CRISPR-Cas system of a prevalent human gut bacterium reveals hyper-targeting against phages in a human virome catalog

Bacteriophages are abundant within the human gastrointestinal tract, yet
their interactions with gut bacteria remain poorly understood,
particularly with respect to CRISPR-Cas immunity. Here, we show that the
type I-C CRISPR-Cas system in the prevalent gut
Actinobacterium Eggerthella lenta is transcribed and
sufficient for specific targeting of foreign and chromosomal DNA.
Comparative analyses of E. lenta CRISPR-Cas
systems across (meta)genomes revealed 2 distinct clades according
to cas sequence similarity and spacer content. We
assembled a human virome database (HuVirDB), encompassing 1,831 samples
enriched for viral DNA, to identify protospacers. This revealed matches
for a majority of spacers, a marked increase over other databases, and
uncovered “hyper-targeted” phage sequences containing multiple
protospacers targeted by
several E. lenta strains. Finally, we
determined the positional mismatch tolerance of observed
spacer-protospacer pairs. This work emphasizes the utility of merging
computational and experimental approaches for determining the function and
targets of CRISPR-Cas systems.