NETs of neutrophils
University of Bristol researcher investigates immune cell defense against microbes
BRISTOL, U.K.—Dr. Borko Amulic, a researcher who recently moved from the Max Planck Institute in Germany to the University of Bristol, received a £1.2-million Career Development Award from the Medical Research Council. The five-year award will enable Amulic and his team of researchers in the School of Cellular and Molecular Medicine to study how and whether the natural ability of neutrophil immune cells can be increased to fight infection “in the post-antibiotic age,” according to the University of Bristol.
Neutrophils—immune cells that protect the body from infection by bacteria, fungi and parasites—are the most abundant immune cells in humans. Without these cells, humans would be defenseless against pathogens. The researchers will investigate how neutrophil responses are regulated and how they carry out tasks such as engulfing parasites or entrapping them in neutrophil extracellular traps (NETs), webs of DNA that neutrophils release in a kamikaze cell death attempt to control infections.
According to Amulic, NETs are composed of extruded chromatin with antimicrobial and immunostimulatory properties. Released by an active process called NETosis, the NETs are believed to trap microbes as well as signal to the rest of the immune system. However, excessive or dysregulated neutrophil responses are destructive and contribute to pathology in malaria, autoimmunity and cancer. Thus, mechanisms that fine-tune neutrophil responses are critical for health.
In defining the role of NETs in immunity, Amulic explained that NETosis is an anti-microbial strategy that causes neutrophil death and helps to achieve pathogen control and elimination. As he explained in an article published in Current Biology, “In vitro, the microbicidal properties of NETs have been clearly demonstrated: they trap pathogens and prevent them from dispersing, while simultaneously destroying them through exposure to a high concentration of anti-microbial effectors. These anti-microbial effectors include, as expected, the anti-microbial proteins of the neutrophil granules. Perhaps unexpectedly, the histones in NETs are also key components of the anti-microbial repertoire. It has long been known that histones are some of the most powerful anti-microbial agents that exist.
“Nevertheless, exactly how this anti-microbial activity of histones could be effectively harnessed was a long-standing and intractable mystery. The discovery of NETs presents a satisfying explanation for this apparent dilemma. Through NET formation, neutrophils provide histones with an opportunity to execute their alternative, non-structural function: microbial killing.”
Amulic and his team “want to understand how neutrophils are regulated at the molecular level and to use these insights to interrogate their function in immunity and inflammation,” he said. The researchers “also aim to develop therapies targeting neutrophils in malaria, a devastating disease that affects millions of people in developing countries.”
In Bristol, Amulic will work with key collaborators in the Faculty of Biomedical Science, including experts in the fields of immunology, microbiology and biochemistry. He will also have access to cutting-edge facilities such as the Wolfson Bioimaging facility. With research that spans cell biology and immunology, the team will use molecular biology techniques such as CRISPR/Cas9 knockout to characterize genes regulating human neutrophil behavior. The researchers will employ various disease models and patient samples to investigate neutrophils in vivo.
As Amulic said, “Our goal is to propose targets for therapies in inflammatory diseases (including malaria, autoimmunity and cancer), as well as to discover ways to boost neutrophil microbicidal activity in settings such as immunodeficiency and antimicrobial resistance. The emergence of antimicrobial resistance threatens human health, and one strategy to combat infection is to boost the natural ability of neutrophils to kill pathogens. It is my hope that this award will allow us to discover the genes and biochemical pathways regulating neutrophil functions so we can do just that.”
He added, “I am also very keen to understand how neutrophils contribute to inflammatory diseases. Excessive neutrophil activation often damages our own tissues and contributes to diseases such as autoimmunity and cancer. By better understanding the link, we can begin to investigate how to negate this impact.”