Published on 27.01.2020
The innate (or non-specific) response is our body's first line of defense against bacterial, viral or other forms of attack. It is rapidly deployed, unlike adaptive immunity, which takes longer to set up, but is targeted at an intruder.
The ability of the host, in this case the attacked cell, to rapidly modify the expression of its genes to trigger a reaction is a crucial element of its effectiveness," explains Mickaël Ménager, research fellow at INSERM and Atip-Avenir director of the "Inflammatory Responses and Transcriptomic Networks" laboratory at the Institut Imagine. As soon as a pathogen is detected by the cell, a whole series of reactions follows, leading to the production of certain genes essential to the immune
It is an extremely fine mechanism whose slightest deregulation can have unfortunate consequences. Moreover, defects in the innate immune response are found in many diseases such as chronic viral infections, neurodegenerative diseases, diabetes and cancer. In the case of HIV-1 infection, the most frequent form of HIV in France, this first line of defense of the immune system is largely insufficient to ensure the protection of the host and even deteriorates as AIDS progresses.
Why doesn't the innate response kick in?
To answer this question, Mickaël Ménager and his team, assisted by numerous collaborators in France and the United States, have developed an approach that combines experiments and computational biology to map the innate response to HIV-1 infection in dendritic cells. Indeed, these cells, often compared to sentinels, explore our body in search of intruders. They then sound the alarm, especially to T cells, to start the hostilities against these intruders. By forcing HIV-1 to infect these dendritic cells, we have uncovered a network of 542 genes that can activate 21,862 other genes," explains the immunologist. With this mapping, the researchers have highlighted pathways whose activation could improve the "warning" capacities of dendritic cells.
These interaction networks thus provide a new vision of the very complex universe of the immune system. They also open new avenues for effective dendritic cell activation pathways in order to develop new therapeutic strategies.
A discovery that has an impact on genetic diseases
It is thought that the AIDS virus has evolved not to infect dendritic cells, in order not to be detected," says Mickaël Ménager. When HIV is forced (as in the Cell Reports paper) to infect dendritic cells, the latter, equipped to recognize it, sound the alarm in the form of an inflammatory molecule called type-I interferon (IFN-I).
However, it has already been shown at Institut Imagine that, on the contrary, some patients produce excessively, uncontrollably and in the absence of viral infection, this inflammatory molecule which then has very deleterious effects on their organism. The map produced by Mickaël Ménager's team potentially highlights new regulatory pathways for the production of this inflammatory molecule. It thus opens up new avenues of research for the various genetic diseases associated with uncontrolled production of interferon.
These first results from Michael Ménager's young team indicate the potential of these innovative approaches combining experimentation and computational biology to advance research on diseases, and particularly on genetic diseases.