Lacy-Hulbert & Stuart Laboratories
The immune system provides us with many layers of defense against infection by bacteria, viruses and other microbes. These range from highly specialized ‘adaptive’ immune responses, which include antibodies and killer T cells that recognize specific microbial components through ‘innate’ immune mechanisms that are designed to react to macromolecules shared by many microbes, to barrier mechanisms, which physically prevent infection in the skin, lung, gut and other mucosal surfaces. The Lacy-Hulbert and Stuart Laboratories work closely together to understand how these different aspects of the immune system cooperate to identify and combat potentially infectious organisms while preventing immune attack against innocuous microbes or the body’s own self. The research is currently focused in these main areas:
SARS-CoV2 and COVID-19
Like many laboratories at BRI and elsewhere, we have been impacted by the ongoing COVID 19 pandemic, which has required a lot of adjustments and changes in pace and focus. We have been actively working to find ways in which we can contribute our knowledge, expertise and resources to help understand how COVID19 develops and how we can treat infections and prevent disease.
In our lab, we are now applying our forward genetic screening approaches to identify genes and cell pathways that can increase cellular resistance to SARS-CoV2, the virus that causes COVID-19. We hope that this allow to quickly find new genes and therapeutic targets that can be used to combat infections, or help to understand why some people develop severe disease, while others have mild symptoms, or none at all. We are also working with our lung immunity team here at BRI, including Dr Steven Ziegler, Dr Jessica Hamerman and Dr Daniel Campbell, along with collaborators at Seattle Children’s Research Institute and the University of Washington, to test whether the antiviral mechanisms discovered in our Ebola and Influenza studies can also act against SARS-CoV2. More information about our COVID-19 work can be found here.
Distinguishing Pathogens From Self
The cells of the innate immune system, particularly specialized phagocytes such as dendritic cells (DCs) and macrophages, represent a ‘first line’ of surveillance and defense against infection. Major advances over the past 20 years have led to the identification of an armory of receptors that recognize common microbial components and stimulate cytokine release, which in turn promote adaptive immune responses. However, many of these microbial components are shared by innocuous or commensal microbes that are present in large numbers in the intestine and other sites in the body. Furthermore, it is now clear that these same receptors can be triggered by self-derived macromolecules, such as nucleic acids, lipids and polysaccharides. We believe that inappropriate activation of the innate immune system by self-associated components may be a major driving force behind many autoimmune or chronic inflammatory diseases. Research in the labs is directed at understanding how innate immune cells recognize and distinguish self from pathogens, and respond accordingly.
A major focus of the laboratory’s work in this area is the recognition of cells that die by apoptosis or other mechanisms. Apoptosis is a ‘silent’ form of cell death, used for removal of cells that are damaged or no longer needed. Cells that initiate apoptosis are rapidly removed by phagocytes or neighboring cells. The lab team has shown that when dendritic cells phagocytose apoptotic cells, they adopt a ‘regulatory’ phenotype that promotes immune tolerance. The researchers believe that this mechanism allows the immune system to constantly survey self antigens and maintain immune tolerance. Current research is focused on understanding how recognition of apoptotic cells modifies innate immune signaling to promote immune tolerance, and how defects in this process may lead to autoimmune diseases such as systemic lupus erythematosus (SLE).
Work in the Stuart lab is also identifying additional mechanisms for recognition of pathogens. Pathogenic bacteria are distinguished from closely related non-infectious strains by the expression of ‘virulence factors’. These are proteins that target host cell functions to aid infection and colonization. In plants, it has been proposed that the cells can sense the action of these virulence factors and initiate immune responses to combat infection. Several years ago the lab showed, for the first time, that metazoans (fruit flies and mammals) use analogous mechanisms to sense pathogens and trigger innate immune signaling pathways. Ongoing research is aimed at identifying more of these mechanisms, and understanding how they promote immune defense. Recently, the lab has discovered a new way for human cells to induce repair and defense against a virulence factor of a deadly bacteria, Staphylococcus aureus.
Finding out how innate immune cells recognize potential targets and respond appropriately is essential to the understanding of both defense against infection and autoimmunity.
Regulation Of Immune Responses
Our laboratory is interested in genes and pathways that regulate immune signaling, and understanding how changes in these mechanisms can lead to autoimmune diseases such as Systemic Lupus Erythematosus (SLE) or Inflammatory Bowel Disease (IBD). We use genetics, biochemistry and cell biology approaches to understand how these pathways function in different immune cell types, and in vivo models to work out how these mechanisms contribute to autoimmunity.
A long term interest of the lab is in the co-operation between a family of cell surface receptors, the alpha-v integrins and the cytokine TGF-beta. TGF-beta is critical for regulation of the immune system, and signals to multiple immune cell types to dampen immune responses and resolve inflammation. TGF-beta is mostly synthesized in an inactive form and must be released before it can signal. The lab has shown that DCs and macrophages can bind and activate TGF-beta through alpha-v beta 8 integrin, leading to TGF-beta signaling to other immune cell types including T cells. Currently, the lab is working to understand how DCs come to express alpha-v beta-8, how this triggers TGF-beta activation and whether targeting this process may provide a therapeutic strategy for IBD and Multiple Sclerosis (MS), as well as other disease such as cancer.
Recently we have identified a new role for genes involved in autophagy in regulating immune signaling. Autophagy is the process by which cells ‘eat themselves’ during starvation or in response to stress or cellular damage. We have found that some components of the autophagy pathway are triggered when immune cells are activated through toll-like receptors (TLRs), and reduce TLR signaling. TLRs recognize specific macromolecules present in pathogens, such as bacterial cell walls or viral genomes, and trigger production of inflammatory cytokines to induce immune responses. However, components of our own cells can also trigger TLR signaling and this is thought to contribute to autoimmune diseases such as SLE. We think that this autophagy pathway exists to prevent overactive TLR signaling to self-derived ligands and we have found that disruption of this pathway contributes to autoimmunity. Current work in the lab investigates how this pathway works in B cells, plasmacytoid DCs and macrophages to control autoimmune responses, and how genetic variation in autophagy components contribute to SLE in patients.
Forward Genetics to Identify New Mechanisms in Immunity and Host Defense
The understanding of innate immunity and host defense is incomplete, and there are many mechanisms and components to be discovered. To help in this process, the lab has developed forward genetic techniques using transposon mutagenesis and high throughput gene sequencing, which can be used to probe immune mechanisms in mammalian cells. An important feature of this system is the ability to perform large scale gain- and loss-of-function screens simultaneously across the genome in multiple cell types. The initial system was validated in a screen for resistance to cytotoxic cancer drugs, but the current focus is in host defense and immunity. Currently, the lab is using this approach to identify mechanisms of resistance to viral infections, with a major focus on Ebola and Influenza viruses. From this screen we are identifying genes that confer resistance to virus entry or replication, with the ultimate aim of identifying or developing drugs that could be used to prevent viral infection.
The genetic studies have revealed mechanisms of cell trafficking that are hijacked by these pathogens. Using multiple microscopy techniques, including confocal, live imaging, high-throughput and Virtual Reality, the lab is able to precisely localize the pathogen and the reorganization it induces. Understanding these mechanisms is essential to developing new treatments for related autoimmune diseases or infections.
Work in the laboratories has been funded by the National Institutes of Health, Department of Defense, Crohn’s and Colitis Foundation of America, Wellcome Trust, Lupus Research Alliance, Heidner Foundatrion and the Seattle Foundation.
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