Senescent CD8+ T and NK cells contribute to immunopathogy duting cutaneous leishmaniasis
Description: Parasites belonging to the genus Leishmania are among the most diverse of human pathogens, both in terms of geographical distribution and in the variety of clinical syndromes caused by them. Currently, 12 million people are infected worldwide in 88 tropical/subtropical countries, 2 million new infections are reported annually, and 350 million people are under infection risk. In the past decade, the number of cases in endemic areas has increased sharply. In addition, leishmaniasis is spreading to several non-endemic areas of the world due to coinfections with HIV. Control measures currently available are case detection and treatment with drugs, which are expensive, not always available and cannot be self-administered. The problem is further aggravated by the surge of drug resistance parasites necessitating the development of an anti-Leishmania vaccine or other immunological therapies urgent.
Research has demonstrated the importance of the immunity in controlling both cutaneous and mucocutaneous leishmaniasis, however the severe skin lesions that develop at the infected site is largely due to non-specific tissue damage but the reasons for this are unclear. The majority of this work has been performed on blood samples taken from patients and not from the site of infection at the skin. In this context, a unique feature of the current proposal is that we will be investigating the blood as well as the skin from the same patients, taken from both lesional and non-lesional sites.
The main hypothesis of this grant application is that the severity of cutaneous immunopathology in infected individuals is due to non-specific damage mediated by both two types of immune cell namely the natural killer (NK) cells and a type of T cell that represent the "Dad's Army" of the immune system. Both these cell types are probably not triggered by the parasite in the skin lesions, instead they recognize decoy molecules in non-infected skin cells that cause them to be destroyed. This results in the large skin lesions that contain few parasites but huge numbers of dangerous white cells.
In this study we will investigate the nature of the white cells in the skin lesions of patients. We will identify the decoy receptors that promote the non-specific tissue damage. We will also look at the wide array of genes that are activated in the skin to identify clue of how the interactions between the immune system and the skin are organized. We will also identify genes that will give us clues as to what other processes may be occurring that do not allow the lesions to resolve. In other parts of the study we will mimic the interaction of cell that are in the skin by growing them in a test tube to probe their interactions and find a way to block them. Finally we will investigate the involvement of a set off molecules known as sestrins, that we previously showed were involved in setting up the decoy mechanisms that may lead to skin lesion formation in patients with cutaneous leishmaniasis.
As added value to this proposal, The Federal University of Espirito Santo will contribute 1 Technician and 1 PhD student to work on aspects of this grant.
Funder: Medical Research Council
Amount: £732,300
Funding type: research
Start date: 2020-06-30
End date: 2024-02-28
Funded outputs count: 12
Funder award ID: MR/T015853/1
OpenAlex ID: G4993375408