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Han and Yoon: Cyclic di-guanosine monophosphate signaling regulates bacterial life cycle and pathogenicity

Abstract

In order to deal with various environmental conditions, most living organisms adapt and respond to environmental cues through nucleotide-based second-messenger signaling. Such signals regulate various endogenous factors required for environmental adaptation. In bacteria, there are five kinds of nucleotide-based second messengers, one of which is cyclic di-guanosine monophosphate (c-di-GMP). The molecule is known to regulate many cellular functions including growth, motility, biofilm formation, and virulence. Various environmental cues cause changes in the intracellular concentration of c-di-GMP, depending on the activity of specific c-di-GMP synthases and hydrolases in cells. In this review, we provide insights into nucleotide signaling in bacteria, emphasizing its impact on basic metabolism, its association with other signaling mechanisms, and its role in regulating the virulence of a wide range of bacteria. Moreover, we discuss recent studies suggesting a role for the implicated signaling molecules in bacterial persistence and antibiotic resistance.

INTRODUCTION

A multiplicity of living species lives in different natural environments. Some organisms live only in a particular environment, whereas others can adapt to different conditions. All living things detect and respond to changes in environmental cues such as temperature, humidity, light, and nutrients [11]. Many organisms utilize nucleotide-based signaling molecules as second messengers that link environmental signals to the actual organism responses [23]. There are five kinds of nucleotide-based signaling molecules in bacteria such as guanosine tetraphosphate (ppGpp), cyclic di-guanosine monophosphate (c-di-GMP), cyclic di-adenosine monophosphate (c-di-AMP), cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) [29]. These signaling molecules control many physiological functions including growth, biofilm formation, resistance, and virulence.
Nucleotide-based second-messenger-related studies have been conducted in various areas following the first reports about cAMP (1957), ppGpp (1970), cGMP (1974), c-di-GMP (1987), and c-di-AMP (2008) [14]. These signaling molecules have important roles in bacterial physiological control such as the regulation of the lactose operon; cAMP, stress response; ppGpp, cyst formation; cGMP, biofilm formation; c-di-GMP, and cell growth [14]. Another type of signaling in bacteria is quorum sensing, one of the most important signaling systems in bacteria. Quorum sensing is controlled by the population density among the inter- and intra-species of bacteria present, and it uses various molecules such as AI-2, AHL, and PQS [50]. For example, bacteria can detect an excess concentration of AI-2 in the media which indicates a large number of adjacent bacteria. Quorum sensing is important in bacteria because not only is it associated with the nucleotide-based second-messenger response, but also it has critical roles in the survival of bacteria [58]. Many signaling molecules affect the life of bacteria; however, among them, c-di-GMP is the most important second messenger that helps bacteria adapt to various environmental cues and affects the life cycle of the bacteria.
In this review, we introduce c-di-GMP signaling and describe its functional interactions with other signal molecules. In addition, we address the role of c-di-GMP-mediated signaling in the control of bacterial virulence in major pathogens (Table 1). Furthermore, we discuss the role of signaling molecules in the recently emerged phenomenon of antibiotic resistance.

Metabolism and basic role of c-di-GMP

Metabolism of c-di-GMP

Many bacteria have a life cycle that alternates between planktonic cell and biofilm states, and one of the most important factors regulating this cycle is the second messenger, c-di-GMP [21]. c-di-GMP is present in most bacteria and its production is controlled by several synthases and hydrolases. An important c-di-GMP synthase is diguanylate cyclase (DGC), comprising a GGDEF or GGEEF domain and producing c-di-GMP from two GMP molecules [29]. The control of c-di-GMP synthesis is based on an allosteric inhibition mechanism, which prevents excess synthesis and is based on the combination of c-di-GMP with an intermediate site of the DGC protein. An important c-di-GMP hydrolase is called phosphodiesterase (PDE), which contains a HD-GYP or EAL domain and cleaves c-di-GMP into two GMP molecules. PDE activity requires Mg2+ ions, which bind to the active site of PDE and lead to c-di-GMP hydrolysis [48]. Bacterial genomes contain a high copy number of DGC and PDE genes, which is reflected by the presence of 12 GGDEF, 17 EAL, and 7 GGDEF-EAL protein isoforms in Escherichia coli K-12 [43].

