Differential Leukocyte Expression of IFITM1 and IFITM3 in Patients with Severe Pandemic Influenza A(H1N1) and COVID-19

Abstract

Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk IFITM1 and IFITM3 mRNA expression dynamics and their correlation with clinical outcomes have not been extensively addressed in patients with respiratory infections. In this study, we evaluated the expression of IFITM1 and IFITM3 in peripheral leukocytes from healthy controls and individuals with severe pandemic influenza A(H1N1) or coronavirus disease 2019 (COVID-19). Comparisons between participants grouped according to their clinical characteristics, underlying disease, and outcomes showed that the downregulation of IFITM1 was a distinctive characteristic of severe pandemic influenza A(H1N1) that correlated with outcomes, including mortality. Conversely, increased IFITM3 expression was a common feature of severe pandemic influenza A(H1N1) and COVID-19. Using a high-dose murine model of infection, we confirmed not only the downregulation of IFITM1 but also of IFITM3 in the lungs of mice with severe influenza, as opposed to humans. Analyses in the comparative cohort also indicate the possible participation of IFITM3 in COVID-19. Our results add to the evidence supporting a protective function of IFITM proteins against viral respiratory infections in humans.

Gene expression profiling of host lipid metabolism in SARS-CoV-2 infected patients: a systematic review and integrated bioinformatics analysis

“…IFITM3 is a gene that encodes for Interferon (IFN) induced transmembrane protein 3. Increased IFITM3 expression was a regular feature of severe COVID-19 cases, which was reported in a study by Regino-Zamarripa et al (2022) [ 33 ]. IFITM3 is an IFN-induced antiviral protein that could cause havoc in the homeostasis of intracellular cholesterol.…”

“…The terms lysosome (KW-0458), endosome (KW-0967), response to virus (GO:0009615), defense response to virus (GO:00516057), lysosomal membrane (GO:0005765) and late endosome membrane (GO:0031902) contributed to virion degradation by the lysosome. IFITM3 is concentrated in endo-lysosomal membranes [ 35 ] since IFITM proteins are one of the host factors that restrict virus infection by impeding with cellular entry at endosomes [ 33 ]. Furthermore, the mechanisms involved blocking membrane fusion pore formation by IFITM3 in late endosomes [ 33 , 36 ].…”

“…IFITM3 is concentrated in endo-lysosomal membranes [ 35 ] since IFITM proteins are one of the host factors that restrict virus infection by impeding with cellular entry at endosomes [ 33 ]. Furthermore, the mechanisms involved blocking membrane fusion pore formation by IFITM3 in late endosomes [ 33 , 36 ]. The viral particles would be retained in late endosomes, which would then be targeted for lysosomal degradation [ 37 ].…”

Metacell-based differential expression analysis identifies cell type specific temporal gene response programs in COVID-19 patient PBMCs

“…We also notice that IFITM1 expression falls below baseline after 28 days, suggesting potential downregulation of this gene upon clearance of the virus. IFITM1 has been found to be downregulated following severe influenza infection in mice [46], so we wonder whether our findings could point toward the need to study the differential effects of this gene’s expression in severe and minor COVID-19.…”

Interferon-Induced Transmembrane Protein 3 rs34481144 C/T Genotype and Clinical Parameters Related to Progression of COVID-19

“…The differences in these studies could be influenced by polymorphisms in IFITM genes. As shown in genomic investigations, there is a strong association between certain SNPs within the IFITM3 gene and mortality in different ethnic groups [ 25 – 27 ]. For example, the role of IFITM3 rs12252 with infection severity has been shown in several studies [ 13 , 28 , 29 ].…”