Autoantibodies against interferons, or why certain viruses affect us differently

In their publication in Journal of Experimental Medicine, 3 researchers from the "Human Genetics of Infectious Diseases" team at Institut Imagine (Inserm, AP-HP, Université Paris Cité) have shown that the development of encephalitis following infection with the West Nile virus can be explained in around 40% of patients by the presence of autoantibodies against type I interferons, directed against the immune system's own defences.

Published on 26.07.2023

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Over the last few years, Jean-Laurent Casanova's team at Institut Imagine and Rockfeller University has been working to understand why we have different responses and symptoms to SARS-CoV-2 (the cause of COVID-19) and the influenza virus. What these two diseases have in common is that they are triggered by a viral infection, which causes fever and pneumonia of varying degrees of severity in infected patients.

As the COVID-19 pandemic illustrated, some people will be completely symptom-free, while others will develop a fever and/or pneumonia requiring hospitalisation. In 15% of severe cases of COVID-19, and in 5% of severe influenza cases, the team has shown the presence of highly specific antibodies, known as 'autoantibodies', capable of neutralising the body's immune response to the virus. These autoantibodies bind to type I interferon (IFN-I), a molecule produced by the human body to activate the antiviral immune response, thereby neutralising its action. As a result, the level of the immune response is reduced, allowing the viral infection to progress.

In one of their latest publications, the team looked at another viral infection caused by West Nile Virus (WNV), which is transmitted by mosquitoes. The majority of infected individuals develop no or very few symptoms, and less than 1% of those infected will develop a severe form requiring hospitalisation. In collaboration with Alessandro Borghesi's team at the San Mateo Research Hospital in Pavia, Jean-Laurent Casanova's team studied patients from the European Union and the United States. They showed that interferon-neutralising autoantibodies were detected in around 35% of patients hospitalised with severe forms of the disease. Even more strikingly, in patients suffering from encephalitis (an inflammation of the brain directly linked to viral infection), the most severe form of West Nile infection, autoantibodies were detected even more frequently: they were found in 40% of these patients. These autoantibodies have even been identified in the cerebrospinal fluid of a majority of encephalitis patients, suggesting their involvement in the neurological damage caused by the disease. Conversely, individuals who are asymptomatic for this infection have extremely low levels of autoantibodies, comparable to those found in the general population.

These discoveries have major implications in terms of public health. As the West Nile virus is present in almost every country in the world, and more particularly in certain areas such as certain African countries and Italy, it could be envisaged to preventively test people travelling to a particularly high-risk area, especially if they have risk factors associated with the presence of autoantibodies (for example, the elderly or people suffering from an autoimmune disease). In addition, the introduction of curative treatments, in particular with an interferon that is not neutralised or only weakly neutralised by autoantibodies, has already shown its benefits in severe forms of COVID-19 and could be used for patients infected with the West Nile virus.

The causes leading to the appearance of these autoantibodies are not yet well known. Furthermore, the presence of autoantibodies increases the risk of a severe response to a viral infection when faced with several types of virus. It is possible that this mechanism can be observed for many other viral infections, in particular severe infections by at least a hundred other Arboviruses, a family of emerging viruses to which West Nile virus belongs and which are already found throughout the world. All these questions remain to be explored by the research teams.