Intraepithelial T lymphocytes (IEL) are at the forefront of mucosal immunity - the first immune cells that pathogens encounter in the gut. IEL are central to the protection of the gut against infection and dietary stress, but dysregulated IEL responses are also associated with autoimmune inflammatory bowel diseases such as Coeliac and Crohn’s disease. Importantly, these specialised T cells reside between nutrient-absorptive intestinal epithelial cells, close to the anaerobic microbes in the intestinal lumen.
Reversible protein phosphorylation, catalysed by protein kinases and phosphatases, is a fundamental regulatory mechanism of numerous cellular processes. Post-translational modification of proteins with phosphate residues can alter their cellular fates, such as modulating their activity or changing their subcellular distribution. Protein kinases add phosphate residues primarily on serine, threonine and tyrosine residues of target proteins, whilst phosphatases remove them. Yet kinases outnumber phosphatases by approximately ten to one.
Our chromosomes are frequently subjected to insults that damage DNA, and if not rectified the resulting DNA lesions can cause genome mutations and human disease. Mutations in the major DNA repair pathways – such as homologous recombination (HR) – cause heightened susceptibility to a range of human cancers. These HR-defective cancers become highly dependent on minor, accessory DNA repair pathways that are not required in normal tissues, an example of what is often referred to as “synthetic lethality”.
Diarrheal diseases cause about 10% of deaths of children under the age of 5. Recently, it was revealed that cryptosporidiosis is the second leading cause of this severe diarrhea disease. Unfortunately, there is no vaccine and no effective treatments are available. In the Pawlowic lab, we use genetic tools to better understand the basic biology of this overlooked protozoan parasite. Specifically, we are interested in the Cryptosporidium oocyst. The oocyst is the life cycle stage that is transmitted through the faecal-oral route via contaminated water or food.
A central tenet of cancer immunotherapy is that the immune system actively recognizes and eliminates malignant cells (1). However, tumours develop mechanisms to evade the immune response, which hinder the efficacy of cancer immunotherapies. One such evasion mechanism is the generation of a highly acidic tumour microenvironment (TME), which contributes to blunt the effectiveness of antitumor immunity (2).
Eukaryotic cells make a single copy of their chromosomes in every cell cycle, using a large molecular machine known as the replisome. To preserve genome integrity, chromosome replication must normally be completed before sister chromatids are segregated during mitosis. However, in eukaryotic species with large genomes, it is hard to ensure that replication is always finished before mitosis has begun.
The Kulathu lab is interested in understanding the molecular mechanisms by which posttranslational modifications mediate signal transduction. The innate immune response is the first line of defence against bacteria, viruses and parasites. When innate immune receptors are triggered they lead to the formation of a large oligomeric signalling complex called the Myddosome. Within the Myddosome, the IRAK kinases are activated to trigger a signalling cascade that culminates in the expression and secretion of cytokines that shape the immune response to invading pathogens.