Covid-19: Intracellular observation of reconstituted human respiratory epithelium MucilAir™ infected with SARS-CoV-2. © Manuel Rosa-Calatrava, Inserm; Olivier Terrier, CNRS; Andrés Pizzorno, Signia Therapeutics; Elisabeth Errazuriz-Cerda UCBL1 CIQLE. VirPath (International Research Center in Infectiology U1111 Inserm – UMR 5308 CNRS – ENS Lyon – UCBL1). Colorized by Noa Rosa C.

Several months after SARS-CoV-2 infection, some patients continue to have symptoms. This phenomenon, known as “post-COVID condition” or, more commonly, “long COVID”, remains poorly documented. In order to address this and improve patient care, research teams are trying to improve their understanding of the underlying biological and immunological mechanisms. In a new study, scientists from Inserm and Université de Montpellier at the Montpellier Cancer Research Institute, in collaboration with Montpellier University Hospital[1], have highlighted the possible role of the dysregulation of a part of the innate immune defense. They suggest that the production of “extracellular neutrophil traps”, a first-line defense mechanism against pathogens, could play a role in the persistence of symptoms six months later in patients having developed a severe form of COVID-19. Their findings have been published in the Journal of Medical Virology.

Neutrophils are the most abundant class of white blood cells and the first line of defense against viruses and bacteria. When activated, they are capable of producing a specific defense mechanism known as “neutrophil extracellular traps” (NETs). Made up of DNA fibers, bactericidal enzymes and pro-inflammatory molecules, NETs contribute to fighting pathogens, but in some cases can also trigger excessive inflammation that is harmful to the body.

In previous studies, Inserm researcher Alain Thierry’s team at the Montpellier Cancer Research Institute had shown that part of the innate immune response is dysregulated in patients with severe forms of COVID-19. In these patients, the formation of NETs is amplified, resulting in multi-organ damage.

In their new study, the scientists wanted to go further in studying the biomarkers characteristic of COVID-19. To do this they analyzed the biological samples of over 155 patients. These were individuals with COVID-19 in the acute non-severe (hospitalized) or severe (intensive care) phases, or who had a post-acute infection assessment more than six months after their discharge from critical care. These samples were compared with those of 122 healthy individuals.

NETS and auto-antibodies persisting in the body

The analyses performed in this study confirm that NET production is higher in SARS-CoV-2 patients than in healthy individuals. In addition, the patients have higher levels of auto‑antibodies known as “anticardiolipin auto-antibodies”. Produced by the immune system, these auto‑antibodies are often associated with the abnormal formation of clots in the veins (phlebitis) and in the arteries (arterial thrombosis).

Furthermore, the data collected by the research team also suggest that this dysregulated immune response is maintained in people who present symptoms of long COVID, six months after being hospitalized for a serious form of the disease. The amplified and uncontrolled production of NETs six months after infection as well as the persistent presence of auto‑antibodies could partly explain the symptoms of long COVID, notably via the formation of microthromboses.

“Our findings could indicate the persistence of a sustained imbalance of the innate immune response, and potential prolonged pro-thrombotic activity that could explain the sequelae of post-acute infection or ‘long COVID’. It is necessary to continue the research in order to both confirm this and better understand the nature of this phenomenon, which could be serious and long-lasting, to improve patient care,” concludes Thierry.

Research is already underway in some laboratories around the world to consolidate this data and explore other avenues of interest, with the aim of gaining a better understanding of the long COVID phenomenon in all its complexity. Thierry’s team had also filed an international patent application in August 2022.

[1] The research was partially funded by SIRIC Montpellier Cancer.

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