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A role for the immunomodulatory capsular polysaccharide Sp1 expressed by Streptococcus pneumoniae in the treatment of Asthma

Final Report Summary - SP1 AND ASTHMA (A role for the immunomodulatory capsular polysaccharide Sp1 expressed by Streptococcus pneumoniae in the treatment of Asthma)

The overall aim of this project was to facilitate the establishment of the applicant’s independent research career and development of their international reputation in the field of host-pathogen interaction. Support from this Marie Curie IRG has been instrumental in the establishment of the Host Pathogen Interactions group at the school of Biochemistry and Immunology at TCD (http://www.biochemistry.tcd.ie/research/r_mcloughlin.php) and has enabled the development of an innovative research program that focuses on understanding the interaction of bacteria such as Streptococcus pneumoniae and Staphylococcus aureus with the host’s immune system. Bacteria such as S.pneumoniae and S.aureus are unique in the fact that in contrast to their invasive infectious potential these organisms are also common commensal colonisers of human upper (S.aureus) and lower (S.pneumoniae) respiratory tracts. Despite significant advances in our understanding of immunity to invasive disease caused by these bacteria, there is a fundamental lack of knowledge on how these organisms interact with the host’s immune system during commensal colonisation. We hypothesize that the unique relationship cultivated by these organisms with the host’s immune system to enable colonisation, is likely to have downstream effects on the hosts ability to response to subsequent infection, vaccination and potentially allergic disease.

During the course of this Marie Curie IRG we have made significant advances towards addressing this hypothesis. Specifically we have:

1) Demonstrated that exposure to S.aureus expands a population of γδT-cells that are capable of generating protective memory against subsequent invasive infection (Maher et al., Infect & Immunity 2013, Murphy et al., J Immunol 2014).
2) Identified S.pneumoniae secreted toxin pneumolysin as a novel inflammasome activator that promotes expansion of Th17 T-helper cells, identifying this molecule as a potential vaccine candidate (Mc Neela et al., PlosPathogen 2010).
3) Identified the squameous cell envelop protein loricrin as the ligand targeted by the S.aureus surface protein clumping factor B to facilitate nasal colonisation by this organism (Mulcahy et al., PlosPathogen 2012).
4) Demonstrated that exposure to S.pneumoniae capsular polysaccharide Sp1 specifically induces immunomodulatory effects that contribute to protection against allergic airway inflammation (Asthma) (see Supp Fig).

To execute these studies a significant effort was required to establish robust and reproducible in vivo models. This Marie Curie IRG was instrumental in generating a number of the models currently established in our lab by contributing to the salary of 2 individual research assistants who were highly skilled in in vivo model development. These research assistants contributed to a number of distinct projects in the lab in addition to working on the specific scientific aims outlined in this work program.

The scientific objective of this project was to establish if a capsular polysaccharide isolated from S.pneumoniae could induce immunomodulatory cytokine production locally in the lungs thus protecting against allergic airway inflammation (AAI). Our studies demonstrate that treatment of mice with Sp1 conferred protection against AAI (Supp Fig 1). Sp1 promoted the expansion of antigen specific IL-10 producing and IFN-γ producing T-cells (Supp Fig 2) suggesting that the ability of Sp1 to skew the immune response away from a type 2 response (pro allergy) and towards a type 1 and/or regulatory response (anti allergy), underlies the protective effects of this molecule in AAI. To categorically establish this, we induced AAI in mice deficient in either IFN-γ or IL-10 and then treated with Sp1 to see if the protective effects of Sp1 were lost. Unfortunately these experiments were inconclusive, likely due to the fact that these cytokines maybe compensating for one another’s effects. As an alternative approach, we are currently developing adoptive transfer studies. T-cells will be expanded in vitro, treated with Sp1, phenotyped, and then transferred to mice prior to AAI challenge. In addition we have embarked on a collaboration with Prof Aras Kadioglu (University of Liverpool). Prof Kadioglu is a world expert in S.pneumoniae pathogenesis. He is currently testing the ability of Sp1 to drive expansion of regulatory T-cells in his S.pneumoniae colonisation model.

Supported by this Marie Curie IRG the candidate has established a wholly independent research group at the Trinity Biomedical Sciences Institute. The group currently comprises 3 PhD students and 3 post-doctoral researchers (first PhD student graduated in July 2014). The group has developed multiple successful collaborations within the department (Dr Ed Lavelle, Adjuvant Research Group), with other schools within the discipline (Prof. Tim Foster, Microbiology) and internationally (Prof Aras Kadioglu, University of Liverpool). This is exemplified by a number of collaborative publications, one directly relating to the research being carried out under the Marie Curie IRG (McNeela et al.). During the course of this IRG the applicant has secured a number of prestigious research awards (Health Research Award 2012, Science Foundation Ireland Investigator Project 2013, Irish Research Council Government of Ireland Postdoctoral Fellowship 2014). Their success in continuing to obtain research funding provides a secure future for their research group and reflects the continued success of their career development in Ireland.

In September 2011 the applicant was awarded a faculty position within the School of Biochemistry and Immunology. A critical parameter assessed at interview was their ability to raise independent research funding. Thus the Marie Curie IRG was a key factor in their success in obtaining a faculty position.

Overall this research program contributes significantly to our understanding of how molecules expressed by commensal bacteria can be targeted as novel immunomodulatory therapies for the treatment of both infectious and allergic disease and as novel vaccine candidates. The study supports a novel approach for the treatment of asthma, facilitating development of new therapeutic strategies for the treatment of this debilitating disease, which represents a major social and economical burden to the EU. High-risk innovative research like this has the potential to make a major impact on world health will enhance the community’s scientific competitiveness on the biomedical research global stage.

The strategic development of both Ireland and the EU’s scientific communities relies on the recruitment of quality researchers but more importantly retaining these researchers within the EU. This Marie Curie IRG has facilitated the recruitment to and retainment at, Trinity College Dublin, of an individual who has trained in high profile research institutes in the US and UK. This individual is currently responsible for the supervision of postdoctoral researchers, postgraduate students and undergraduate students who are benefitting directly from the new ideas, skills and approaches to tackling research questions that they have introduced. They can equip these researchers with the skills to carry out high profile translational immunology research in the area of host-pathogen interactions, facilitating their own research career development within Ireland and on a global stage.