Cutting-edge research in the fields of inflammation, hematology, virology and immunoendocrinology
The GIGA-Inflammation, Infection & Immunity (GIGA-I3) research unit is composed of 10 laboratories that study various but complementary aspects of immunity. The 10 laboratories of the GIGA-I3, independently of each other, carry out research in varied fields of immunology. Nevertheless, 4 research themes are particularly explored and give rise to numerous collaborations within the GIGA-I3. These research themes are inflammation, hematology, virology and immunoendocrinology.
Understanding cellular and molecular mechanisms in chronic inflammation
The cellular and molecular mechanisms implicated in inflammation, and particularly in chronic inflammation, are extensively studied in the GIGA-I3. The GIGA-I3 laboratories mainly focus their research on the most common inflammatory lung diseases, namely asthma and chronic obstructive pulmonary disease (COPD), on persistent inflammatory joint diseases and on obesity-linked inflammation.
Clinical studies and translational research in hematopoietic stem cell transplantation (HSCT)
The GIGA-I3 is also involved in clinical studies and translational research in the field of hematopoietic stem cell transplantation (HSCT). In this context, the GIGA-I3 aims at optimizing HSCT but also evaluates the consequences of HSCT on the immune system.
Viral diseases research and immune system regulation
The GIGA-I3 pays particular attention to the study of viral diseases. The GIGA-I3 indeed investigates the role and the regulation of Varicella-Zoster Virus (VZV) proteins, develops humanized murine models for rapid and large-scale screening of anti-HIV responses to new immunostimulatory approaches, and takes advantage of a research model, the uterine cervical cancer associated with infection by the human papillomavirus (HPV), to study the role of natural immunity (NK cells and TCRηδ) in anti-tumor and anti-viral responses.
Identifying the relationships between the immune and endocrine systems
The GIGA-I3 is particularly involved in research aimed at identifying the relationships between the immune and endocrine systems. In this context, the GIGA-I3 studies thymic IGF-2 in programming central self-tolerance to pancreatic islet cells, the role of the GH/IGF-1 axis on thymic function and T-cell development and implantation/tolerance of the embryo.
Research laboratories within GIGA-I3
Research work in the GIGA-I3 is carried out by the Laboratory of Cellular and Molecular Immunology, the Laboratory of Immunophysiology, the Laboratory of Hematology, the Laboratory of Immunoendocrinology, the Laboratory of Immunometabolism and Nutrition, the Laboratory of Molecular Immunology and Signal transduction, the Laboratory of Organogenesis and Regeneration (Marc Muller), the Laboratory of Pneumology (Renaud Louis), the Laboratory of Rhumatology (Michel Malaise), the Laboratory of Translational Gastroenterology (Edouard Louis), and the Laboratory of Virology and Immunology.
Better understanding mechanisms promoting common lung diseases
Co-led by Fabrice Bureau, Christophe Desmet and Nathalie Jacobs, the Laboratory of Cellular and Molecular Immunology aims at identifying and characterizing novel innate immune mechanisms that influence the response of the lung to varied environmental challenges, such as viruses, air pollution and allergens. Most studies in the field focus on the mechanisms that promote common lung diseases such as asthma or chronic obstructive pulmonary disease (“PRO” mechanisms).
In the “PRO” line of research, the team has notably identified the dendritic cell subset responsible for triggering respiratory allergy. They have also documented a role for our own self-DNA in triggering pro-allergic immune responses when released in the extracellular milieu. The lab also investigates the little-studied innate immune mechanisms that normally protect the lung from unwanted detrimental immune responses (“ANTI” mechanisms). Among those ANTI-mechanisms, the team has notably identified a subset of anti-allergic regulatory macrophages in the lung interstitium. They also have documented a regulatory function for homeostatic lung eosinophils. Part of their current efforts aim at translating their “ANTI” findings toward the clinic, in the form of diagnostic tools and cellular therapeutics.
Developing new targeted approaches for the prevention of respiratory diseases
For its part, the Laboratory of Immunophysiology (Thomas Marichal) aims to investigate the biology of myeloid and epithelial cells at mucosal sites during homeostasis and in the context of immune-mediated disorders such as asthma. In the lung and intestinal mucosa, epithelial cells, neutrophils and macrophages are particularly exposed and responsive to external threats such as pollutants, allergens, microbes or microbial products. Understanding how these cells interact with each other to regulate homeostasis and disease development is of fundamental biological importance and has critical implications for the prevention of immune-mediated disorders such as asthma or inflammatory bowel diseases.
