Two - faced interferon
Scientists at the Scripps Research Institute have made an unexpected discovery that may form the basis of new methods of combating chronic infectious processes of a viral nature characteristic of diseases such as AIDS, as well as hepatitis B and C.
The authors, working under the guidance of Professor Michael B. A. Oldstone, are studying the activity of proteins related to type I interferons. Until now, it has been assumed that these proteins, discovered more than 50 years ago, are powerful antiviral agents that control the development of an immune response. However, the results showed that type I interferons in mice initiate the chronization of infectious processes and limit the development of an effective antiviral immune response.
For several decades, virologists around the world have been trying to understand the mechanisms by which some viruses manage to remain in the human body in the form of a chronic (persistent) infection. One of the recent important findings in this field is the identification of the ability of such viruses to penetrate into dendritic cells. The main function of these cells of the immune system is that they act as detectors of infection entering the body and usually react to the detected enemy by releasing type I interferons and other cytokines that trigger the immune response. In parallel, dendritic cells release proteins, such as those with immunosuppressive properties and necessary to maintain the activity of the immune response at an acceptable level of interleukin-10 and PD-L1 – Programmed Death Ligand-1, the ligand of the programmed cell death protein-1 (ligand is a molecule that binds and disrupts the protein).
Viruses prone to chronization can use this immunosuppressive effect for their own purposes. In some experimental models of persistent infections, as well as in patients with such infections, it was shown that an increase in the synthesis of interleukin-10 and PD-L1 is followed by a decrease in the number and activity of T-lymphocytes selectively affecting viruses. At the same time, many of the remaining cells lose their effectiveness. The latter phenomenon is known as depletion, or low reactivity of T cells.
To understand in detail the mechanisms of this immunosuppressive reaction, the authors used a standard animal model developed by Oldstone almost 30 years ago – a line of laboratory mice infected with lymphocytic choriomeningitis virus.
One of the first observations surprised them: a day after infection, the levels of type I interferons in the blood of animals with persistent infection were at least several times higher than the levels of type I interferons in the blood of animals with non-persistent infection.
It turned out that during infection in mice of a line prone to chronic lymphocytic choriomeningitis virus, there was a significantly more active penetration of viral particles into the so-called plasmacytoid dendritic cells, which are considered the main source of type I interferons in viral infections. On the contrary, significantly fewer type I interferons were synthesized in the body of animals of the line that were not subject to virus chronization, but there was an active formation of effector CD8 T lymphocytes with antiviral activity. As a result, the infection was suppressed for 7-10 days.
The production of type I interferons by plasmacytoid dendritic cells has traditionally been considered an important component of the immune response to viral pathogens. In other words, it was assumed that the more interferons are synthesized in the body, the better. However, experiments have shown that the result of blocking type I interferon receptors with monoclonal antibodies, leading to a sharp decrease in the synthesis of immunosuppressive cytokines (interleukin-10 and PD-L1), was an increase in the number of viral particles circulating in the bloodstream in the first days after infection, followed by strengthening of the antiviral immune response and getting rid of the virus. Moreover, blocking these receptors even after the infection was chronicled significantly increased the animals' chances of recovery.
The authors plan to continue their work on the study of immune mechanisms mediated by type I interferons. The main purpose of the work is to clarify the possibility of using the strategy of blocking interferon receptors for the treatment of chronic infections in humans. The researchers also hope to find small molecules with the same pharmacological activity.
Article by J. R. Teijaro et al. Persistent LCMV Infection Is Controlled by Blockade of Type I Interferon Signaling published in the journal Science.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Scripps Research Institute:
Scripps Research Institute Scientists Find Interferon, One of the Body’s Own Proteins, Induces Persistent Viral Infection.
16.04.2013