Low basal expression and slow induction of IFITM3 puts immune cells at risk of influenza A infection

Abstract

The interferon-induced transmembrane protein, IFITM3, has been shown to restrict influenza virus infection in murine and in vitro settings for ten years, but no explanation has been found to explain why this virus infection is so highly contagious and infects most individuals it comes in contact with. We confirm that the expression level of IFITM3 plays a role in determining the level of viral infection through manipulation of IFITM3 levels with interferon (IFN) stimulation and overexpression systems. Low basal expression may put some immune cells, including lymphocytes and lung-resident macrophages, at risk of influenza virus infection. Investigating the induction of IFITM3 by IFN, we find a strong preference for Type I IFN in IFITM3 induction in both cell lines and primary human cells. While myeloid cells can increase expression following stimulation by Type I IFN, lymphocytes show minimal induction of IFITM3 following IFN stimulation, suggesting that they are always at risk of viral infection. Surprisingly, we found that the time it takes for maximal induction of IFITM3 is relatively slow for an interferon-stimulated gene at around 36 hours. Low basal expression and slow induction of IFITM3 could increase the risk of influenza virus infection in selected immune cells.ImportanceInfluenza virus infection remains one of the top ten threats to global health, causing significant deaths and hospitalisations across the world each year. Understanding mechanisms for controlling influenza virus infection remain a priority. The interferon-induced transmembrane protein IFITM3 can restrict influenza infection by limiting replication of the virus. The precise mechanisms of how IFITM3 reduced replication of influenza are unknown, although it is predicted to prevent release of viral contents into the cytosol by preventing pore formation on the endosomal compartments where it is suggested to reside. Here we have shown that the expression level of IFITM3 is important in determining the control of influenza virus infection. We find an expression pattern for IFITM3 that varies based on cell type, tissue locality, differentiation state and cell naivety, all of which highlights cells that may be at the highest risk of influenza infection.

Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell epitope mapping

“…Downregulation of the IFN-stimulated gene was still pertained despite increased JAK-STAT signaling in the WTAGAAAYY epitope-binding T EM1 cells in the severe group compared to mild COVID-19. As previously described, IFITM proteins have been implicated in the restriction of SARS-CoV-1 cellular entry 43 and baseline expression of IFITM3 has been shown to determine the susceptibility to influenza A virus infection 41,42 . It is therefore possible that in individuals who develop only mild COVID-19, a higher baseline expression of IFITM3 restricts cellular entry into CD8 + T cells, therefore leading to reduced viral loads and less impairment of JAK-STAT signaling compared to severely infected patients.…”

“…3C). IFITM3 has previously been reported to confer protection against H1N1 influenza A virus 41,42 and IFITM proteins have been shown to restrict cellular entry of SARS-CoV-1 43 . Therefore, our finding could indicate a potential role for IFITM3 in protection from severe courses of SARS-CoV-2 infection.…”

Relevance of HLA-DP/DQ and INF-λ4 Polymorphisms to COVID-19 Outcomes

“…It was reported that IFN-λ is secreted by Plasmacytoid dendritic cells (pDC) that respond to this cytokine in an autocrine manner to surge the anti-viral responses (29). Moreover, Wellington et al (30) have found that IFN-λ induce IFITM3 expression in pDC cells to a level similar to induction by type I IFN. IFITM3 produces an immune effector protein that promotes mucosal immune cell durability by increasing CD8+CTL number in the airways, which is vital in immunity against viral diseases.…”