Enhanced RNAi does not provide efficient innate antiviral immunity in mice

Area of Science:

• Molecular Biology
• Virology
• Immunology

Background:

• RNA interference (RNAi) is an antiviral mechanism in many species, but its role in mammals is unclear.
• Mammalian Dicer enzyme is primarily adapted for microRNA processing, leading to inefficient siRNA production for RNAi.
• Endogenous RNAi in mammals is considered rudimentary with uncertain antiviral significance.

Purpose of the Study:

• To investigate the in vivo antiviral potential of mammalian RNA interference.
• To assess the response of modified mice with enhanced Dicer activity to various RNA viruses.
• To establish a benchmark for studying viruses susceptible to mammalian RNAi.

Main Methods:

• Modification of the mouse Dicer locus to express a truncated, RNAi-stimulating variant (DicerΔHEL1).
• Infection of DicerΔHEL1/wt mice with four different RNA viruses: coxsackievirus B3, encephalomyocarditis virus, tick-borne encephalitis virus, and lymphocytic choriomeningitis virus (LCMV).
• Analysis of viral response in DicerΔHEL1/wt mice, including studies in embryonic stem cells and a transgenic mouse model.

Main Results:

• Increased Dicer activity in DicerΔHEL1/wt mice did not confer a general antiviral effect against the tested viruses.
• Sufficiently high expression of DicerΔHEL1 demonstrated suppression of LCMV in both embryonic stem cells and a transgenic mouse model.
• The study suggests that mammalian RNAi's antiviral function is specific and not universally effective.

Conclusions:

• Endogenous mammalian RNAi appears to have an insignificant general antiviral function in vivo.
• Enhanced Dicer activity can suppress specific viruses, indicating a potential, albeit limited, role for RNAi in mammalian antiviral defense.
• DicerΔHEL1 transgenic mice serve as a valuable model for identifying and studying viruses susceptible to mammalian RNAi.