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      Deletion of the Small RNA Chaperone Protein Hfq down Regulates Genes Related to Virulence and Confers Protection against Wild-Type Brucella Challenge in Mice

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          Brucellosis is one of the most common zoonotic epidemics worldwide. Brucella, the etiological pathogen of brucellosis, has unique virulence characteristics, including the ability to survive within the host cell. Hfq is a bacterial chaperone protein that is involved in the survival of the pathogen under stress conditions. Moreover, hfq affects the expression of a large number of target genes. In the present study, we characterized the expression and regulatory patterns of the target genes of Hfq during brucellosis. The results revealed that hfq expression is highly induced in macrophages at the early infection stage and at the late stage of mouse infection. Several genes related to virulence, including omp25, omp31, vjbR, htrA, gntR, and dnaK, were found to be regulated by hfq during infection in BALB/c mice. Gene expression and cytokine secretion analysis revealed that an hfq-deletion mutant induced different cytokine profiles compared with that induced by 16M. Infection with the hfq-deletion mutant induced protective immune responses against 16M challenge. Together, these results suggest that hfq is induced during infection and its deletion results in significant attenuation which affects the host immune response caused by Brucella infection. By regulating genes related to virulence, hfq promotes the virulence of Brucella. The unique characteristics of the hfq-deletion mutant, including its decreased virulence and the ability to induce protective immune response upon infection, suggest that it represents an attractive candidate for the design of a live attenuated vaccine against Brucella.

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          Most cited references 32

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          Regulatory RNAs in bacteria.

          Bacteria possess numerous and diverse means of gene regulation using RNA molecules, including mRNA leaders that affect expression in cis, small RNAs that bind to proteins or base pair with target RNAs, and CRISPR RNAs that inhibit the uptake of foreign DNA. Although examples of RNA regulators have been known for decades in bacteria, we are only now coming to a full appreciation of their importance and prevalence. Here, we review the known mechanisms and roles of regulatory RNAs, highlight emerging themes, and discuss remaining questions.
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            The role of Hfq in bacterial pathogens.

            The ubiquitous RNA-binding protein, Hfq, has been shown to be required for the fitness and virulence of an increasing number of bacterial pathogens. Mutants lacking Hfq are often sensitive to host defense mechanisms and highly attenuated in animal models, albeit there is considerable variation in both severity and extent of phenotypes. RNomics and deep sequencing (RNA-seq) approaches discovered the small RNA and mRNA targets of Hfq, and indicated that this protein might impact on the expression of up to 20% of all genes in some organisms, including genes of type 3 secretion systems. Hfq also facilitates post-transcriptional cross-talk between the core and variable genome regions of bacterial pathogens, and might help integrate horizontally acquired virulence genes into existing regulatory networks. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Mechanism of RNA silencing by Hfq-binding small RNAs.

               H Aiba (2007)
              The stress-induced small RNAs SgrS and RyhB in Escherichia coli form a specific ribonucleoprotein complex with RNAse E and Hfq resulting in translation inhibition, RNAse E-dependent degradation of target mRNAs. Translation inhibition is the primary event for gene silencing and degradation of these small RNAs is coupled with the degradation of target mRNAs. The crucial base-pairs for action of SgrS are confined to the 6 nt region overlapping the Shine-Dalgarno sequence of the target mRNA. Hfq accelerates the rate of duplex formation between SgrS and the target mRNA. Membrane localization of target mRNA contributes to efficient SgrS action by competing with ribosome loading.

                Author and article information

                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                20 January 2016
                : 6
                1Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University Chengdu, China
                2Institute of Disease Control and Prevention, Academy of Military Medical Science Beijing, China
                3Inner Mongolia Key Laboratory of Molecular Biology, Inner Mongolia Medical University Hohhot, China
                4Experimental Animal Center, Academy of Medical Sciences Beijing, China
                5Department of Laboratory Medicine, The General Hospital of Chinese People's Armed Police Forces Beijing, China
                6College of Medicine, Shihezi University Shihezi, China
                Author notes

                Edited by: Heinrich Korner, Menzies Institute for Medical Research, Australia

                Reviewed by: Yongqun “Oliver” He, University of Michigan, USA; Gregory T. Robertson, Colorado State University, USA; Sukanya Narasimhan, Yale University School of Medicine, USA

                *Correspondence: Yufei Wang yufeiwang21@ ;
                Guangneng Peng pgn.sicau@ ;

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology

                †These authors have contributed equally to this work.

                Copyright © 2016 Lei, Zhong, Ke, Yang, Xu, Ren, An, Yuan, Yu, Xu, Qiu, Shi, Wang, Peng and Chen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 43, Pages: 12, Words: 7582
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81171530
                Award ID: 31272592
                Award ID: 81401646
                Award ID: 81071320
                Funded by: Natural Science Foundation of Beijing Municipality 10.13039/501100004826
                Award ID: 6122030
                Award ID: 7132153
                Funded by: Chinese Center for Disease Control and Prevention 10.13039/501100004476
                Award ID: 2013ZX10004-203
                Award ID: 2013ZX10004-217-002
                Award ID: 2013ZX10004805-006
                Original Research


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