Phagocyte Biology Laboratory

Dr. Bryan Heit, Western University

About Us

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.

Lab News

Rab17 Mediated Antigen Sorting

Model of Rab17 Function

Model of Rab17 Activity (click for full-size). Legend: EE – early endosome, LE – late endosome, LY – lysosome, RE – recycling endosome

We are excited to announce the publication of a follow-up paper to last-years study of Rab17 mediate sorting of antigens. In our first study we identified Rab17 as a protein which allowed macrophages to prevent generating immune responses after engulfing dead cells (a process termed efferocytosis), while still allowing macrophages to generate immune responses after engulfing pathogens. In this new study we have further explored this Rab17-dependent sorting pathway, revealing the details of how this process works.

Background:

To understand what Rab17 is doing we first need to talk – briefly – about how macrophages process pathogens. Macrophages “eat” pathogens, with engulfed pathogens ending up in a “stomach” called the “phagosome”.The phagosome then moves towards the centre of the macrophage, where it can fuse with lysosomes. This fusion delivers  enzymes that destroy the pathogen. The resulting pathogen debris (termed ‘antigens’) are loaded onto a molecule called “MHC II”, which then presents the antigens to the immune system. This antigen presentation allows for other immune cell types to begin targeting the pathogen.

How Rab17 Works:

The problem is that macrophages also phagocytose cells in our bodies are they are turned over during tissue maintenance. The phagocytosis of these cells – termed ‘efferocytosis’ – must avoid presenting any antigens from these cells, as this results in autoimmune disease. This is where Rab17 gets involved – Rab17 “grabs” the phagosome immediately after it fuses with lysosomes, and redirects the phagosome to fuse with another cellular compartment called the “recycling endosome”. Here, the debris are either absorbed by the macrophage or expelled into the extracellular space, thereby avoiding loading onto MHC II. This allows macrophages to “clean” our tissues of old, damaged and unneeded cells, while preventing autoimmunity.

Reference:

Charles Yin, Dean Argintaru & Bryan Heit (2017). Rab17 mediates intermixing of phagocytosed apoptotic cells with recycling endosomes. Small GTPases. Eprint ahead of publication. [Article] [Pubmed]


 

Welcome New Students

The Heit lab is excited to announce that two new students are joining our lab. Adam Tepperman will be joining us as a summer student, and will be investigating antigen sorting following efferocytosis and phagocytosis. Darius Lau, a former honours student in our lab, is staying on as a graduate student and will be continuing his exciting work into the function of CD93 in efferocytosis.


 

2017 RGE Lecturer – Dr. Peter Mugyenyi

Next Thursday we will be hosting the 2017 RGE Murray Lecturer, Dr. Peter Mugyenyi from the Joint Clinical Research Centre. Dr. Mugyenyi is a Ugandan medical doctor, researcher and promoter of equitable medical care. He is currently the Executive Director of Joint Clinical Research Centre, Kampala, the largest provider of HIV care and research in Africa. He was a pioneer in the introduction of antiretroviral therapy to Africa, in the delivery of ARVs to rural areas, and in making life saving AIDS treatment accessible to low and middle income countries. He has received many awards including A Hero of Medicine Award and Science Diplomacy Prize, as well as honorary degrees from Mbarara University in Uganda and the University of Ireland.

Dr. Mugyenyi’s research cover a wide spectrum of HIV/AIDS and related diseases, including paediatric and adult HIV treatment, drug trials, HIV resistance, HIV prevention, immunological studies including HIV vaccine trials, pharmacokinetic, molecular and epidemiological studies as well as social and economic impact of HIV. Internationally, he is on several boards of institutions and organisations in Africa, UK and the USA. He previously served as a temporary Board Member of the Institute of Medicine of the National Academies, and as an advisory member of the HIV Vaccine Trials Network, USA.

Dr. Mugyenyi will be presenting his work on Thursday May 11, 2PM, in 3M Building Room 3250.


 

Using Evolution to Understand Phagocytes

MERTK Evolution

Quantifying MERTK Evolution

The Heit lab is excited to announce the publication of our most recent study, which uses evolution as a tool to investigate the biology of the receptor MERTK.

Every day the normal turnover of cells in our tissues results in the production of around 100 billion dying cells. These dying cells must be removed to keep our tissues healthy. MERTK plays a central role in this process – in fact, MERTK is one of the major receptors used by cells such as macrophages to recognise and remove these dying cells. In humans, defects in MERTK function can lead to many diseases including retinitis pigmentosa – a form of blindness, autoimmune diseases such as multiple sclerosis, heart diseases such as atherosclerosis, and even infertility. Furthermore, viruses such as HIV and Ebola, as well as some cancers, use MERTK to gain access to our cells and to manipulate our immune system. Despite these multiple roles in human health, we still have a poor understanding of how MERTK functions.

In our newest study, currently available as a corrected proof at Molecular Biology and Evolution, we use an evolutionary approach to better understand the function of MERTK. Unexpectedly, we discovered that MERTK has undergone recent positive selection – a form of evolution rarely observed in human genes. Further investigation into this evolution revealed that human MERTK has evolved to be present in smaller amounts on our macrophages than in our ancestors, while simultaneously evolving to self-structure into miniature “islands” on the macrophage surface. While it may seem counter-intuitive to reduce the amount of an important gene expressed by our cells, as this would make the gene less able to do its work, the lower expression decreased the ability of viruses to parasitize MERTK-expressing cells. The increase in MERTK clustering evolved to counteract this decreased expression, through enhancing the avidity of MERTK. Thus, MERTK has evolved to limit the extent to which viruses can parasitize it, and compensates for the reduced levels of MERTK by increasing its avidity.

The evolutionary trend we observed is especially exciting as it is consistent with a form of evolution termed “antagonistic coevolution”, or more commonly referred to as the red queen hypothesis. In this form of evolution, a pathogen and its host become locked in an arms-race, in which advantages gained by evolution of the host are rapidly counteracted by coevolution of the pathogen. The end-effect is a zero-sum change in the interaction between the host and the pathogen – i.e. the host and pathogen still survive, despite being better “armed” to fight each other.

Evolution aside, the observation that MERTK is structured into preformed islands on the cell surface is of great interest, as this type of clustering is often a result of interactions with other proteins. As such, these “islands” may represent a previously unsubscribed interaction between MERTK and some form of human-specific co-receptor. The Heit lab is currently investigating this possibility, in the hopes that by understanding these newly evolved interactions that we may gain further insights into the human diseases caused by MERTK dysfunction.

Reference:
Evans AL, Blackburn JW, Taruc K, Kipp A, Dirk BS, Hunt NR, Barr SD, Dikeakos JD, Heit B. Antagonistic Coevolution of MER Tyrosine Kinase Expression and Function. Mol Biol Evol. 2017 Mar 23. Pubmed ID: 28369510.

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Upcoming Events

May 16-20, 2017
Canadian Society for Molecular Biology Annual Conference - Ottawa, Canada.


June 11-16, 2017
Phagocytes GRC Meeting - Waterville Valley, New Hampshire, USA


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