Lung Protection vs. Infection Resolution: Interleukin 10 Suspected of Double-Dealing in COVID-19

Abstract

The pathological processes by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that make the virus a major threat to global health are insufficiently understood. Inefficient viral clearance at any stage is a hallmark of coronavirus disease 2019 (COVID-19). Disease severity is associated with increases in peripheral blood cytokines among which interleukin 10 (IL-10) increases particularly early and independent of patient age, which is not seen in active SARS-CoV infection. Here, we consider the known multi-faceted immune regulatory role of IL-10, both in protecting the lung from injury and in defense against infections, as well as its potential cellular source. While the absence of an IL-10 response in SARS is thought to contribute to early deterioration, we suspect IL-10 to protect the lung from early immune-mediated damage and to interfere with viral clearance in COVID-19. This may further both viral spread and poor outcome in many high-risk patients. Identifying the features of the viral genotype, which specifically underlie the different IL-10 dynamics as an etiological endotype and the different viral load kinetics and outcomes as clinical phenotype, may unveil a new immune evasive strategy of SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; endotype; interleukin 10; lung; viral clearance.

Figure 1

Viral genotype-endotype-clinical phenotype relationships in COVID-19 and SARS. At the bottom, the dynamics of the IL-10 response to SARS-CoV-2 (red) and SARS-CoV (blue) infections is schematized as horizontal bars. Dark color and white represent high and low levels, respectively, of IL-10 in peripheral blood (section IL-10 in COVID-19). In severe COVID-19 but not in SARS, IL-10 was found increased already in the first week of symptoms (9). Data on the levels of blood IL-10 in relation to the resolution of symptoms and in COVID-19-convalsecent blood has not yet been reported explicitly, but they appear to slowly decline with symptoms over the course of 2–3 weeks. We refer to IL-10 dynamics as endotype. In light of the lung protective properties of IL-10 and its role in microbial persistence (section Ambiguous Role of IL-10 in Lung Injury and Infection), we propose that the difference in this endotype contributes to the different viral load kinetics in COVID-19 and SARS (section SARS-CoV-2 Transmission vs. Clearance). Viral load kinetics are schematized at the top left in an analogous manner to the endotype and are referred to as clinical phenotype. The open arrow connecting clinical phenotype and viral genotype considers viral evolution in general inclusive of species jumping. The genotype schematic at the top right focuses on specific genome regions of the two viruses with sequence differences that give rise to the indicated numbers of amino acid (aa) changes in non-structural proteins 2 and 3 (nsp2, nsp3) and the spike (S) protein (section Discussion). One or a combination of such variations is likely responsible for the differential IL-10 response. However, a functional role of silent mutations cannot be excluded. It also has to be noted, that the annotation of open reading frames in the SARS-CoV-2 genome appears not yet complete, and new polypeptide products are being discovered (126). This type of diagram can be adapted in a flexible manner. For instance, it can be used to represent a variety of differences in viral genotypes, i.e., phylogenetic diversity, and putatively related endo- and phenotypes including those that may emerge during SARS-CoV-2 pandemic (–130). Instead of the viral genotype, host genetic risk factors of COVID-19 (–134) and their endotype and phenotype relations can be illustrated. Accordingly, endotypes can consist, for instance, in various immune evasion strategies and clinical phenotypes in any patient outcome. Moreover, external factors that influence evolution (top arrow), infection (right arrow), and pathogenesis (left arrow) can be incorporated, such as environmental influences.