Immune cells called neutrophils selectively deploy large
web-like structures to trap and kill large pathogens such as fungi,
according to new research from the Medical Research Council's
National Institute for Medical Research (NIMR; now part of
the Francis Crick Institute).
The findings have implications for improving treatments for
patients whose immune systems are unable to effectively mount such
defences to large pathogens, as well as for understanding
autoimmune diseases where this method of defence goes awry and can
result in damage to a patient's own body.
Dr Veni Papayannopoulos of NIMR explained: "Microbial pathogens
come in different sizes. Much is known about how immune cells deal
with microbes that are small enough to be taken up and killed
inside cells through a process called phagocytosis. In contrast,
how the immune system counters large microbes is much less
clear.
"Immune cells called neutrophils are the foot soldiers of the
immune system. Our study shows that they can sense microbial size
and mount a strategy that captures and kills large microbes outside
cells by releasing web-like structures called neutrophil
extracellular traps (NETs)."
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Dr Papayannopoulos and his team studied cell cultures of human
neutrophils and microbes and performed experiments using mouse
models of infection to identify the importance of the NETs for
immune defence.
Previously, it was assumed that neutrophils, which were once
thought to be relatively 'simple-minded' cells, released NETs
indiscriminately in response to pathogens. However this study
highlights their ability to make sophisticated decisions depending
on the type of infection they encounter.
Dr Papayannopoulos said: "Deficiency in neutrophil function in
humans is associated with life threatening susceptibility to
bacterial and fungal infections. However, the contribution of NETs
in human immunity has been difficult to dissect, because most
mutations in patients with weakend immune systems disrupt both NET
release and phagocytic killing.
"By showing that NETs are selectively implemented to specifally
fight large pathogens our study has separated the roles of these
two antimicrobial strategies in immune defense and explains why
human patients with specific defects in neutrophil function are
susceptible to particular pathogens. We hope that these new
findings will help clinicians formulate more targeted treatments
for these patients.
"On the other hand, abnormal release and insufficient clearance
of NETs are implicated in a number of inflammatory and autoimmune
diseases. Our experiments show that mutations that block
phagocytosis disrupt the ability of neutrophils to distinguish
between small and large microbes and, as a consequence, these cells
misfire NETs in response to small pathogens causing unnecessary
tissue damage. We hope that our work may offer new insights into
the cause and treatment of such diseases."
The paper, Neutrophils sense microbe size and selectively release neutrophil
extracellular traps in response to large pathogens,
is published in Nature Immunology.