Papayannopoulos lab

Antimicrobial Defense Laboratory

: Areas of interest


Our lab studies how the immune system adjusts its responses to ensure efficient microbial clearance while averting chronic and acute inflammatory disease.

Our work centres on innate immune cells called neutrophils. These phagocytes play central microbicidal and regulatory roles during the course of inflammation. We are studying how these cells interact with microbes and other immune cells to protect against infection but also how they promote diseases such as atherosclerosis.

Neutrophils are among the first immune cells recruited to sites of infection, undertaking several strategies to eliminate 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. However, NET overabundance is also linked to inflammatory and autoimmune disease.

Pathogen-tuned immune responses

One major theme in our studies has been to understand how microbe size affects neutrophil responses and inflammation particularly during pulmonary infection. We have shown that the clearance of microbes of different size such as bacteria and fungi requires different neutrophil strategies and inflammatory programmes. Our work has uncovered novel cell biological mechanisms that enable neutrophils to clear microbes more efficiently by adapting their own responses and tuning inflammation to microbe size. These mechanisms also ensure that neutrophil responses do not cause unnecessary tissue damage.

The Competition between phagocytosis and NETosis fine-tunes the neutrophil response to fungal infection.

Figure 1: 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.

Oxidative signaling

We have had a long standing interest in reactive oxygen species (ROS). Neutrophils produce a higher level of ROS than any other cell. ROS kill microbes directly but can also play important regulatory roles.

We have uncovered a novel complex that we termed the azurosome that serves as the first example of an oxidative signaling protein scaffold and regulates NET formation. Moreover, we have shown that neutrophils are sensitive to the cellular localization of ROS, enabling ROS to serve as a sensor of microbe size that regulates inflammation by tuning neutrophil-derived cytokine expression and potentially many other signaling pathways.

Neutrophils in sterile inflammation during atherosclerosis

In addition to their protective role against infection, neutrophils contribute to chronic inflammation that promotes atherosclerosis and other inflammatory diseases. We have shown that NETs are critical in the early stages of atherosclerotic lesion development by inducing macrophage activation. We are now studying how NET deployment is regulated during atherogenesis and how NETs are modulating the responses of other immune cells during sterile inflammatory disease.