infections of the middle ear (chronic otitis media), are common in children and are typically unresponsive to conventional therapies such as antibiotic treatment.

Chronic forms of respiratory diseases including chronic otitis media (COM) have been attributed to the formation of a bacterial biofilm, often as a polymicrobial infection involving several bacterial species. Commonly, the pathogens identified in these chronic diseases are the bacterial species Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. There is very little known about the molecular interactions between these species that enable cohabitation and their transit to the middle ear, their persistence in this multispecies environment or the nature of their multispecies biofilm. Knowledge of these molecular factors is essential to identifying potential pathogenic strains and subsequently targets for the development of novel therapies.

Previously, my research investigated the interactions of the two important otopathogens H. influenzae and S. pneumoniae utilising a novel continuous growth flow cell system, and made unique findings in their growth pathways and molecular interactions.

Currently, I am investigating the molecular interactions in the more complex microbial environment of three otopathogens, as is common in COM, using the continuous growth flow cell system. In addition, I am analysing the bacterial species present and prevalent in clinical COM samples and in samples from colonised healthy children.

This project is working to analyse the global, whole-cell molecular and transcriptional profiles of H. influenzae, S. pneumoniae and M. catarrhalis are different when in a mixed-species situation during a chronic state, compared to a mono-species environment. I hypothesise, that these molecular profiles define factors involved in chronic infections. 

2. Please include any additional details you would like to share

During my study of H. influenzae and S. pneumoniae inter-species interactions, I have made some important discoveries on the nature of their co-existence. Firstly, I have identified the ability of S. pneumoniae to induce a novel viable but non-culturable state in H. influenzae in standard batch culture growth. This state of existence enabled H. influenzae to survive in the non-optimal conditions presented by S. pneumoniae. In contrast, in a continuous growth flow cell system, both species were able to co-exist without competition.

Importantly, I have identified that each species alters its transcriptional response in the co-culture setting compared to the single-species state, in nutrient rich media. The transcriptional response depended on the growth system used, and also on the time-point of growth. Importantly, in S. pneumoniae a significant up-regulation of genes involved in carbohydrate uptake and utilisation was observed in co-culture. This suggested for a potential metabolic dependency between the two species.

To further study this metabolic link between H. influenzae and S. pneumoniae, both species were grown in a flow cell system with a chemically defined medium with glucose. In this system in co-culture, S. pneumoniae emerged as a novel small colony variant. This small colony variant had distinct transcriptional and genomic changes compared to the wild-type, including mutations in capsule biosynthesis, proline biosynthesis and DNA repair systems, suggesting the evolution of a cell type more adapted to persistence in a polymicrobial setting.

The current project expands on the data of H. influenzae and S. pneumoniae interactions to study a triple-species bacterial environment, and with the use of transcriptomics and continuous growth assays, as well as ex-vivo sampling from chronic otitis media patients, new data will uncover the nature of the interactions between H. influenzae, S. pneumoniae and M. catarrhalis, and the molecular pathways governing these interactions.



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