H2020Индивидуална стипендия2021–2023

PYRAMID · PYHIN-Regulated Memory T cell protection for Infectious Diseases

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-09-01 → 2023-08-31
Финансиране от ЕС: 184 591 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Протеините PYHIN в дендритните клетки се изследват за това как регулират имунния отговор при вирусни инфекции. Разбирането на този механизъм помага за създаването на по-ефективни ваксини, които да стимулират по-силен отговор от Т-клетките.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

PYHIN-Regulated Memory T cell protection for Infectious Diseases

PYHIN proteins play key roles in innate immunity as viral restriction factors, nucleic acid sensors and transcriptional regulators of cytokines and type I interferons (IFN-I). However, much of the work resolving these roles has been performed in cell lines or macrophages, while little is known about how PYHINs might influence adaptive immunity. Herein, we sought to better understand how PYHINs regulate innate immunity in dendritic cells (DCs), the primary antigen presenting cell, responsible for driving adaptive immunity. The type and magnitude of DCs response to noxious stimuli has a profound effect on the ensuing T cell response, both in terms of its quality and longevity. An inability to drive robust T cell responses is a limitation of many licensed vaccines, including current seasonal influenza vaccines, and underpins the attenuated protection they confer against divergent or newly emerging strains or variants. Thus, a better understanding as to how these responses are regulated will aide the rational design of next generation vaccines capable of inducing robust T cell responses. The overall objective of this project is to understand how PYHIN proteins contribute to innate immune responses in DCs, via three distinct work-packages: Characterise PYHIN expression in DC cell subsets before and after stimulation with known pathogen-associated molecular patterns (PAMPs). Determine whether altering PYHIN expression influences innate cytokine and IFN-I secretion from DCs following exposure to viral PAMPs. Assess the contribution of PYHINs to T cell responses in vivo. Major Conclusions: Type 1 and type 2 DCs exhibit different patterns of expression of PYHINs e.g Ifi205 almost exclusively expressed in DC1 at both the mRNA and protein level. Deletion of the entire murine PYHIN locus (or Aim2 alone) results in enhanced pro-inflammatory and IFN-I responses in response to transfected DNA, but not other stimuli including RNA or toll-like receptor (TLR) agonists. This enhanced responsiveness includes increased activation of several intracellular signalling pathways. The enhanced IFN-I response seen in Aim2-/- and ALR-/- DCs leads to enhanced antigen processing and up-regulation of co-stimulatory molecule expression. In vivo, treatment of tumour-bearing ALR-/- mice with a proprietary cationic polymer results in tumour eradication.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Pyrin and HIN domain (PYHIN) proteins play an integral role in the innate immune response to DNA and RNA viruses via direct detection of viral DNA and transcriptional regulation of pro-inflammatory and anti-viral cytokines respectively. Although expressed by various cells of the myeloid lineage, including some classical antigen presenting cells, the role of PYHINs in the context of T cell-mediated adaptive immunity has yet to be investigated. This project aims to elucidate how PYHIN proteins modulate acute and long-term CD8+ memory T cell responses to influenza A virus (IAV), a respiratory RNA virus which causes significant morbidity and mortality annually. Current seasonal IAV vaccines, exhibit variable efficacy and the neutralising antibodies they induce cannot protect against alternative IAV strains, particularly those with pandemic potential. In contrast, IAV-specific CD8+ memory T cells can elicit such cross-protective immunity by targeting conserved viral proteins, thus making the identification of mechanisms which give rise to these cells high priority in the search for a universal IAV vaccine. Herein, we will perform in-depth characterisation of PYHIN expression in human and murine dendritic cells. We will also perform genetic manipulation of PYHIN expression in primary immune cells to interrogate functionality and undertake infection studies in transgenic mice lacking certain PYHIN family members to determine their role in the formation of IAV-specific T cell memory in vivo. Overall, this project is extremely timely, providing crucial mechanistic insight which can inform rational vaccine design aimed at eliciting cross-protective T cell responses to respiratory RNA viruses.

Оригинален текст от CORDIS (на английски).

Участници

THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD, OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN · DublinКоординаторИрландия