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

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.