The Role of Paleoviral Sequences in Immune Tolerance to Ebola Virus Infections

Abstract

Filoviruses such as Ebola virus (EBOV) cause severe disease in human and non-human primates (NHP) with fatality rates of up to 90%. EBOV disease (EVD) is characterized by exacerbated inflammatory response leading to multiorgan failure in severe cases. Conversely, EBOV seems to be non-pathogenic for other mammalian species such as bats and rodents. The reasons for this outstanding difference in pathogenesis have still not been elucidated. A common characteristic of some species of bats, rodents, and marsupials is that they all possess filovirus-like sequences inserted in their genomes. Until recently, only retroviral sequences had been found integrated into host genomes. However, it has been discovered that non-retroviral ribonucleic acid (RNA) virus elements are also present in mammalian genomes. These remnants of ancient viral infections, known as non-retroviral integrated RNA virus elements (NIRVs), further underscore the dynamic interactions between viruses and their hosts throughout the course of evolution. These paleoviral sequences often retain intact open reading frames (ORFs) and for some of them, messenger RNA (mRNA) can be detected. Despite their prominence, their exact role and origin mechanism remain largely unknown. However, studies suggest that these sequences might influence susceptibility and resistance to viruses and the diseases they cause. In this study, we focused on the characterization of a specific NIRV derived from the nucleoprotein (NP) of EBOV (NP-NIRV) present in mice (Mus musculus). We found that NP NIRV was expressed as mRNA in the spleen, kidney, and thymus. Intriguingly, we observed that its expression was particularly unique to medullary thymic epithelial cells (mTECs), which is known to play an important role during T cell development. Our findings demonstrate that NP-NIRV was expressed under the control of autoimmune regulator (AIRE) and recognized as a self-peptide rather than a foreign immunogenic peptide in mice. This strongly suggests that NP-NIRV induced immune tolerance against EBOV infection in mice. Depletion of NP-NIRV in mice did not result in changes in either pathogenesis or inflammatory responses after EBOV infection, but depletion of all regulatory T cells (Tregs) resulted in enhanced pathogenesis suggesting the presence of additional NIRVs. Finally, through in-silico analysis, we demonstrated that several other peptides putatively derived from filoviruses and other viruses of the order Mononegavirales exist in the thymus of mice but not humans, suggesting an evolutionary strategy to tolerate infection with specific virus families.