Cas13-induced cellular dormancy prevents the rise of CRISPR-resistant bacteriophage

Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci of prokaryotes are composed of 30-40 bp repeats separated by equally short sequences of plasmid and bacteriophage origin known as spacers(1–3). Spacers are transcribed and processed into short CRISPR RNAs (crRNAs) that are used as guides by CRISPR-associated (Cas) nucleases to recognize and destroy complementary sequences (known as protospacers) within invaders(4,5). In contrast to most Cas nucleases which destroy the invader’s DNA(4–7), the type VI effector nuclease Cas13 employs RNA guides to locate complementary transcripts and catalyze both sequence-specific cis-, and non-specific trans-RNA cleavage(8). While it has been hypothesized that Cas13 naturally defends against RNA phages(8), type VI spacer sequences have exclusively been found to match the genomes of double-stranded DNA (dsDNA) phages(9,10), suggesting that Cas13 can provide immunity against these invaders. However, whether and how Cas13 utilizes the cis- and/or trans-RNA cleavage activities in defending against dsDNA phages is not understood. Here we show that trans-cleavage of transcripts halts the growth of the host cell and results in the abortion of the infectious cycle. This depletes the phage population and provides herd immunity to uninfected bacteria. Phages harboring target mutations, which easily evade DNA-targeting CRISPR systems(11–13), are also depleted due to the activation of Cas13 by co-infecting wild type phages. Thus, by acting on the host rather than directly targeting the virus, type VI CRISPR systems not only provide robust defense against DNA phages but also prevent outbreaks of CRISPR-resistant phage.