A CRISPR/Cas system mediates bacterial innate immune evasion and virulence

Abstract

The CRISPR/Cas system known to aid bacterial defences by targeting invading DNA can also act to evade eukaryotic defences through a different class of small RNAs downregulating an endogenous immunogenic bacterial lipoprotein. Bacteria handle unwelcome exogenous material from plasmids and phages using a series of small RNAs to degrade incoming DNA. It has been suggested that the system involved, known as CRISPR/CAS, has other functions too. Here David Weiss and colleagues show that the pathogenic bacterium Francisella novicida, which is able to invade the cells of its eukaryote hosts, uses its CRISPR/CAS system to suppress production of one of its own lipoproteins, which would otherwise be recognized as foreign by the host's innate immune system. Other pathogens, including Neisseria spp. and Campylobacter spp., also have active CRISPR/CAS systems that might serve similar anti-immunity functions, raising the possibility of a previously untapped source of targets for antibacterial interventions. CRISPR/Cas (clustered regularly interspaced palindromic repeats/CRISPR-associated) systems are a bacterial defence against invading foreign nucleic acids derived from bacteriophages or exogenous plasmids1,2,3,4. These systems use an array of small CRISPR RNAs (crRNAs) consisting of repetitive sequences flanking unique spacers to recognize their targets, and conserved Cas proteins to mediate target degradation5,6,7,8. Recent studies have suggested that these systems may have broader functions in bacterial physiology, and it is unknown if they regulate expression of endogenous genes9,10. Here we demonstrate that the Cas protein Cas9 of Francisella novicida uses a unique, small, CRISPR/Cas-associated RNA (scaRNA) to repress an endogenous transcript encoding a bacterial lipoprotein. As bacterial lipoproteins trigger a proinflammatory innate immune response aimed at combating pathogens11,12, CRISPR/Cas-mediated repression of bacterial lipoprotein expression is critical for F. novicida to dampen this host response and promote virulence. Because Cas9 proteins are highly enriched in pathogenic and commensal bacteria, our work indicates that CRISPR/Cas-mediated gene regulation may broadly contribute to the regulation of endogenous bacterial genes, particularly during the interaction of such bacteria with eukaryotic hosts.