Research Arvid Suls

Abstract

Herpes viruses are ubiquitous in human society and cause several common diseases, such as cold sores (Herpes simplex) and chickenpox (Varicella). The eight species of herpes viruses known to primarily infect humans are all clinically relevant and of these, five are known to be extremely widespread amongst humans with seroprevalence rates as high as 90%. Not all individuals are equally susceptible to equivalent viral pathogens. After infection, some individuals do not become symptomatic, while others experience a high severity of the disease with serious complications. For example, a relatively benign disease such as chickenpox can become life-threatening in a small set of individuals. These differences in disease susceptibility are likely to be caused in part due to the variation in the human immune system, but remain largely unknown up to date. A key step in the activation of the adaptive immune system is the presentation of viral epitopes, usually peptides (p), by the major histocompatibility complex (MHC) present on antigen presenting cells (APC) and the recognition of this complex by a T-cell receptor (TCR). There exist many allelic variants of the genes coding for the MHC genes within the population and each variant has a different propensity to bind immunogenic (viral) peptides. This variability in the MHC alleles is one of the underlying factors that leads to differences in disease susceptibility. Previous research has demonstrated that high accuracy models can be established for the affinity of the MHC molecules for the presentation of peptides, based on machine learning methods. The resulting affinity prediction models have made it possible to assess the affinity for almost all human MHC alleles for any given peptide. However, the MHC recognition variability is only part of the story, as each individual has a unique repertoire of T-cells with a large diversity of TCR variants. The variability in TCR epitope recognition is also an important factor in differences between individual immune responses. Unfortunately, few TCR recognition models exist and they are all very limited in scope and accuracy. Therefore, the scope of this project is to develop, evaluate and apply state-of-the-art computational approaches to enable the interpretation of complex MHC-p-TCR interaction data and to elucidate the patterns that govern this system. Within this scope, a key point of interest will be the modelling of the molecular interaction between the MHC complex, encoded by its corresponding HLA allele, the antigen-specific TCR and the peptide antigen itself. Ultimately, this will result in the development of computational tools capable of predicting personalized immune responses to Herpes viruses and the efficacy of vaccine-induced viral protection.

Researcher(s)

• Promoter: Laukens Kris
• Co-promoter: Ogunjimi Benson
• Co-promoter: Suls Arvid
• Fellow: De Neuter Nicolas

Research team(s)

• ADReM Data Lab (ADReM)

Project type(s)

• Research Project

Abstract

This project aims to take advantage of epileptic encephalopathies (EE) as a genetic model to unravel and subsequently to functionally investigate uncharacterized proteins of the synaptic vesicle endocytosis pathway. So, the front-end of this project is a genetic discovery part in severe epilepsy patients to unravel mutations in proteins likely to be involved in synaptic vesicle endocytosis. The second and main part of this project is the in vivo characterisation of one of the already identified genes (DGKD) in transgenic fruit flies by using state-of-the-art complementary techniques, including electrophysiology, live imaging and electron microscopy. Not only will these findings be of importance for understanding the pathophysiology of EE, but they will also further unravel the cell biology of synaptic vesicle endocytosis; a crucial process in neuronal communication and brain homeostasis.

Researcher(s)

• Promoter: Suls Arvid

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

In this proposal I aim to take advantage of epileptic encephalopathies (EE) as a genetic model to unravel and subsequently to functionally investigate uncharacterized proteins of the synaptic vesicle endocytosis (SVE) pathway. Mutations in genes leading to the dysregulation of SVE were recently shown to cause EE. Via whole exome sequencing we identified variants of unknown significance in six genes likely to be involved in SVE based on indirect evidence (e.g. the protein product (1) contains domains known to be functional in SVE or (2) is involved in endocytosis, but the role in SVE is unknown). I will perform a mutation analysis of these genes in 500 EE patients by gene panel analysis, allowing me to identify mutations in multiple unrelated patients providing the necessary genetic evidence to determine causality. For causative genes identified by this approach, I hypothesize that the inappropriate neuronal firing/seizures may be due to abnormalities in the regulation of synaptic transmission. Furthermore, I will investigate the functionality of one of the already identified causative genes in vivo by creating transgenic fruit flies modelling genes deficiency using state-of-the-art methodologies and analyse these mutants using complementary techniques, including electrophysiology, live imaging and electron microscopy. Not only will these findings be of importance for understanding the pathophysiology of EE, but they will also further unravel the cell biology of SVE.

Researcher(s)

• Promoter: De Jonghe Peter
• Fellow: Suls Arvid

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

This project aims to unravel further aspects of the pathophysiology behind epilepsy by investigating another level of genetic complexity, namely epigenetics. Through this research we aim to identify the causal link between epimutations (methylation status) and epilepsy.

Researcher(s)

• Promoter: Suls Arvid

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

My research project plans to further dissect the genetic etiology of epilepsies via the analysis of consanguineous families, especially from Gypsy origin, as they have a unique genetic heritage. By applying complementary strategies (SNP genotyping, CNV analysis, and next-generation sequencing) major genetic factor(s) implicated in epilepsies in this population will be detected. Once identified, the search for additional pathogenic mutations in our extended collection of epilepsy patients will start (from different ethnicities and geographic backgrounds) and the functional consequences of the mutated genes will be studied, thus providing additional evidence for the causality of the observed mutations and their contribution to the pathophysiology of epilepsy. This knowledge could facilitate the development of novel/innovative treatments, improve diagnostics, genetic counseling and disease prevention."

Researcher(s)

• Promoter: De Jonghe Peter
• Fellow: Suls Arvid

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

Epilepsy is a clinically and genetically heterogeneous disorder affecting ~50 million patients worldwide. So far, more than 20 genes have been implicated in epilepsy pathogenesis as a result of almost exclusively linkage studies on familial epilepsies. A significant fraction of the known "epilepsy genes" are dosage sensitive and therefore haploinsufficiency of these genes is the most likely underlying pathomechanism of several epilepsy syndromes. Furthermore, increasing evidence shows that the nature of the mutation in some of these genes, either loss-of-function or gain-of-function, determines the severity of the epileptic phenotype. Still, mutations in these genes explain only a minor portion of all genetic forms and progress in gene discovery has been slow in recent years. Thus, the molecular genetics of epilepsies remains a major challenge, where innovative approaches and unexplored strategies should be sought to speed up gene identification. We plan to further dissect the genetic etiology of epilepsies by applying "copy number variation (CNV)" analysis to identify de novo submicroscopic variations encompassing dosage sensitive genes on a cohort of patients with severe complex phenotypes and epilepsy as the core feature. Once de novo CNVs are identified, the next goal is the identification of the culprit gene within these CNVs. For this goal we will perform mutation analyses of the positional candidate genes in an extended collection of epilepsy patients, hopefully identifying other pathogenic mutations, thus providing the additional evidence for the causality of the culprit gene. Finally, identifying mutations in similar or milder epileptic phenotypes will enable us to get a better understanding of the genotype-phenotype spectrum associated with these genes, leading to improved diagnostics, genetic counseling and possibly therapy.

Researcher(s)

• Promoter: Suls Arvid

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project