Identification of RNase L-Dependent, 3'-End-Modified, Viral Small RNAs in Sindbis Virus-Infected Mammalian Cells

Girardi, Erika; Chane-Woon-Ming, Béatrice; Messmer, Mélanie; Kaukinen, Pasi; Pfeffer, Sébastien

Mammals have evolved a very sophisticated innate immune response to ward off pathogens that is based on the sensing of pathogen-associated molecular patterns (PAMPs) by dedicated pattern recognition receptors (PRRs). When it comes to viral infection, one of the most potent PAMPs is dsRNA. The recognition of dsRNA by PRRs triggers a signaling cascade that ultimately leads to the activation of interferon-sensitive genes (ISGs) (40) . RNA silencing is another type of antiviral innate immunity, which, as of now, has mostly been demonstrated in plant and insect organisms (1). Nonetheless, a role for RNA silencing as a host defense system against mammalian viruses could reasonably be considered. Indeed, Dicer, the key enzyme for dsRNA cleavage is conserved in higher vertebrates, and although its main substrate in vivo is pre-miRNA molecules, it is able to process long dsRNA into short RNAs in vitro (41) . However, the question as to which other types of dsRNA molecules mammalian Dicer can cleave in vivo has been the matter of intense research, and especially so when considering RNAs of viral origin. Here, we wanted to make our contribution to the field by studying the prototypical arbovirus, Sindbis virus. This type of virus can infect both insects and mammals, and as such is a useful tool to study the conservation of antiviral mechanisms in both phyla. Intriguingly, it has been shown for some members of the alphavirus genus that their genomic RNA can be processed into both siRNAs and piRNAs in insect somatic cells (42, 43) .