How Children Are Protected From COVID-19? A Historical, Clinical, and Pathophysiological Approach to Address COVID-19 Susceptibility

Abstract

The origin and the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) in early 2020 was accompanied by high rates of mortality in regions belonging to the ancient silk road, such as the south of China, Iran, Turkey and the northern parts of Italy. However, children seem to be spared in the epidemic as very small percentage worldwide being ill. The protection of children and neonates suggests the involvement of a specific component of adaptive immunity present at early development. Native immunoglobulin belonging to the class of IgM is abundantly present in neonates and children and is known for its recognition of self- and altered self-antigens. Native IgM may be able to neutralize virus by the recognition of endogenous "danger signal" encoded in the viral envelope and originally imprinted in the membranes of infected and stressed cells. Noteworthy, thrombosis and vasculitis, two symptoms in severely affected adult and pediatric patients are shared between COVID-19 and patients with Behcet's disease, an autoimmune disorder exhibiting a region-specific prevalence in countries of the former silk road. Molecular mechanisms and clinical indicators suggest reactive oxygen species as trigger factor for severe progression of COVID-19 and establish a link to the innate immune defense against bacteria. The selective pressure exerted by bacterial pathogens may have shaped the genetics of inhabitants at this ancient trade route in favor of bacterial defense, to the detriment of severe COVID-19 progression in the 21th century.

Keywords: ACE-2 receptor; B1 B cells; COVID-19; Kawasaki-like disease; children; natural IgM; reactive oxygen species; silk road.

Figure 1

The Yang-Yin of immune defense. The genetic traits favoring the defense against bacterial pathogens in the past (ROS and IgM) appeared to be vulnerable for COVID-19–related mortality in the 21th century. The left side demonstrates how bacterial pathogens shaped the genome in human populations by selective survival of individuals with single nucleotide polymorphisms (SNPs) in genes facilitating bacterial defense, such as the generation of reactive oxygen species (ROS) in phagocytes. The right side shows a newborn with the inherent high polyclonality of its natural IgM. Natural IgM recognize altered self-antigens and are important for removal of apoptotic cells in the developing neonate. Altered self-antigens are also present in the viral envelope of corona viridae. Such as natural IgM removes apoptotic cells in absence of inflammation, the virus is neutralized without inflammatory symptoms and disease. Reactive oxygen species represent the inflammatory and anti-bacterial part of immune defense, associated with Yang in traditional Chinese medicine (TCM). The natural IgM represents the anti-inflammatory and self-recognizing part of immune system involved in tissue remodeling, associated with Yin in TCM.