Is mild COVID-19 in children due to stronger antiviral innate immunity in the upper airway?
Younger patients, including adolescents, are less likely to suffer severe coronavirus disease 2019 (COVID-19) symptoms. This is the case even though the risk of infection with its causative pathogen  the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)  is not necessarily reduced in this age group. This has led to the supposition that stronger innate immunity against viral infections exists in children, allowing them to control viral replication early in the course of infection. A new preprint on the medRxiv* server adds fuel to this train of thought, showing that the required cell program is already active in children  namely, a higher expression of specific pattern recognition receptors (PRRs), which mediate an interferon (IFN) response. Study aims  Earlier studies have demonstrated that the innate immune response must be activated early on, consisting of the pattern recognition receptors (PRR)-dependent triggering of type I and III IFN pathways. Children and adults lacking this response develop severe COVID-1I. The current study was aimed at delineating the molecular basis of this protective mechanism that is already in force in the majority of children. Using transcriptomics, the researchers examined the upper airway, where most SARS-CoV-2 exposure and infection occur in infected and uninfected children and adults. The range of participant age extended from 4 weeks to 77 years. Since the aim of the study was to detect the protective mechanisms operating during early infection, only mild and moderate cases were included. The findings were surprisingly in line with the hypothesis. The immune and epithelial cell profiles in the nasal mucosa showed distinct and marked differences. While healthy or uninfected adults lacked immune cells in their nasal mucosa, immune cells streamed in following SARS-CoV-2 infection. Goblet cells were lower and ciliated cells increased in adults. Conversely, uninfected children had high numbers of immune cells belonging to practically every subset. Following infection with the virus, the immune-epithelial ratio remained intact in children. Neutrophils dominated the picture, however, with a more activated phenotype than in adults, as shown by markers like CCL3 and CXCR1/2. The SARS-CoV-2 entry receptor ACE2 and the entry-associated proteases TMPRSS2, FURIN, CTSB, CTSL, and CTSV showed no difference in expression between children and adults or following mild-to-moderate COVID-19, suggesting they do not contribute much to childhood immunity against this virus. Higher virus sensing in children  The PRR MDA5 (also called IFIH1) may play a major role in sensing this virus in epithelial cells, assisted by LGP2 (DHX58), which improves the detection of viral ribonucleic acid (RNA), and perhaps also by RIG-I (DDX58). While PRRs are always expressed at low levels on many such cell types within epithelia, they are strikingly increased either when the cell becomes infected or when it is exposed to the antiviral type I or III interferons (IFN). This cascade is essential to catch the infection early. In fact, some genetic variants affecting this pathway enhance the risk of severe COVID-19, which is also far more likely in the presence of autoantibodies against these IFNs. Uninfected children showed higher expression of the RIG-I, MDA5 and LGP2 genes, as well as increased immune cells, in their nasal mucosa. This indicates that they are more prepared to respond to viral infections. This is confirmed by the dramatic upregulation of these genes at the beginning of COVID-19 symptoms, which then decreases over the next four days to remain at a lower plateau throughout the second week of the disease. Thus, during the first four days, or early phase, of COVID-19 infection, children are already prepared to sense and fight the virus successfully, compared to adults. Higher antiviral interferon and cytotoxic response  Once virus detection occurs, the IRF3/NFkB signaling pathway prompts the expression of multiple primary antiviral effectors and cytokines, which produce positive feedback to further increase PRR expression and thus the host cell response to the presence of the virus. The result is an activation of interferon-stimulated genes (ISGs) such as LY6E, IFITM2, and BST2. ISG expression in epithelial cells was markedly higher in infected children, compared to adults, throughout infection, though it showed a decreasing tendency over time. In cells with high MDA5 expression, the presence of lentivirus infection led to the transcription of IFN and ISG at higher levels. In contrast, in cells with low MDA5 expression, virus sensing was inefficient, allowing the virus to replicate rapidly and synthesize molecules that antagonize host immunity, and very small amounts of IFN/ISG were detected. These findings corroborate the central role of MDA5 expression prior to infection for sensing SARS-CoV-2 and inducing a swift and robust ISG response.  Certain immune cell subsets occur mostly in children, including NKG2A+ cytotoxic T cells (CTL2). The NKG2A marker is crucial in preventing apoptosis and maintaining the specific cytotoxic response against the virus-infected cell. It has a strong baseline expression of cytotoxic molecules as well as IFN-G, and CCL5, a powerful chemotactic agent. These are strikingly raised in infected children compared to adults, indicating, again, that the former mount a far more efficient antiviral response. This includes a memory CD8+ T cell phenotype as well, almost completely absent in adults. The findings of this transcriptomics study demonstrate the preparedness of the immune-epithelial cell profile in the upper airway in children when it comes to viral infection, particularly SARS-CoV-2. Not only are they pre-warned, but they are pre-armed. This is an important consideration with viruses, since their replication is associated with the early production of antagonists that prevent host immune activation. This is especially true of this virus since it rapidly and extensively replicates within host cells and shuts off antiviral responses, namely, the interferon response, almost completely. In contrast, respiratory syncytial virus (RSV) induces the IFN pathway by itself, limiting its pathogenicity. Nonetheless, IFN therapy quickly prevents SARS-CoV-2 replication, even after the infection is accomplished, in vitro. Thus, it is essential to take advantage of the narrow window of opportunity to prevent viral replication, and this is observed in children rather than in adults. The team concludes:  The enhanced innate antiviral capacity in children together with the high IFN sensitivity of SARS-CoV-2 may explain why children are better able to control early-stage infection as compared to adults and therefore have a lower risk of developing severe COVID-19.  *Important notice  medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.