Small non-coding RNAs in virulence and immunity of Brucella

doi:10.15406/jbmoa.2018.06.00204

Journal of

eISSN: 2469 - 2786

Bacteriology & Mycology: Open Access

Mini Review Volume 6 Issue 3

Small non-coding RNAs in virulence and immunity of Brucella

Khalid A Enanm

Verify Captcha

Regret for the inconvenience: we are taking measures to prevent fraudulent form submissions by extractors and page crawlers. Please type the correct Captcha word to see email ID.

College of Life Sciences, Guangzhou University, China

Correspondence:

Received: May 12, 2018 | Published: May 29, 2018

Citation: Ahmeda W. Small non-coding RNAs in virulence and immunity of Brucella. J Bacteriol Mycol Open Access. 2018;6(3):197-198. DOI: 10.15406/jbmoa.2018.06.00204

Download PDF

Abstract

Brucella species are equipped with a variety of well-organized immune evasion strategies to establish chronic infection, including the use of small non-coding RNAs (sRNAs). In this review, the involvement of sRNAs in regulation of virulence and intracellular survival of Brucella is discussed. Further it highlights the role of sRNAs in modulation of innate and adaptive immune response mechanism of Brucella, which will improve our understanding of brucellosis and development of effective therapeutic approaches to treat this infectious disease.

Keywords: Brucella, small non-coding RNA, immunity, virulence, CRISPR sRNAs

Introduction

Bacterial small non-coding RNAs (sRNAs) have equipped with various mechanisms to balance their target gene expression and respond to environmental changes, stressful conditions and pathogenesis. These sRNAs are typically 50-200nt in length and act on independently expressed targets, do not encompass fully expressed open reading frames (ORFs).¹ These molecules are employing multiple molecular strategies to regulate gene expression, and divided into different classes such as cis-encoded sRNAs, trans-encoded sRNAs, CRISPR sRNAs and protein binding sRNAs. They modulate a variety of functions ranging from DNA maintenance or silencing, translation, transcription and mRNA stability.²

Brucella is Gram-negative, intracellular in nature, facultative, non-motile, non-spore-forming anaerobe which mainly causes infertility and abortion in wide range of animals and induces debilitating febrile diseases in humans. Brucella displays different strategies to modulate the immune response mechanism of its host to adapt the diverse environments through virulence factors or adaptation to structural components such as residing within phagocytic cells.^3,4 The activation and differentiation of innate and adaptive immune cells is associated with well-organized set of post-transcriptional and transcriptional events. sRNAs are linked directly or indirectly to regulate expression of gene related to virulence, quorum-sensing or adaptive stress-responses, which are essential for Brucella survival within host.⁵ sRNAs critical roles in modulation of immune response mechanism upon Brucella infection is now growing. In this review, we summarize the role of sRNA in regulation of innate and adaptive immune response, host-pathogen interaction as well as implication of these modulations in the pathogenesis of brucellosis.

sRNA in modulation of virulence and intracellular survival of Brucella

sRNA plays critical roles in modulation of virulence and intracellular survival of Brucella. Caswell et al.⁶ identified two highly conserved AbcR sRNAs (AbcR1 and AbcR2) that are essential for the ability of the Brucella to establish a chronic infection in mice.⁶ Interestingly, AbcR sRNAs seem to be functionally redundant, as construction of a double abcR1 abcR2 (abcR1/2) deletion mutant strain leads to significant attenuation in vitro and in vivo.^6,7 Furthermore, AbcR sRNA plays key roles in regulation of ABC-transport system, such as B. abortus VtlR transcription regulator regulate several mRNAs that are directly targeted by AbcR sRNAs, and increased gene regulatory expression was observed with ΔAbcR sRNAs.⁸