The Immunophysiology lab mainly uses innovative transgenic tools in mice in combination with single cell technologies to address this question.
On top of that, the European Research Council has just awarded a €1.5 million ERC Starting Grant to Thomas Marichal, FNRS Research Associate and Welbio investigator at GIGA-I3. This funding, which extends over a period of 5 years, will enable him to develop his “IM-ID” project which aims to study in depth the identity and function of a population of a lung regulatory macrophage that proves to be a promising new target in the treatment of respiratory diseases, such as asthma.
A strong interest in the biology and therapeutic use of stem cells
The Hematology Group (Hematology laboratory, Laboratory of Cell and Gene Therapy, and the Division of Clinical Hematology at the CHU of Liège under the leadership of Yves Beguin) has developed several major research avenues. The Hematology laboratory has elaborated a strong interest in the biology and therapeutic use of stem cells. It has investigated ex vivo expansion of hematopoietic stem cells (HSC) and particularly the relationships between cell cycle, expression of adhesion molecules and the migration and homing of HSC. It has acquired a solid expertise in the field of erythropoiesis, in particular in the quantitative assessment of erythropoietic activity and iron metabolism, including the diagnostic use of the soluble transferrin receptor and the therapeutic use of erythropoietic agents and iron.
The Hematology laboratory investigates different options to improve graft-versus-leukaemia effects while minimizing acute and chronic GVD reactions. In particular, active research programs are carried out on mesenchymal stem cells (MSC) for tissue repair and immunosuppression (notably in the field of HSC transplantation) as well as on the ability of regulatory T cells (Tregs) to attenuate experimental graft-versus-host disease (GVHD). The lab has extensive expertise in pre-clinical studies involving cell transplantation in mice (i.e. humanized murine models of GVHD or of liver damage in NOD/SCID/IL-2Rη(null) mice) and requiring analyses by flow cytometry.
Another important program is developed on the biology of multiple myeloma, including basic science investigations of several molecules such as galectins, animal investigations of graft-versus-myeloma effects, and new imaging modalities of bone involvement and extramedullary disease. The lab has a large biobank containing thousands of blood and marrow samples from patients with haematological malignancies or undergoing hematopoietic stem cell transplantation, on which numerous tests may be carried out, including sophisticated investigations of immune function and studies on immune reconstitution after hematopoietic stem cell transplantation.
Access to the different GIGA technological platforms (Genotranscriptomics, Proteomics, Imaging and Flow Cytometry, Bioinformatics, Immunohistology, Mouse Facility and transgenics, Zebrafish Facility and transgenics, Viral vectors, Interactomics) completes the offer of available services.
Thymus and type 1 diabetes
The Laboratory of Immunoendocrinology is headed by Vincent Geenen, Director of Research at the F.R.S.-FNRS, Professor of Embryology and History of Biomedical Research at the University of Liege, and Head of the Endocrinology Clinic at the University Hospital of Liege.
For nearly 30 years, Vincent Geenen and his team have been working on the thymus, the central lymphoid organ of the immune system. His research has shown that the thymus has a unique role in educating the immune system to recognise and tolerate neuroendocrine functions, and that thymus dysfunction is involved in the development of selective autoimmunity in type 1 diabetes.
Currently, the Laboratory of Immunoendocrinology is developing a new type of negative/tolerant vaccination against type 1 diabetes.
At the interface between immunological and metabolic processes
The Laboratory of Immunometabolism and Nutrition is led by Sylvie Legrand and Nicolas Paquot. Immunometabolism is an emerging field that investigates the interplay between immunological and metabolic processes. Obesity has reached epidemic proportions globally, with an estimated 1.9 billion adults being overweight or obese. Obesity-related diseases, which include not only type 2 diabetes (T2D) and heart disease but also cancer, threaten to shorten the human lifespan by 5-20 years.
Obesity causes a chronic low-grade inflammation which plays a role in the development of insulin resistance. This inflammation originates from the recruitment of macrophages constituting up to 50% of all adipose tissue cells and secreting pro-inflammatory cytokines.
Obesity is a heterogeneous disease; some patients are obese but “metabolically healthy” while others develop metabolic abnormalities related to insulin resistance. The protective mechanisms by which these “healthy” obese individuals escape the harmful consequences of obesity are not yet fully understood. The topography and the different pro-inflammatory activities of adipose tissue seem to play a role. A more in-depth comparison of the two obesity phenotypes would allow to better understand the mechanisms involved in the development of such metabolic abnormalities.
