Activation of Evolutionarily Young Endogenous Retroviruses Is Implicated in COVID-19 Immunopathology

The dysfunction of the innate immune system is well-described as a clinical characteristic of COVID-19. While several groups have reported human endogenous retroviruses (ERVs) as enhancing factors of immune reactivity, characterization of the COVID-19-specific ERVs has not yet been sufficiently conducted. Here, we revealed the transcriptome profile of more than 500 ERV subfamilies and innate immune response genes in eight different cohorts of platelet, peripheral blood mononuclear cells (PBMCs), lung, frontal cortex of brain, ventral midbrain, pooled human umbilical vein endothelial cells (pHUVECs), placenta, and cardiac microvascular endothelial cells (HCMEC) from COVID-19 patients (total; n = 124) and normal samples (total; n = 53) using publicly available datasets. While upregulation of ERV subfamilies was found in platelets, PBMCs, and placenta, the immune reactivity was confined to only platelets and PBMCs. It is noteworthy that the evolutionary ages of the upregulated ERV subfamilies detected in platelets and PBMCs were younger than other ERV subfamilies, but the tendency was not seen in the upregulated ERV subfamilies in placenta. The results suggest that only evolutionarily young ERVs can function as enhancing factors of the immune reactivity in COVID-19 patients. The finding should be instrumental in understanding the COVID-19 immunopathology.