Functional characterization of the role of transcription factors IRF1 and IRF8 in inflammation in the context of cerebral malaria and Leishmaniasis

Inflammation is a key part of our body’s defense mechanisms, responsible for activating the immune system against perceived external threats, such as infections. However, when the inflammation process is unregulated, it can either overreact to a stimulus or misperceive something harmless as a threat. In this case, the inflammation becomes problematic and excessive, leading to consequences such as edema, fibrosis or shutdown of the affected organs. Inflammation therefore moves from the status of a necessary moderator to that of the very cause of the disease. Autoimmune diseases result from an attack on the body by its own cells, such as Crohn’s disease and rheumatoid arthritis. Another type is the disproportionate reaction to a pathogen, such as the Covid-19 virus or the malaria parasite. These diseases have one important thing in common: limited or expensive treatment options, leading to chronic conditions, poor quality of life and many deaths. Inflammatory diseases therefore pose a heavy socio-economic burden on large affected populations.

This project will focus on malaria and leishmaniasis, two high-morbidity diseases that contribute to the cycle of poverty in vulnerable populations. These tropical parasitic diseases present dysregulated immune processes. Neuromalaria is the most serious complication of malaria, responsible for more than 750,000 deaths per year, 70% of them children, and a third of survivors suffering from the effects of brain damage. This makes it one of the deadliest diseases worldwide when counting the total number of years of life lost. It is estimated that leishmaniasis causes one million new cases per year. The incidence is linked to poverty, poor sanitary conditions and malnutrition. Untreated visceral leishmaniasis is fatal in more than 95% of cases, and cutaneous leishmaniasis can result in lifelong stigmatization due to scarring left by the parasite. The WHO has classified it among the most dangerous parasites in terms of epidemic potential and mortality. These diseases cause significant intergenerational socio-economic burdens contributing to extreme poverty in the regions where they are endemic. Neither disease has a treatment to reverse immune dysregulation; the only treatment options are antiparasitic drugs, to which parasites quickly develop resistance. The incidence of these diseases and affected populations are at risk of rapid increase due to climate change, increased population mobility and the development of resistance to antiparasitic drugs. The studies on this immune dysregulation will allow the identification of key disturbances which could become the targets of new treatments, which will have the potential to improve the survival of a large population.

Project details

Basic Science

Apr 2023 — Mar 2027

$49,303

Canada