Panoply™ Human CEACAM1 Knockdown Stable Cell Line

Cells in our bodies can induce hundreds of antiviral genes upon viral sensing, many of which remain poorly characterized. CEACAM1 has previously been shown to be induced by multiple innate systems. However, the reasons for its tight integration with innate sensing remain unclear. Here, researchers demonstrate that upon detection of human cytomegalovirus (HCMV) and influenza virus, CEACAM1 is induced by their respective DNA and RNA innate sensors, IFI16 and RIG-I. This induction is mediated by IRF3, which binds to an ISRE element present in the human (but not mouse) CEACAM1 promoter. Furthermore, the researchers demonstrate that, upon induction, CEACAM1 inhibits HCMV and influenza virus through a SHP2-dependent process and achieves its broad antiviral efficacy by inhibiting mTOR-mediated protein biogenesis. Finally, the studies demonstrate that CEACAM1 also inhibits viral spread in ex vivo human decidual organ cultures.

To test whether CEACAM1 affects viral infection, the researchers silenced CEACAM1 expression in HFF cells (Figure 1A) and then infected these cells with HCMV. Importantly, CEACAM1 was observed to inhibit HCMV, as silencing its expression significantly increased viral production (Figure 1B). HCMV is a master of immune evasion, and recent studies have shown that it utilizes its pp65 protein to evade the IFI16 innate cellular antiviral response. The researchers hypothesized that HCMV might also exploit pp65 to evade the full antiviral capacity of CEACAM1. Consistent with this, while infection of HFF cells with wild-type (WT) HCMV at a low multiplicity of infection (MOI) did not induce CEACAM1 expression (compared to the high MOI used in previous experiments), infection with HCMV lacking the pp65 protein (Δpp65) resulted in robust induction of CEACAM1 (Figure 1C). Given that CEACAM1 is induced more efficiently in cells infected with Δpp65 than in cells infected with WT HCMV, it follows that infection of CEACAM1-knockdown cells with Δpp65 virus could fully unleash the antiviral potential of CEACAM1. To test this, the researchers compared the fold change in viral titer in HFF cells infected with WT or Δpp65 virus after CEACAM1 knockdown. In the absence of pp65, viral titers of Δpp65 virus were 10-fold higher than those of WT virus after CEACAM1 knockdown (Figure 1D). Surprisingly, CEACAM1 also inhibited influenza virus, as knockdown of its expression in A549 cells (Figure 1E) resulted in persistently elevated influenza virus titers upon infection of these cells (Figure 1F).

Figure 1. CEACAM1 Expression Suppresses Viral Replication through SHP2. (Vitenshtein A, et al., 2016)