CRISPR (clustered regularly interspaced short palindromic repeats)–Cas (CRISPR-associated) systems are known to mediate bacterial defence against foreign nucleic acids. We recently demonstrated a non-canonical role for a CRISPR–Cas system in controlling endogenous gene expression, which had not previously been appreciated. In the present article, we describe the studies that led to this discovery, beginning with an unbiased genome-wide screen to identify virulence genes in the intracellular pathogen Francisella novicida. A gene annotated as encoding a hypothetical protein, but which we now know encodes the Cas protein Cas9, was identified as one of the most critical to the ability of F. novicida to replicate and survive during murine infection. Subsequent studies revealed a role for this protein in evasion of the host innate immune response. Specifically, Cas9 represses the expression of a BLP (bacterial lipoprotein) that could otherwise be recognized by TLR2 (Toll-like receptor 2), a host protein involved in initiating an antibacterial pro-inflammatory response. By repressing BLP levels, Cas9 mediates evasion of TLR2, promoting bacterial virulence. Finally, we described the molecular mechanism by which Cas9 functions in complex with two small RNAs to target the mRNA encoding the BLP for degradation. This work greatly broadened the paradigm for CRISPR–Cas function, highlighting a role in gene regulation that could be conserved in numerous bacteria, and elucidating its integral contribution to bacterial pathogenesis.
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December 2013
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Conference Article|
November 20 2013
Cas9-dependent endogenous gene regulation is required for bacterial virulence
Timothy R. Sampson
;
Timothy R. Sampson
*Microbiology and Molecular Genetics Program, Laney Graduate School, Emory University, 201 Dowman Drive, Atlanta, GA 30322, U.S.A.
†Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, U.S.A.
‡Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, U.S.A.
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David S. Weiss
David S. Weiss
1
†Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, U.S.A.
‡Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, U.S.A.
§Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, U.S.A.
1To whom correspondence should be addressed (emaildavid.weiss@emory.edu).
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Biochem Soc Trans (2013) 41 (6): 1407–1411.
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Received:
July 23 2013
Citation
Timothy R. Sampson, David S. Weiss; Cas9-dependent endogenous gene regulation is required for bacterial virulence. Biochem Soc Trans 1 December 2013; 41 (6): 1407–1411. doi: https://doi.org/10.1042/BST20130163
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