H2020Индивидуална стипендия2022–2024

FEBRIS · In vitro brain microvascular model to tackle fever in cerebral malaria

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

Период: 2022-09-01 → 2024-08-31
Финансиране от ЕС: 172 932 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Биоинженерен 3D модел на човешки мозъчни микросъдове се използва за проучване на церебралната малария и запушването на кръвоносните пътища в мозъка. Това помага да се разбере развитието на заболяването, тъй като живият човешки мозък е недостъпен за наблюдение по време на инфекция.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

In vitro brain microvascular model to tackle fever in cerebral malaria

Malaria remains a significant global health challenge and economic burden in 85 countries, with Africa bearing the heaviest impact. In 2022, there were 249 million new cases and 608,000 deaths reported worldwide. Infection is primarily caused by Plasmodium falciparum, which accounts for over 90% of cases and deaths, particularly affecting children under five. These children are especially vulnerable to cerebral malaria, one of the most fatal outcomes of P. falciparum infection. Currently, no vaccine or treatment specifically targets this condition, highlighting the urgent need for innovative tools and interventions. Cerebral malaria (CM) is characterised by the accumulation of malaria-infected red blood cells in the brain vasculature which lead to vascular blockage, blood flow impairment, brain-blood-barrier inflammation and disfunction leading to brain haemorrhages and swelling. A major challenge in studying cerebral malaria (CM) is the brain's inaccessibility during active infection. Current knowledge is based largely on autopsies, which do not reflect disease onset or progression. This gap highlights the need for models that capture the complex pathogenesis of CM. Existing in vitro models, such as 2D cultures and flow chambers, lack flow or fail to replicate the vascular tree's multicellular complexity. While brain organoids are promising as 3D models, their heterogeneous architectures and lack of perfusable vasculature limit their use. Furthermore, animal models show minimal intracerebral accumulation, a key feature of human malaria infection. To overcome these limitations, during my Marie Skłodowska-Curie postdoctoral fellowship in the Bernabeu Lab at EMBL Barcelona, I developed a bioengineered 3D model of human brain microvessels to study the pathogenesis of cerebral malaria (CM). I investigated the binding mechanism between malaria-infected red blood cells and endothelial proteins in the brain microvessels. Specifically, I: 1. Identified antibodies from individuals exposed to malaria that inhibit a specific parasite-host interaction, representing a common mechanism of acquired immunity to CM. 2. Demonstrated that febrile temperatures during malaria infection increase parasite accumulation in the brain microvessels. 3. Designed and fabricated prototypes of a 3D in vitro microvasculatures, serving as preliminary models for developing brain-region-specific microvasculature chips for white matter, grey matter, and the basal ganglia.

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

Цел на проекта

Malaria still claims more than 400,000 deaths every year, above all in children under 5. All symptoms are caused by the blood stage of the deadliest parasite species Plasmodium falciparum (Pf), which infects human red blood cells. Cerebral malaria (CM) is the most severe complication, with 20% mortality rate even after administration of fast-acting antimalarials, and is due to build-up of parasites in the brain microvasculature leading to vessel occlusion, blood-brain-barrier disruption, and brain swelling. Current knowledge of CM is based primarily on autopsy analysis, because of limitations of suitable animal models, where disease onset and progression cannot be studied. Additionally, different areas of the brain with distinctive vascular patterns show CM-specific lesions supporting the hypothesis of different regional microcirculations. In my project FEBRIS I will tackle, for the first time, human CM process in vitro models of white and grey matter, and basal ganglia, with cutting-edge bioengineering approaches. I will develop 3D microfluidic devices coated with endothelial cells mimicking vessel networks and physiological flow rates of these three regions of the brain. Numerical simulations will identify critical factors causing blood stagnation, predicting where and when a clog could form. Using this technology brings a unique angle to malaria research to systematically evaluate the unexplored effect of fever on molecular and biophysical mechanisms of Pf sequestration, and the concurrent vascular damage. The obtained findings will be validated with parasites from the field and brain samples from CM patients, examined with pioneer 3D autopsy imaging. This interdisciplinary approach, favoured by my host, aims to provide a holistic understanding of CM pathogenesis. The acquired knowledge could lead to new therapies to reduce fatality by malaria disease and, in a broader context, this innovative platform could be employed to study other neurovascular diseases.

Оригинален текст от CORDIS (на английски).

Участници

EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergКоординаторГермания