Venizelos Papayannopoulos

Antimicrobial Defence Laboratory

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. Neutrophils 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 extracellular web-like structures composed of decondensed chromatin and antimicrobial proteins that trap and kill pathogens. Humans lacking NETs are susceptible to infection. However, NET overabundance has also been linked to inflammatory and autoimmune disease. We are 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. We have shown that a neutrophil-specific granule protease translocates to the nucleus via an alternative pathway that does not involve membrane fusion events. Once inside the nucleus this protease processes histones to promote chromatin decondensation.

Despite these molecular insights, until recently the relevance of NETs in innate immune defense and their contribution to tissue damage in vivo had been unclear. We recently showed that NETs are released selectively to specifically clear large pathogens while avoiding unnecessary NET-mediated tissue damage when the microbes are small enough to be killed intracellularly.

We are currently exploring other novel functions of NETs in infection and inflammatory disease. 

 

Competition between phagocytosis and NETosis.

The Competition between phagocytosis and NETosis fine-tunes the neutrophil response to fungal infection. Phagocytosed yeast particles drive the translocation of NE to the phagosome via fusion with azurophilic granules, sequestering NE away from the nucleus. In contrast, hyphae are too large to be phagocytosed, allowing NE to be released in the cytosol and translocate to the nucleus, processing histones to drive chromatin decondensation and NETosis. By inhibiting NETosis, phagocytosis prevents unnecessary tissue damage when microbes are small enough to be killed intracellularly. (Click to view larger image)

Selected publications

Warnatsch, A; Ioannou, M; Wang, Q and Papayannopoulos V (2015) Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science  349 (6245), 316-320.
Click here for PDF and here for Full Text. 

Branzk, N; Lubojemska, A; Hardison, SE; Wang, Q; Gutierrez, MG; Brown, GD and Papayannopoulos, V (2014) Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogensNature Immunology 15, 1017-1025

Metzler, KD; Goosmann, C; Lubojemska, A; Zychlinsky, A and Papayannopoulos, V (2014) A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosisCell Reports 8, 883-896

Papayannopoulos, V; Staab, D and Zychlinsky, A (2011) Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy. PLOS ONE 6, e28526

Venizelos Papayannopoulos

veni.p@crick.ac.uk

  • Qualifications and history
  • 1998 BA, Rutgers University, USA
  • 2004 PhD, University of California San Francisco, USA
  • 2006 Postdoctoral fellow, Max Planck Institute for Infection Biology, Berlin, Germany
  • 2012 Program Leader, Medical Research Council National Institute for Medical Research, Division of Molecular Immunology, London, UK
  • 2015 Group leader, The Francis Crick Institute, London, UK