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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Sampson, TR; Napier, BA; Schroeder, MR; Louwen, R; Zhao, J; Chin, C-Y; Ratner, HK; Llewellyn, AC; Jones, CL; Laroui, H; Merlin, D; Zhou, P; Endtz, HP; Weiss, DS

Published Date

  • July 29, 2014

Published In

Volume / Issue

  • 111 / 30

Start / End Page

  • 11163 - 11168

PubMed ID

  • 25024199

Pubmed Central ID

  • PMC4121812

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1323025111


  • eng

Conference Location

  • United States