Work, carried out on respiratory mucosa reconstituted in the laboratory, has made it possible to study the dynamics of infection by SARS-CoV-2 in children and adults, as well as the associated immune responses. A difference in the rate of release of a mediator of antiviral innate immunity, interferon III, could explain the lesser severity of Covid-19 in the youngest.
From the start of the pandemic, it appeared that Covid-19 was more severe in adults than in children, without any obvious explanation being put forward. Also, three teams of researchers came together from the first confinement to look into this question. ” SARS-CoV-2 infections begin in the upper airways (nose, throat, etc.). Severe forms occur after dissemination of the virus in the lower airways (in the lungs)explains Harald Wodrich, one of the scientists who participated in this work. We therefore assumed that distinct phenomena occur early in the adult and in the child. By combining their expertise in virology, imaging and pulmonology, these scientists were able to identify several pediatric particularities.
To study the dynamics of infection and immune response From the first days after contact with the virus, the researchers used samples of respiratory epithelia (the mucous membranes covering the surface of the airways) taken from adults or children. They used these samples to reconstruct epithelia functional, placed in supports which make it possible to mimic physiological conditions, at the interface of a culture medium (liquid) and the outside air. These epithelia were then infected with SARS-CoV‑2.
« In adults, we observed faster cell infection kinetics than in children. More importantly, we noted that after 3-4 days, cells that line the outer face of the epithelium (epithelial cells) fuse with deeper cells (basal cells) to form large clumps that contain many copies of the virus. These clusters, called “syncytia”, are able to break away fromepithelium. Ils can then migrate into the lower airways. However, their presence has also been described in the lungs of patients who died of Covid-19.. This compact release of the virus could therefore contribute to the severity of the disease. “, explains the researcher.
A key role of interferon III
At the same time, the scientists observed that certain epithelia obtained from samples taken from children are more resistant to infection, with an attenuated inflammatory response and faster interferon III (IFN-III) secretion than in adults. Syncytia formation also seemed less frequent, probably due to the slower time to infection. To better understand the role of IFN-III in the response to infection, the researchers conducted another series of experiments: We found that delivering this interferon to an adult epithelium reduces viral replication and that, conversely, deleting the gene encoding IFN-III promotes virus progression and syncytia formation. All of these observations could explain the age-related differences in susceptibility to SARS-CoV-2 infection, even if some adults have a response close to that of children and vice versa.
« Our approach was original because the combination of microscopy and molecular biology allowed us to visualize the differences in the spread of the infection according to the origin of the epithelia (children or adults), and to correlate these observations with the inflammatory response. and viral kinetics », stresses Harald Wodrich.
The researcher wishes to continue this work to find out whether these phenomena are specific to infection by SARS-CoV‑2 or whether they are found with other respiratory viruses. With his laboratory and his partners, he is currently carrying out the same tests using adenoviruses and rhinoviruses, viruses responsible for generally benign respiratory infections (colds, nasopharyngitis, etc.). ” The fact that each of the epithelia we use comes from a single patient (adult or child), unlike most marketed epithelia, will allow us to know whether the differences in response are determined by the nature of the viruses or by the characteristics of the “epithelium donor”such as his age. »
As for the fight against Covid-19, these results already offer a better understanding of the phenomena at the origin of the severity of the disease. They could help clinicians in optimizing treatments developed to combat severe forms.
Harald Wodrich leads the team Spatial and temporal control of virus-host interactions in the UMR 5234 Fundamental Microbiology and Pathogenicity at the University of Bordeaux.
Source : G Beucher et coll. Bronchial epithelia from adults and children : SARS-CoV‑2 spread via syncytia formation and type III interferon infectivity restriction. PNAS Accessed 2022 Jun 24. doi: 10.1073/pnas.2202370119
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