Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer's disease

George D Vavougios; Christiane Nday; Sygliti-Henrietta Pelidou; Konstantinos I Gourgoulianis; George Stamoulis; Triantafyllos Doskas; Sotirios G Zarogiannis

doi:10.1016/j.bbih.2021.100243

Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer's disease

Brain Behav Immun Health. 2021 Jul:14:100243. doi: 10.1016/j.bbih.2021.100243. Epub 2021 Mar 26.

Authors

George D Vavougios^{1

2

3}, Christiane Nday⁴, Sygliti-Henrietta Pelidou⁵, Konstantinos I Gourgoulianis², George Stamoulis^{6

3}, Triantafyllos Doskas¹, Sotirios G Zarogiannis⁷

Affiliations

¹ Neuroimmunology Laboratory, Department of Neurology, Athens Naval Hospital, P.C., 115 21, Athens, Greece.
² Department of Respiratory Medicine, Faculty of Medicine, University of Thessaly, Biopolis, P.C., 41500, Larissa, Greece.
³ Department of Computer Science and Telecommunications, University of Thessaly, Papasiopoulou 2 - 4, P.C., 35 131, Galaneika, Lamia, Greece.
⁴ Laboratory of Medical Physics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, P.C., 5414, Thessaloniki, Greece.
⁵ Department of Neurology, Faculty of Medicine, University of Ioannina, P.C., 45110, Ioannina, Greece.
⁶ Department of Electrical and Computer Engineering, University of Thessaly, 37 Glavani - 28th October Str, Deligiorgi Building, 4th Floor, P.C., 382 21, Volos, Greece.
⁷ Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, 41500, Greece.

Abstract

Background: IFITM3 is a viral restriction protein that enables sequestration of viral particles and subsequent trafficking to lysosomes. Recently, IFITM3 upregulation was found to induce gamma - secretase activity and the production of amyloid beta. The purpose of this study was to determine whether dysregulation of IFITM3-dependent pathways was present in neurons and peripheral immune cells donated by AD patients. As a secondary aim, we sought to determine whether these perturbations could be induced by viruses, including SARS-CoV-2.

Methods: Gene set enrichment analyses (GSEA) previously performed on publicly available transcriptomic data from tissues donated by AD patients were screened for enriched pathways containing IFITM3. Subsequently, signature containing IFITM3, derived from entorhinal cortex (EC) neurons containing neurofibrillary tangles (NFT) was screened for overlap with curated, publicly available, viral infection-induced gene signatures (including SARS-CoV-2).

Results: GSEA determined that IFITM3 gene networks are significantly enriched both in CNS sites (entorhinal and hippocampal cortices) and in peripheral blood mononuclear cells (PBMCs) donated by AD patients. Overlap screening revealed that IFITM3 signatures are induced by several viruses, including SARS-CoV, MERS-CoV, SARS-CoV-2 and HIV-1 (adjusted p-value <0.001; Enrichr Database).

Discussion: A data-driven analysis of AD tissues revealed IFITM3 gene signatures both in the CNS and in peripheral immune cells. GSEA revealed that an IFITM3 derived gene signature extracted from EC/NFT neurons overlapped with those extracted from publicly available viral infection datasets, including SARS-CoV-2. Our results are in line with currently emerging evidence on IFITM3's role in AD, and SARS-CoV-2's potential contribution in the setting of an expanded antimicrobial protection hypothesis.

Keywords: Alzheimer’s disease; Epigenetics; IFITM3; Neuroimmunology; Systems biology.