Dr Borko Amulic

Regulation of neutrophil development and function

Neutrophils are essential immune cells with important roles in defence against pathogens. They rapidly migrate to sites of infection and kill microbes by phagocytosis, ROS production, degranulation and release of neutrophil extracellular traps (NETs). Absence of neutrophils results in severe immunodeficiency. On the other hand, excessive or dysregulated neutrophil responses are destructive and promote inflammatory pathology in malaria, autoimmunity and cancer. Mechanisms that fine-tune neutrophil responses are therefore critical for health.

We aim to understand how neutrophils are regulated and to use these insights to interrogate their function in infection and inflammation. We also aim to develop therapies targeting neutrophils in malaria, a devastating disease that affects millions of people in the global South. 

Main research topics:

1. Molecular control of neutrophil development

Dysregulation of neutrophil development can lead to neutropenia or hyperinflammation. We investigate how genetic, metabolic and environmental factors regulate neutrophil differentiation from hematopoietic stem cells. We aim to understand the molecular details of neutrophil development in order to fine tune neutrophil functions. This includes boosting neutrophil antimicrobial responses as a way to combat antimicrobial resistance (AMR), as well as suppressing neutrophil activity in inflammatory diseases such as malaria and autoimmunity.

2. Molecular mechanism of NET formation

Neutrophils externalise their chromatin in the form of NETs, which trap microbes and prevent dissemination of infection. NET formation predominantly occurs via a regulated form of cell death, which is immunostimulatory and pro-inflammatory. We investigate the role of mitochondria and cell cycle proteins in regulation of NET formation.

3. Fine tuning neutrophil responses in malaria

Malaria, caused by the protozoan parasite Plasmodium falciparum, affects up to 200 million people annually, predominantly in sub-Saharan Africa. P. falciparum infects erythrocytes and can lead to severe disease such as cerebral malaria and acute respiratory distress. We showed that neutrophils have a central role in triggering severe malaria, by activating the endothelium and promoting inflammatory organ damage. However, neutrophils can also be protective in malaria by suppressing parasite proliferation. We aim to therapeutically modulate neutrophil development and function in malaria, in order to reduce pathogenic responses and enhance protective ones.

4. Neutrophil transfusion therapies

Neutrophils excell at killing microbes and synergise with antibiotics to suppress bacterial and fungal infections.  We are optimising ex vivo manufacture of neutrophils as a potential cellular therapy for treatment of neutropenia and resistant infections.