In addition, they identified two M1 (CUCCCA) and M2 (GUUCCC) motifs in AbcR sRNA. These complementary motif sequences were identified in AbcR-regulated mRNA transcripts, suggesting that M1 and M2 motifs within the AbcR sRNAs are essential for direct binding and regulation of Brucella transcripts.⁹ The conserved seed region of AbcR1 is responsible for regulating multiple target mRNAs belonging to transcriptional factor and two component response regulator of Brucella melitensis.¹⁰ A BSR0602 sRNA directly target gntR mRNA and play important roles in bacterial adaptation to stress conditions and thus facilitates the intracellular survival of Brucella.¹¹ A large number of Brucella sRNA was identified using strand-specific RNA deep-sequencing approach, and BSR0441 was further characterized that involved in the virulence and stress adaptation of Brucella.¹²

A new cis-encoded sRNA, Brucella sRNA regulating HemH, BsrH , was considered to be first stress response related sRNA identified and functionally characterized.¹³ Dong et al.¹⁴ identified 129 sRNA of Brucella that plays significant roles in diverse biological processes ranging from physiology to virulence as well as in host-pathogen interaction.¹⁴ In Brucella melitensis 16M ΔotpR, 877 cis-encoded and 99 trans-encoded sRNAs were identified and functionally characterized under acidic stress. These newly identified sRNAs are involved in various pathways including metabolism, lipids, carbohydrates, nucleotides transport, cell membrane biogenesis, quorum sensing, virulence and intracellular trafficking of Brucella.¹⁵ Recent advancement in next-generation sequencing technologies have led to the identification of 33 sRNAs and 62 Hfq-associated mRNAs that play key roles in the pathogenesis and intracellular survival of Brucella.¹⁶

sRNA in regulation of innate and adaptive immune response of Brucella

MicroRNAs are integral constituent of small noncoding RNA plays significant role in modulation of immune response, gene expression, cellular mechanisms, signal transduction and apoptosis. Although knowledge and involvement of miRNAs in developing and regulating immune response mechanism of Brucella is on initial stages, recent evidences found that miRNAs plays important function in modulation of immune mechanism. Zheng et al.¹⁷ reported differential expression of miR-181b, miR-1981, miR-92a, let-7b and miR-93 in Brucella melitensis infected cells as compared with mock infected cells, suggesting the involvement of these miRNAs in apoptosis, autophagy and immune response mechanism.¹⁷ miR-125b-5p down regulation was observed during Brucella abortus infection that result in higher expression of A20 protein, highlighting the role in inhibition of NF-κB activation as well as increasing Brucella intracellular survival.¹⁸

Recently, miRNA expression analysis of human CD8+ T cells revealed the involvement of miRNAs in cytokine-cytokine receptor interactions, regulation of actin cytoskeleton, MAPK signaling pathway, focal adhesion and endocytosis, suggesting miRNAs key roles in establishing chronic Brucella infection.¹⁹ Furthermore, Brucella Omp25 prompts miR-21-5p, miR-23b and miR-155 to negatively modulate interleukin-12 production at posttranscriptional and transcriptional level through regulating PD-1 signaling pathway, which describe the novel mechanism underlying macrophage/monocyte dysfunction in Brucella chronic infection.²⁰ In contrast, inhibition of miR-351-5p, miR-146a, miR-181a and miR301a-3p reduced the inhibitory effects of Omp25 in RAW264.7 cells, while miR-351-5p, miR-146a, miR-181a and miR301a-3p leads to decrease in production of LPS-induced TNF-α in PAMs, indicating reduced intracellular bacteria number and higher TNF-α production in both cells.²¹

Conclusion and future perspectives

sRNA plays pivotal function in modulation of virulence gene expression and provides favorable environment to pathogenic bacteria to survive and proliferate within host. The incredible attention in sRNAs as watchdogs of bacterial gene expression keeps powering the inspiration of researchers in their interest for investigating novel strategies for identification and functional characterization of bacterial pathogens. sRNA plays critical roles in regulation of virulence and intracellular survival, as well as in modulation of innate and adaptive immune response mechanism of Brucella. However, further investigation are required to fully understand the involvement of miRNAs in modulation of innate and adaptive immune response such as how they monitor the TLR signaling pathway, miRNA based stealth strategies of Brucella for immune evasion. How do miRNAs participate in regulation of apoptosis and autophagy mechanism of Brucella is an open question.