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Constructing a ‘Eubiosis Reinstatement Therapy’ for Asthma

Periodic Reporting for period 2 - CURE (Constructing a ‘Eubiosis Reinstatement Therapy’ for Asthma)

Reporting period: 2018-10-01 to 2020-03-31

The asthma pandemic imposes a huge burden on patients and health systems in both developed and developing countries. Notwithstanding major efforts in untangling its pathophysiology, we are not even close to reaching a cure. Despite available treatments, symptom control is generally suboptimal and hospitalisations and deaths remain at unacceptably high levels. This calls for disruptive innovation towards a long-term treatment strategy.
Asthma is an inflammatory condition associated with immune deviations, most often atopic allergy. However, a key characteristic of asthma that remains relatively unexplored is susceptibility to infection. Most acute asthma attacks follow upper respiratory infections; infections are also associated with asthma initiation and persistence.
Recent studies reveal that the respiratory microbiome is characteristically imbalanced in asthma (dysbiosis). Our own data indicate that a feature of dysbiosis in asthma is reduced abundance of bacteriophages (phages). These bacterial viruses infect and are able to naturally control bacterial populations. Phage therapy has been grossly neglected in the western world and is currently just appearing as a novel tool against infection. However, it has never been used for rebalancing dysbiosis in humans.
We propose that reinstating a balanced microbiome (eubiosis) within the asthmatic airway through phage therapy is feasible and will be able to control the immune dysregulation and clinical presentation of the disease. To achieve this, we must be able to predict the effects of adding phage mixtures to the complex ecology of the airways and design appropriate interventions. In CURE, we will develop a predictive model using information from virus-bacteria interactions, host responses and clinical disease expression, validated and fine-tuned using an in-vitro host-microbe-phage interface system. The project will develop phage preparations as candidates for clinical testing in asthma. The challenge and scope of the project has become even more pertinent with the advent of the COVID-19 pandemic, the effects of which on asthma patients are currently under scrutiny.
During the first year of the project, cohorts of patients with asthma and controls have been established to obtain samples for longitudinal dynamics assessment; in addition, the temporal and geographical variation of the respiratory metagenome has been assessed in samples from a previous cohort. This data, together with data that is been produced from the CURE cohorts have been provided in order to start the modeling. Furthermore, initial evaluation and characterization of the immune responses to phages, as well as interactions between phages and the respiratory mucosa have been performed. Significant effort has been put towards isolating phages for bacteria that appear to be relevant in asthma dysbiosis, without however being able to identify new strains.

During the second period of the project (months 13-30), the follow-up of patient cohort has been completed providing clinical data as well as samples for varying time-periods ranging from hours up to one year. Longitudinal variations of the respiratory microbiome have been assessed in different dataset and with various approaches; the main findings suggest that microbial communities of the respiratory track characterize each individual, similarly to what is known about the gut. Furthermore, the disease state appears to be more variable than the healthy communities. Several new phages have been isolated and phage-bacteria networks characterized. It appears that phages do not affect structural integrity of the mucosa, however, they influence and activate innate lymphoid cells with a potential for immunoregulation. Theoretical challenges in modeling have been addressed and continue to be explored.
The achievement of the CURE Objectives will have major impact upon science and technology, both directly and through enabling new research and innovation potential on a number of domains, including respiratory metagenomics, prediction software and phage technologies. Importantly, CURE will transform phage therapeutic technology and spearhead a new industry: while phage therapy is currently re-emerging in the Western world and tries to find its place in the medical and regulatory environments, CURE will kick-start a new European research and innovation domain around it.

CURE has coined the concept of Eubiosis Reinstatement (ER), as an innovative proposal for intervening in disease states that include dysbiosis, such as asthma. Thirty months from the beginning of the project, the concept remains novel and challenging. The key expansion that will eventually determine the feasibility and potential of the project, revolves around time. Microbiomes are highly variable, but the principles underlying their longitudinal dynamics are not well understood, particularly for the upper respiratory track which is our focus. Causality is difficult to be proven outside interventional trials and modelling depends very much on the abundance of available data. Such data continue to be generated and scrutinised, in parallel to developing a deep understanding of host responses and phage-bacteria interactions, all of which contribute towards constructing the project’s impact.

The project remains at the forefront of its emerging field and continues to generate considerable interest in a multitude of scientific meetings and other interaction opportunities. The project has been recognised in local media and has been represented and generated interest within the EU Innovation Forum. Occasional, but regular requests from patients for possible bedside implications need to be rationalised, taking into account that the work focuses on a proof of concept, notwithstanding the potential for rapid development.
Interactions with external partners continues, particularly around virus discovery.
Knowledge domains contributing to CURE and their interactions