Periodic Reporting for period 1 - Tick ThaNK (Tick-borne encephalitis Targeted by Human Active NK cells)
Période du rapport: 2019-01-01 au 2020-12-31
The European TBEV causes a mortality rate of 1-2% and deaths occur in average one week after the onset of neurological signs and symptoms. The Far-Eastern TBEV strain is more severe, and the mortality rate rises up to 5-20%.TBE may cause a long recovery period, leaving long-term or even permanent neurologic sequelae in 30 to 60% of patients with the disease.
TBE is a disease occurring in different areas within Europe and Asia and is transmitted by the bite of an infected tick. The incubation period takes in average seven days after the bite of an infected tick. Most of the TBEV infections are asymptomatic, however those who develop symptoms show a clinical debut with a biphasic pattern. Unspecific symptoms such as fever, headache, myalgia and nausea appear during the first phase that lasts from 2-10 days. An asymptomatic period follows and subsequently, a second phase with neurological involvement occurs producing meningitis, encephalitis or meningoencephalitis. Since there is no cure or specific treatment for TBE, hospitalization, supportive care, use of anti-inflammatory drugs such as corticosteroids, intubation and/or ventilator support may be considered based on disease severity.
NK cells constitute a first line of defense against viral infections and tumors. According to the expression of the CD56 molecule on their surface, NK cells are classified into two main subsets, both with specific functions and locations within the body. The CD56dim NK cell population is predominant in peripheral blood and has a cytotoxic function, whereas the CD56bright immunoregulatory subset is mainly found in peripheral and lymphoid tissues.
Recently, the field of tissue resident NK cells (trNK) in solid organs and their function in tissue development and remodeling have gained increasing interest. However, in the brain tissue, knowledge has been limited with respect to the existence of tissue resident lymphocytic populations including NK cells. Conventionally, the CNS was known as an immune privileged site with low penetrability of immune cells. However, recent studies have demonstrated the existence of an important inflammatory response to infection in the CNS. Studies of NK cell recruitment into the brain in pathological conditions such as multiple sclerosis and viral encephalitis have led to important but limited information to understand the role of NK cells in such compartment. The aim of the Tick ThaNK project is to generate knowledge that will provide new insights into innate immunity responses executed by NK cells that could lead to novel strategies to improve treatments for infectious diseases.
Here, we report that among the lymphocytic cell population, the CD56bright, a subset of NK cells, possess a high migratory capability in the presence of brain endothelial cells and the expression of cell adhesion molecules such as CD11a, CD11b and CD29 are important in the total lymphocytic migration process. The cells with higher migratory capability also seem to possess a higher cytotoxic capability as determined by the high specific target cell lysis and the association with a higher activation status determined by high expression of CD69, Granzyme A, Granzyme B and perforin.
About the study of patient samples with TBE, we are still acquiring and processing data. However, we have observed that the CD56bright NK cell population is highly increased in the CFS of TBE patients in comparison to peripheral blood, and the cells also seem to have a similar pattern of activation. Our results in vitro partially resemble the observations we have obtained in vivo and thus, the collection of more TBE patients is crucial to complete a broad picture of the immunological features during a viral infection in CNS. Furthermore, our current studies on the effect of neurotropic viruses on the BBB integrity and on immune cell activation will help us understand more the interplay between different immune components in mounting an immune response towards a viral infection in the CNS. Altogether, we have acquired insights on the migratory capabilities of different cell populations, which may add value in understanding the complex immune mobilization process between blood and tissues taking place to keep a homeostatic balance.