Responsible for an average of 500,000 hemorrhagic cases per year, dengue virus threatens more than two and a half billion people worldwide each year. A Study about it, carried out by the Institut Pasteur du Cambodge jointly with the Institut Pasteur and The Rockefeller University, is the subject of a publication in the journal Science. The researchers reveal that absence of a specific sugar, constitutive of the structure of anti-dengue antibodies, fucose, is responsible for these serious forms of the disease.
Antibodies, molecules that recognize pathogens or antigens, usually perform a protective function of the individuals even after infections. However, they can sometimes cause overreactions of the immune system as is the case in dengue hemorrhagic fever. This disease is caused by the dengue virus, or DENV, which is transmitted to humans by mosquitoes of the genus Aedes. Dengue manifests itself, in its classic form, by nonspecific symptoms including fever, nausea and skin rashes. The most severe form, dengue hemorrhagic fever, on the other hand, can lead to hypovolemic shock which can result in death, especially among young children under 15.
These hemorrhagic complications are particularly occurents in people who have already been infected with DENV during their lifetime and therefore already have antibodies directed against dengue virus. Thus, researchers from the Institut Pasteur du Cambodge, the Institut Pasteur (Paris) and The Rockefeller University set out test to understand which are the features of the anti-dengue antibodies that can exacerbate the symptoms of the disease rather than contain the infection.
To do this, they studied the composition of these antibodies directed against DENV. An antibody is divided into two parts, a constant part called Fc and a variable part, Fab. While the variable part allows the recognition of the different antigens that infect the body, the constant part allows the antibody to bind to other actors of the immune system such as leukocytes or white blood cells. The study was particularly interested in the constant part, Fc. In some anti-DENV antibodies, the structure of Fc is altered by the lack of one of the glycans or molecule of sugar: the fucose. The teams found that this deletion causes too strong binding of anti-DENV antibodies with white blood cells, leading to over-activating the immune system. This results in inflammation as well as destruction of the blood platelets necessary to stem the bleeding typical of the severe form of dengue. Performing at hospital admission, these tests show the link between the lack of fucose and the severe form of the disease. Moreover, as individuals that have a lower amount of these antibodies have no or very little symptoms after infection, it shows that the lack of this fucose is associated to the outcome of infection.
By analyzing plasma samples from people before and after DENV infection, antibody levels without a fucose were found to be higher in patients after infection and during recovery. The study therefore concludes that the detection of fucose-free anti-DENV antibodies in the blood of patients at hospitalization represents a robust indicator for predicting hemorrhagic forms of dengue. An unprecedented tool that could promote early management of potentially fatal cases.
Antibody fucosylation predicts disease severity in secondary dengue infection
Authors: Stylianos Bournazos, Hoa Thi My Vo, Veasna Duong, Heidi Auerswald, Sowath Ly, Anavaj Sakuntabhai, Philippe Dussart, Tineke Cantaert, Jeffrey V. Ravetch