Obesity is not only associated with chronic inflammation but has been also linked to an imbalance in the immune system. Indeed, the dysfunction in systemic metabolism seen in obesity, by disturbing the plasma levels of lipids, glucose, insulin, etc., can impair both intrinsic metabolism and function of circulating immune cells. These immunometabolic modulations contribute to obesity-associated comorbidities (type 2 diabetes, cardiovascular disease, some cancers). The team is currently focusing on cellular and molecular mechanisms underlying obesity-linked inflammation and immune dysfunction: NLRP3 inflammasome (a multi-protein platform), polarization of adipose tissue macrophages and immunometabolic modulations of PBMCs (peripheral blood monocytic cells). Let us hope that these lines of research will lead to new therapeutic options.
Inflammatory disorders and cancer development
The Laboratory of Molecular Immunology and Signal transduction (Emmanuel Dejardin) is focusing on the understanding of immune signaling pathways activated by TNF receptor family members. Its aim is to dissect the mechanisms by which invading pathogens or genetic alterations contribute to inflammatory disorders and cancer development.
The transcription factor NF-λB displays a wide range of biological functions during embryonic development throughout adult life. The mammal NF-λB family encodes five members that are p50, p52, p65, RelB and c-Rel. These subunits homo- and heterodimerize forming a network of transcription factors that fulfil a wide range of biological functions such as cell proliferation, cell survival, inflammation or development and homeostasis of lymphoid organs. Two main pathways control the activation of the NF-λB network: the classical (or canonical) and the alternative (or non-canonical) NF-λB pathways.
The laboratory is dedicated to the understanding of the biological functions regulated by the alternative NF-λB pathway. The team, among others, has dissected this pathway at the molecular level and found that the kinase NIK (NF-λB-Inducing Kinase) in conjunction with the kinase IKKα induce the processing of the NF-λB precursor p100 into its active form p52. This pathway is activated by a subset of TNFR members like LTβR, CD40, BAFF-R or RANK whose biological functions are often subverted in inflammatory disorders and in cancer. The lab has developed in vitro cellular systems and transgenic mouse models to address to what extent the alternative NF-λB pathway contributes to inflammatory disorders. These tools are also the basis of functional screens to identify compounds that modulate the activity of the alternative NF-λB pathway.
An expert in oncolytic herpesviruses
Led by Catherine Sadzot, the Laboratory of Virology and Immunology has a long-lasting experience on human alpha herpesviruses with a special interest on Varicella Zoster Virus (VZV). As all herpesviruses, VZV is assembled via a very complex process, involving many cellular and viral proteins. ORF9p, one of the tegument proteins as well as the two viral protein kinases appear to play an important role in both the primary envelopment at the inner nuclear membrane and the secondary envelopment in the cytoplasm. The exact molecular mechanisms of these processes are under investigation.
The team’s research aims to decipher the different steps leading to VZV assembly with a special interest to the interactions with cellular components driving this process. A Yeast-two-hybrid screen has allowed to identify some cellular proteins interacting with ORF9p, a tegument protein. The interactions between ORF9p and the cellular adaptor complex 1, involved in trafficking, have been confirmed and characterized. In addition, ORF9p seems to be important for the primary envelopment and the nuclear egress. This characterization of ORF9p importance in the nuclear steps of VZV envelopment is ongoing.
What is more, oncolytic viruses are more and more considered as a therapeutic option combined or not to immune or chemotherapies. With its large genome and a well-characterized mechanisms of cell entry, the Herpes Virus Simplex (HSV) 1 appears to be suitable for being engineered to target a cell subpopulation and to introduce a transgene in the infected cells. The characterization of such an oncolytic HSV engineered to target a subpopulation of glioblastoma cells and of the immune response elicited by this virus is ongoing. In this context, the team’s expertise on the BAC technology allowed it to start a new research program aiming at engineering oncolytic herpesviruses designed to specifically target a subpopulation of glioblastoma cells. These viruses are currently characterized in vitro and their efficacy will be evaluated in vivo using a xenograft orthotopic mice model.
One thing is certain: the research activities at GIGA-3I vividly illustrate the complexity of the functioning of the immune system and the countless ways in which we can better understand it in order to prevent the effects of its dysfunction.
