Venizelos Papayannopoulos group

Neutrophils in immune defense and disease

Multicellular organisms evolved sophisticated immune systems to protect themselves against infection. We are interested in understanding how our immune system regulates its responses to microbial challenges. We focus on neutrophils, since these phagocytes play central microbicidal and regulatory roles during the course of infection.

Neutrophils are among the first immune cells recruited to sites of infection, undertaking several strategies to eliminate the invading agents. They engulf and kill microbes intracellularly and release antimicrobial factors that combat pathogens extracellularly through degranulation and the release of neutrophil extracellular traps (NETs).

NETs are web-like structures composed of decondensed chromatin and antimicrobial proteins that trap and kill bacteria, fungi, viruses and parasites. Human patients lacking NETs are susceptible to infection with opportunistic pathogens. However, NET overabundance has also been implicated in inflammatory and autoimmune disease. We studying how neutrophils regulate NET release to respond efficiently to infection while suppressing pathology driven by excessive NET release.

Neutrophils release NETs through a novel cell death mechanism involving some fascinating cell biology where a neutrophil-specific granule protease translocates to the nucleus and partially cleaves histones to promote chromatin decondensation. Recently, we uncovered the mechanism driving selective protease release from granules. In addition we showed that neutrophils selectively release NETs to clear large pathogens avoiding unnecessary NET-mediated tissue damage when the microbes are small enough to be phagocytosed. We are currently exploring other novel functions of NETs in infection and inflammatory disease.

Figure 1

Figure 1

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NETs (red) in the lung of a mouse infected with Candida albicans. The neutrophil marker myeloperoxidase appears in green and DNA in blue.

Figure 2

Figure 2

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NETs (DNA, green) capturing fungal filaments (Candida albicans hyphae, blue).

Figure 3

Figure 3

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Competition between phagocytosis and NETosis. Phagocytosed yeast particles drive the translocation of NE to the phagosome via fusion with azurophilic granules, sequestering NE away from the nucleus. In contrast, the absence of a phagosome during the response to hyphae allows NE to translocate to the nucleus, processing histones to drive chromatin decondensation and NETosis. By inhibiting NETosis, phagocytosis prevents tissue damage caused by uncontrolled NET release.

Papayannopoulos group

Dr Venizelos Papayannopoulos

Venizelos Papayannopoulos
vpapaya@nimr.mrc.ac.uk

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Papayannopoulos biography

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