David L Robertson is a research professor and Head of CVR Bioinformatics at the MRC-University of Glasgow Centre for Virus Research (CVR) and supervises with Nikos Papadopoulos, Mark Muldoon and Tucker Gilman a multidisciplinary team of researchers at the University of Manchester. He also leads a research group within the CVR composed of bioinformaticians, computational biologists and computer scientists focussed on virus research, particularly, on virus-host interactions and change in viral genomes. Prof. Robertson’s interests in research are centred on viral evolution and systems virology with focus on virus-host specificity, change in the virome and the trade-offs between molecular evolution and disease susceptibility.​

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The University of Manchester will conduct the largest and most complete metagenomics analysis of the respiratory track undertaken to date. What does it mean for the clinical and research community to have such knowledge?

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One of the most interesting components of the project is the longitudinal nature of the samples. In the CURE project, we are studying through days, weeks and months the change in the microbiome among asthma patients and healthy individuals (controls). This will result in a large dataset on the ecology and dynamics change of the microbiome in the respiratory system.

 

The premise of the CURE project is that the composition of the microbiome can contribute to an individual’s health and disease status. Based on our data, the respiratory metagenome of healthy individuals seems to be more stable than from asthma patients. Therefore, when looking at a disease state, characterising the dynamics and the composition of the respiratory microbiome, its interaction with the immune system as well as the related problems is key to understanding the relationship between asthma and the microbiome. A central hypothesis of the project is if it will be possible to influence the microbiome so as to control inflammation in the respiratory tract in asthma. Unlike antibiotics, bacteriophage therapy can be used to target individual bacteria with high specificity.

 

For now, the first set of analysis on the geographical and temporal variability of the respiratory metagenome in healthy and asthmatic individuals is completed. What do the results show?

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One of the most interesting findings is the change in bacteriophages present in asthmatic patients. Based on the results from PREDICTA, an EU-funded research project, the presence of bacteriophages appears to be reduced in the airways of asthma patients. Bacteriophages are important regulators of the microbiome, thus, their absence suggests that some bacteria in the system are not present or are present but their numbers unregulated.

 

Our data shows a clear variability of the respiratory metagenome between asthmatic and healthy individuals. Definitely, there is an association between the changes in the microbiome and the disease state of asthma. For example, adenoviruses seem to be more prevalent in asthma patients. While some literature suggests that there might be some causation, this could just as equally be correlate of disease state. It’s important to discriminate when we see change in the microbiome associated with disease, what are causative factors from what are correlated factors, for example, treatments or the action of immune response.

 

The changes in the respiratory microbiome of asthma patients are unpredictable, for example, a person’s age can influence the composition of the system. These factors make it difficult to predict the impact of bacteriophage-based interventions in the respiratory metagenome and, even harder, to define a generic prediction that fit all patients.

 

We are currently studying the longitudinal patterns to identify the composition and dynamics of the system. Working with ecologists and mathematicians at the University of Manchester we can make predictions, but for now we need more data and that is something that is ongoing in the project.

 

 

Do you think that metagenomics patterns may end in predicting the risk of acute asthma exacerbations?

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The microbiome has been shown to influence the progression of asthma and viruses can be key triggers. By identifying the typical characteristics of the species interactions using ecological measures in the asthmatic respiratory tract, we should hopefully be able to predict the microbiome that correlates with the disease state of asthma. Asthma exacerbations are often associated with rhinoviruses, the viruses causing common colds and microbiome composition can be used to predict health status, so yes, an individual being prone to asthma exacerbation, should be predictable.

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At what stage is your research as the UK partner in this project linked to CURE? What are the next steps and objectives?

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We are in the process of finalising the sequencing of the data from asthma patients and healthy individuals involved in the CURE clinical cohort. Half of the samples are already sequenced. We are characterising and classifying the data in order to build a picture of the microbial ecology in the respiratory system. This involves looking at the composition of the data, the species present and inferring interactions between them. The technical challenges of this kind of data shouldn’t be underestimated. In the respiratory system you have particular problems such as the sampling strategy and the presence of eukaryote viruses which when abundant can interfere with detection thresholds. With the existing data and the application of machine learning tools we will be able to define mathematical models to be able to predict future datasets.

                                                                                                                             

What are your expectations about CURE? And what are your main concerns?

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We are studying the nature of the species in the respiratory microbiome in healthy individuals and how it can contribute to a disease state. The real challenge in future work is to use this kind of information with a therapeutic purpose. It seems clear that the microbiome is essential to understand asthma as a disease. A key question is whether it is possible to recreate the healthy microbiome in the respiratory system. This has been done with some diseases of the gut, specifically, faecal transplants have been used to transfer the microbiome from a healthy to a diseased individual with positive outcomes. Whether the respiratory microbiome can be ‘fixed’ in this way is an open question and one we feel worth exploring. Our longitudinal study will be an interesting contribution to this area of research.