A CRISPR-Cas system enhances envelope integrity mediating antibiotic resistance and inflammasome evasion

TR Sampson, BA Napier, MR Schroeder, Rogier Louwen, JS Zhao, CY Chin, HK Ratner, AC Liewellyn, CL Jones, H Laroui, D Merlin, P Zhou, Hubert Endtz, DS Weiss

Research output: Contribution to journalArticleAcademicpeer-review

67 Citations (Scopus)

Abstract

Clustered, regularly interspaced, short palindromic repeats-CRISPR associated (CRISPR-Cas) systems defend bacteria against foreign nucleic acids, such as during bacteriophage infection and transformation, processes which cause envelope stress. It is unclear if these machineries enhance membrane integrity to combat this stress. Here, we show that the Cas9-dependent CRISPR-Cas system of the intracellular bacterial pathogen Francisella novicida is involved in enhancing envelope integrity through the regulation of a bacterial lipoprotein. This action ultimately provides increased resistance to numerous membrane stressors, including antibiotics. We further find that this previously unappreciated function of Cas9 is critical during infection, as it promotes evasion of the host innate immune absent in melanoma 2/apoptosis associated speck-like protein containing a CARD (AIM2/ASC) inflammasome. Interestingly, the attenuation of the cas9 mutant is complemented only in mice lacking both the AIM2/ASC inflammasome and the bacterial lipoprotein sensor Toll-like receptor 2, but not in single knockout mice, demonstrating that Cas9 is essential for evasion of both pathways. These data represent a paradigm shift in our understanding of the function of CRISPR-Cas systems as regulators of bacterial physiology and provide a framework with which to investigate the roles of these systems in myriad bacteria, including pathogens and commensals.
Original languageUndefined/Unknown
Pages (from-to)11163-11168
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of Ame
Volume111
Issue number30
DOIs
Publication statusPublished - 2014

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