Some viruses, such as the influenza virus, stimulate in the host the immediate production of antibodies and an effective immune response. As a consequence, in most cases, after an acute phase of the illness, these pathogens are definitively eradicated from the organism. However, the same does not happen with other viruses, such as HIV or HCV - responsible for AIDS and Hepatitis C, respectively - which often give rise to chronic viral diseases. Why?

A research paper just published in Nature Immunology by Matteo Iannacone and his colleagues, suggests that the answer has to be found in the release of type I interferons, a particular group of messenger molecules of the immune system. It is precisely the production of these molecules - which can be more or less timely, depending on the type of virus - that would direct the body's defense towards a sufficiently rapid production of antibodies (within the first 24 hours) or not. A gap that can make a huge difference in the body's ability to eradicate the pathogen. 

The discovery, made possible thanks to the use of advanced imaging technologies – that allow real-time observation of white blood cells – and transcriptomic analysis, paves the way to the development of new strategies to defeat chronic viral infections and increasingly effective vaccines.

 

Engineering viruses

"It has long been thought that the difference between viruses producing a fast and effective antibody response and those delaying or inhibiting it was due primarily to the proteins expressed by the viruses on their surface (antigens)," explains Mirela Kuka, who coordinated the study with Matteo Iannacone. "Considering that on the basis of these proteins the immune system recognizes the threat and gets activated, it was reasonable hypothesis. We now know it was only partially true”.

To understand what distinguishes viruses that produce a fast and effective antibody response from those that can delay it and often become chronic hosts, researchers have resorted to genetic engineering. The goal was to produce viruses that can give rise to the two different scenarios while having the same surface antigens.

A technological tour de force

Once these two viruses - only apparently similar - were obtained, researchers observed the result of their action in animal models of infection. To do so, they combined an imaging technique called intravital microscopy - which allows for the dynamical observation of the immune cells - with a genetic sequencing technique that allows researchers to identity the cells and to understand what is happening within them, at the molecular level. By integrating this information, scientists were able to trace, for the two different viruses, a detailed scenario of the spatial and temporal distribution of the immune response in the early stages of the infection.

 

The role of Type I Interferons

According to the results obtained, the antibody response depends on specific molecules, type I interferons, which seem to be able to direct the immune system towards the production of antibodies rather than the direct attack of pathogens by effector lymphocytes. In particular, in the case of the two viruses studied by the researchers, the production of Interferon Type I in a short time (within 24 hours of infection) - and therefore the effective antibody response – was linked to the aggressiveness of the virus, i.e. its ability to replicate quickly and damage cells and tissues.

"The fact that the dynamics of interferon type I production plays such a fundamental role in determining the type of immune response to a viral infection has important implications, both practical and theoretical", explains Matteo Iannacone. "It means we can think about modulating these molecules release to our advantage." In particular, intervening in the production of type I interferons could play a role in the production of increasingly effective vaccines.

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Marco De Giovanni, Valeria Cutillo, Amir Giladi, Eleonora Sala, Carmela G. Maganuco, Chiara Medaglia, Pietro Di Lucia, Elisa Bono, Claudia Cristofani, Eleonora Consolo, Leonardo Giustini, Alessandra Fiore, Sarah Eickhoff, Wolfgang Kastenmüller, Ido Amit, Mirela Kuka & Matteo Iannacone, Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4⁺ T cells, Nature Immunology, volume 21, 321–330(2020)