Investigating the basis of neutropenia in Barth syndrome

Borko Amulic, PhD, University of Bristol 

Neutropenia, an abnormally low concentration of neutrophils in the blood, is detected in over 80% of BTHS patients, with 44% satisfying criteria of severe chronic neutropenia. Neutrophils constitute the first line of defence against microbes; they kill pathogens by phagocytosis and release of antimicrobial proteins stored in granules. Consequently, BTHS patients are at elevated risk of life-threatening bacterial infections. 

Despite the prominence of neutropenia in BTHS, we have very little understanding of the molecular and physiological causes of this phenomenon. In patients, neutrophil counts often fluctuate unpredictably, suggesting that extrinsic triggers such as inflammation or metabolic stress may precipitate neutropenia. Furthermore, our recent BSF-sponsored work demonstrated that BTHS patient neutrophils display a hyperdegranulation phenotype, which may affect circulating cell behavior and impact distribution of neutrophils in tissues. 

We will take advantage of proximity to the National Health Service (NHS) Barth Syndrome Service at Bristol Royal Hospital for Children to investigate primary neutrophils and their progenitors from BTHS patients. We will take a dual approach to investigate neutrophil dysregulation in BTHS. First, we will utilize a newly established system to investigate development and differentiation of BTHS neutrophils from circulating progenitor stem cells under conditions of inflammatory and metabolic stress. Secondly, we will build on previously obtained data to examine how hyperdegranulation affects the interaction of BTHS neutrophils with the endothelium both ex vivo and in a mouse model of Barth Syndrome.  

We expect this proposal to result in improved understanding of neutropenia in BTHS and pave the way for therapeutic interventions to correct it.