H2020Индивидуална стипендия2018–2020

MISTRO · Identification of the cellular sites of cytomegalovirus latency that contribute to the induction of inflationary CD8 T cell memory against the virus.

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

Период: 2018-04-01 → 2020-03-31
Финансиране от ЕС: 159 461 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Цитомегаловирусът се проучва в специфични клетки, като например стромалните клетки в далака, където вирусът остава в спящо състояние. Това помага за разбирането на имунната памет и разработването на по-ефективни стратегии за ваксинация.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Identification of the cellular sites of cytomegalovirus latency that contribute to the induction of inflationary CD8 T cell memory against the virus.

Cytomegalovirus (CMV), a β-herpes virus, is an opportunistic pathogen that chronically infects the majority of human population. The virus poses a significant health risk for neonates and immune-compromised individuals. Similar to other herpesviruses, CMV persists in host's cells in a state of latency, from which it reactivates in association with immune suppression. Molecular pathways regulating the state of latency remain ill defined, at least partially due to incomplete characterization of the non-hematopoietic cell types latently infected by CMV in vivo. A further rationale for better understanding of the non-hematopoietic cellular targets of CMV latency is the development of improved vaccination strategies. Accordingly, CMV and CMV-based vaccine vectors elicit robust and durable populations of inflationary memory CD8+ T cells, which confer strong protective immunity, but whose translational application suffers from the lack of insight about the identity of latently infected non-hematopoietic types that promote their generation. This project aimed to: (Work Package 1, WP1) identify and characterize the non-hematopoietic cell types that are latently infected with CMV in vivo; (Work Package 2, WP2) assess the role of such latently infected subsets in driving CMV-specific inflationary memory CD8+ T-cells. During my fellowship, I completed all main project tasks and reached milestones ascribed to each WP. In the frame of WP1, I identified PDGFR+ mesenchymal stromal cells as a novel site of CMV latency in lymphoid tissues. I further characterized the distribution of latent CMV genomes in this cell compartment with unprecedented depth, which revealed that Tcf21+ stromal cells of the splenic red pulp are the most abundant source of latent CMV in lymphoid tissues. In the frame of WP2, I developed a novel genetic tool to ablate viral antigen processing in latently infected cells to study their role in memory inflation. Using this model, I demonstrated that (1) memory inflation of CMV-specific CD8+ T cells is dependent on viral antigen processing by latently infected stromal cells; (2) Tcf21+ stromal cells of the splenic red pulp, despite showing the highest latent virus load, are dispensable for the generation of memory inflation.

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

Цел на проекта

T cell memory is the cornerstone of protective immunity and the key determinant of the efficacy of vaccination approaches. Memory inflation (MI) is a unique type of CD8+ T cell memory characterized by the induction of robust and durable populations of functional effector/effector memory CD8+ T cells that is elicited by latently persistent cytomegalovirus (CMV) infections. Accumulating evidence argues that inflationary T cells can provide exceptionally strong immune protection. Hence, several translational approaches involving MI, such as CMV vector-based vaccines, are subject of ongoing pre-clinical and clinical projects. Despite this, little is known about the cellular and molecular mechanisms governing the induction and maintenance of MI. In this proposal, I aim to identify and characterize the latently infected cell type/-s, which sustain CMV-specific inflationary CD8+ T-cells. To this end, I will combine state-of-the-art stromal cell characterization and isolation techniques with generation of novel recombinant virus-based in vivo models enabling (1) tracking of latently infected cells, (2) conditional ablation of viral peptide processing in selected cell types. The results of this action are expected to improve our understanding of the mechanisms and requirements for MI, laying the basis for the development of improved vaccination strategies. Furthermore, identification of the sites of CMV latency in vivo will have implications for development of future clinical strategies aimed at harnessing the ability of CMV to reactivate in immune suppressed patients. Thus, this proposal explores a basic biological question of broad general interest, but also has robust translational potential for applications in human medicine.

Оригинален текст от CORDIS (на английски).

Участници

HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH · BraunschweigКоординаторГермания