Bats and children 9 years and under may have something in common in their immune responses to COVID which spares them from severe symptoms— immunotolerance. Bats have several mechanisms to prevent over responsiveness to viruses and limit collateral non-specific damage by inflammation. Humans express minimal baseline levels of type I interferons (IFNs), and they are highly inducible upon stimulation, but many bat species, such as the black flying fox (Pteropus alecto), constitutively express some baseline IFNα, and several IFN-stimulated genes before stimulation. Therefore, they are prepared to inhibit viral replication before it can spread to many tissues and prime an overt response with a heavy viral load. The restricted induction of type I IFNs minimizes production of inflammatory cytokines and reactive oxygen species by innate immune inflammatory and phagocytic cells. The kinetics of the IFN response in bats also differs from those of other mammals, in that it has a faster decline for some bat interferon-stimulated genes post-stimulation. Bats have a reduced production of reactive oxygen species compared to similar-sized non-flying mammals, but retain intact activity of the important antioxidant enzymes like superoxide dismutase. These findings suggest either a more effective scavenging of reactive oxygen species or a lower production of reactive oxygen species by bats, or a combination of both.
Immune tolerance in bats is also expressed in dampening of the STING-dependent type I IFN response in several bat species, resulting from a point mutation in the Stimulator of Interferon Genes (STING) https://www.frontiersin.org/articles/10.3389/fimmu.2020.00615/full. STING is an important pattern recognition receptor which triggers cytosolic-DNA-induced signalling and has a key role in infection, inflammation, and cancer. This mutation has the effect of dampening STING mediated responses to infection with bat-borne RNA viruses, which activate STING by inducing host DNA damage. A more recent study has revealed another key mechanism by which bats naturally dampen host inflammation in response to ‘sterile’ danger signals and infections with RNA viruses. NLR-family pyrin (NLRP3), a key inflammasome sensor that recognizes various cellular stresses and pathogen invasion, is dampened at both the transcription and protein translation level in bats. Importantly, reduced NLRP3-mediated inflammatory responses to RNA viruses have no, or minimal, effect on viral loads https://www.nature.com/articles/s41586-020-03128-0.pdf.
In children, which I have discussed in earlier posts, there is a rapid early interferon response to SARS-CoV-2. Community acquired pneumonia in children younger than 5 years old, with severe and life-threatening symptoms, have significantly increased interleukin-17 (IL-17) production. Immune profiling of these children showed that mucosal-associated invariant T (MAIT) cells from the lungs, but not blood, actively produced IL-17 (MAIT17) https://www.nature.com/articles/s41385-020-0273-y.pdf. Previously, I posted that the IL-17/Th17 pathway plays a major role in regulating the severity of COVID and turning it down by removing viruses early with interferon, reducing the viral load and distribution, limiting the reactive oxygen response of this pathway and, therefore, the collateral damage, as seen in most children exposed to COVID who are less than 9 years old. Th17 lymphocytes promote signals typical of early inflammatory events, and serve as a bridge between innate and adaptive immunity https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821718/pdf/nihms-152030.pdf. Therefore, they represent the pivot point between a severe and mild antiviral innate immune response and an effective long term protective adaptive immune response. In children, they produce a mild but virus-eliminating early response, and are less likely to yield a sustained adaptive immune memory as in adults, from the infection, a form of immunotolerance. They sacrifice long term immunity for the lower severity of the disease. Stopping the virus before it systemically disseminates is critical because it can otherwise damage blood vessels in many tissues and organs causing retiform purpura, gangrene and vascular permeability, swelling to bleeding, as well as widespread deposition and activation of neutrophils by activating the complement system. It induces a hypercoagulable state with micro- and macroangiopathy. The activation occurs by forming complement cascade activating antibody-antigen complexes or by the alternate complement pathway activated by the spike glycoprotein acting as a lectin (https://www.translationalres.com/action/showPdf?pii=S1931-5244%2820%2930070-0). However, to achieve long term immune memory one might have to first endure a “baptism of fire”.
Global Biosurveillance 