Phagocyte Biology Laboratory
Welcome! You have reached the homepage for the laboratory of Dr. Bryan Heit. Our lab is part of the Department of Microbiology and Immunology at Western University, and we are members of the Center for Human Immunology, the lead centre for the CIHR Human Immunology Network.
Our interests surround the function of phagocytes – white blood cells which ingest (phagocytose) pathogens, particles, and dead cells. We focus on the cellular and molecular processes which control the function of these cells during the maintenance of homeostasis, infection and chronic inflammatory disease. Central to most of our studies is the study of efferoctyosis – the phagocytic removal of apoptotic (dying) cells, and how failures in this process lead to inflammation, autoimmunity and infection.
What is a Phagocyte?
Phagocytes are a class of white blood cells which have the capacity to engulf large particles such as bacterial and fungal pathogens, and subsequently destroy the engulfed material. The term phagocyte literally translates to “cell that eats”, which is an apt description of the primary function of these cells in our bodies. While there are many types of phagocytes, the Heit lab focuses primarily on macrophages, which play key roles in both maintaining our bodies and in fighting infections.
We use a combination of advanced microscopy techniques, gene expression analysis and functional assays to investigate the activity of macrophages. Some examples of the methods we employ can be found on our YouTube channel.
We are excited to announce our newest preprint. in this study we have identified a novel mechanism by which SARS-CoV-2 prevents antigen presentation on MHC class II. This inhibition of antigen presentation likely acts to delay the onset of adaptive immunity (antibodies and T cells) targeting SARS-CoV-2, and may also impact our ability to produce long-lived immunity against COVID-19.
SARS-CoV-2 achieves this by inactivating the transcription factor CIITA. CIITA is required for MHC II expression, so by inactivating CIITA, SARS-CoV-2 prevents antigen presentation on MHC II. Normally, CIITA expression would be induced by IRF1 and IRF3, which are transcription factors induced by pathogen sensors and inflammatory cytokines, respectively (panel A in the figure below). The SARS-CoV-2 protein NSP5 is able to bind to IRF3, allowing NSP5 to then recruit another host protein – HDAC2 – to the CIITA promoter. Here, HDAC2 deacetyates histones in the CIITA promoter, thus turning off expression of the CIITA gene (panel B in the figure below).
Thank You NSERC!
The Heit lab is excited to announce that we were awarded a 5-year Discovery Grant from the The Natural Sciences and Engineering Research Council of Canada (NSERC). This award will support our ongoing research into understanding how processes such as diffusion, exocytosis, and the cytoskeleton act to structure proteins into functional complexes on the cell surface.
This funding has been central to our previous work, including our development of analysis tools for super-resolution images, our work identifying new membrane structures, and our work investigating how exocytosis and endocytosis structure the diffusion of proteins on the cell surface.
We look forward to continuing this work and would like to thank our reviewers for seeing the potential of this study. Below is a time-series micrograph from a soon-to-be submitted paper stemming from this work!
New Publication – Fluorescent Microscopy
We are excited to announce the publication of the newest work from our lab. This text book, available from Methods in Molecular Biology features chapters by over 50 scientists from around the world. This book opens with an introduction to the basic concepts that imagers need to know to capture and interpret fluorescent micrographs correctly. From these basics, the book presents a series of increasingly complex methods enabling the imaging of a range of biological specimens. The book ends with several chapters on image analysis and quantification. Topics covered include:
- Basic fixed-cell and live-cell imaging
- FRET/FLIM, BiFC, and Biosensors
- Traction force microscopy
- Tissue imaging and expansion microscopy
- Intravital imaging
- Multiple super-resolution techniques
- Machine learning
- And much more!
First Paper of 2021 - Efferocytosis and its Role In Pneumonia
Our first paper of 2021 is now out – an extensive review of the role efferocytosis (the removal of dead and dying cells) plays in the pathogenesis of pneumonia and other lung diseases. This extensive review covers the basic biology of efferocytosis, how efferocytosis “reprograms” lung macrophages in ways which may benefit – or harm – pneumonia patients, how pneumonia-causing pathogens manipulate efferocytosis for their own ends, and an analysis of existing and upcoming therapies that may be useful for manipulating efferocytosis in pneumonia patients.
This review was written by two excellent trainees – David Zheng and Maria Abou Taka, and is published in Pathogens. It would not have been possible if not for the support of the Lung Association and the Canadian Institutes of Health Research.
GATA2 and the Onset of Atherosclerosis
We are excited to announce the publication of our research into the events which initiate atherosclerosis. Atherosclerosis is why we worry about cholesterol in our diets, and is one of the leading causes of death globally. Atherosclerosis is driven by the formation of “plaques” – masses of dead, cholesterol-filled macrophages in the blood vessels of the heart. These plaques can rupture, causing a heart attack or stroke. The processes that start this disease are poorly understood. Our new study – published in Frontiers in Immunology – begins to uncover these early events. We have discovered that pre-plaque macrophages loose expression of the genes which would allow for them to remove and process dying cells – a critical step in preventing plaque formation. This loss of “efferocytosis” (dead cell clearance) sets the stage for the accumulation of dead cells that form the plaque.
The key discovery in this study was the identification of the transcription factor GATA2 as the “mater regulator” of this lost efferocytosis ability. GATA2 controls the expression of other genes, and in these patients’ macrophages, GATA2 turns off many of the genes needed to recognize, engulf and destroy dead and dying cells. In the future, treatments targeting GATA2, or the pathways which activate GATA2, may serve as therapies for preventing or reversing atherosclerosis. This study would not have been possible without the amazing work of our collaborator Dr. David Nagpal of the London Health Sciences Centre, and funding from the Heart and Stroke Foundation of Canada.
COVID-19: Innate Immunity Review
The Heit lab is excited our first piece of COVID-19 work – a detailed review on the interactions of the SARS-CoV-2 virus with the innate immune system. COVID-19 has a plethora of mechanisms to avoid being detected and cleared by the innate immune system, and as such, undergoes highly complex interactions with the innate immune system. This review has been published in Frontiers in Immunology.
November 2020 Update: This article has been read more than 67,000 times – making it one of the most-read articles in 2020 across all of Frontier’s journals!
December 2020 Update: The University of Toronto’s IMM340 course has interviewed the lead author of this paper, and incorporated this interview into a video on COVID-19 research.
January 2021 Update: This review was used as part of an article by the Knoxville News Sentinel!
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