c-di-GMP signaling

c-di-GMP transmits signals through various operating mechanisms. The first mechanism is effector protein-mediated signal transduction, typically involving PilZ domain proteins. PilZ domain proteins do not possess enzymatic activities but do contain a c-di-GMP binding domain that is capable of activating protein-protein interactions [48]. Examples of PilZ domain proteins are VC0042 of Vibrio cholerae, PP4398 of Pasteurella putida, and PA4608 of Pseudomonas aeruginosa [29]. A second signaling mechanism controls gene expression via the direct binding of c-di-GMP to transcription factors. The fleQ gene of P. aeruginosa encodes the biofilm matrix component, Pel, which is activated upon c-di-GMP binding [32]. The third mechanism of c-di-GMP-mediated signaling is the degradation of GGDEF or EAL domain proteins that are involved in the synthesis and degradation of c-di-GMP or in the inhibition of its active site. The LapD protein of Pseudomonas fluorescens does not have an enzymatic activity; but it causes degradation of DGC or PDE proteins when combined with c-di-GMP [48]. Finally, c-di-GMP controls riboswitch, thereby also regulating gene expression. Riboswitch is a newly reported type of RNA, first identified by Breaker’s group in 2002 [61]. Riboswitch is composed of two specific parts that are specific proteins for sensing signals and protein encoding sequences. c-di-GMP may also combine with a riboswitch upstream of the open reading frames of DGC and PDE, to control their expression.

c-di-GMP signaling in bacterial virulence

Escherichia coli.

Different types of E. coli can cause various diseases. Bacterial genes with essential functions related to survival are common to many types of E. coli, whereas other genes are type-specific. Genes of the latter group are usually associated with virulence, such as those encoding enterotoxins, T3SS, and adhesion proteins. For this reason, E. coli classification based on the associated pathology is widely used, along with serological classification. The second group of genes includes those encoding DGC and PDE proteins, which control the intracellular concentration of c-di-GMP in E. coli. According to a comparison of the genome sequences of 61 different E. coli strains, only eight of 30 DGCs and PDEs are considered essential genes [43]. Nevertheless, these genes have important roles in the life cycle of E. coli and in relation to type-specific virulence features. An increase in E. coli c-di-GMP can promote the production of matrix components such as cellulose and poly-N-acetyl glucosamine (PNAG), whereas it can decrease flagellar motility [24]. In uropathogenic E. coli, DGC YfiN is not essential for a urinary tract infection (UTI); however, by raising the level of c-di-GMP, it augments the production of cellulose and curli, thereby reducing virulence [47]. In enterotoxigenic E. coli, a DGC-induced rise in c-di-GMP stimulates the expression of the bcs operon resulting in epithelial cell attachment [30]. In enterohemorrhagic E. coli, a decrease in c-di-GMP, due to PDE overexpression, can upregulate T3SS expression which has important roles in intimate adhesion to epithelial cells [26]. Therefore, as different sets of strain-specific genes are involved, additional studies are needed to comprehensively address the functions of c-di-GMP signaling in E. coli.

Pseudomonas aeruginosa.

P. aeruginosa is generally found in the soil, but it can cause opportunistic infections. For instance, P. aeruginosa infections are known to occur in the lungs of patients with cystic fibrosis (CF), and P. aeruginosa may spread, for instance, due to improperly sanitized surgical tools. The most important factor in P. aeruginosa infection of CF patients is alginate, which is a sticky polysaccharide that can block the patient’s airways. c-di-GMP signaling regulates the alginate synthase Alg44, which is a PilZ domain-containing protein [56]. Consistently, alginate production is regulated by c-di-GMP, and this action can be prevented by mutations abolishing the function of Alg44 [38]. As already mentioned, P. aeruginosa infection may be transmitted through surgical tools, on the surface of which a biofilm may be formed, and such transmission can contribute to the development of bacterial resistance to drug and chemical sterilization. P. aeruginosa biofilm formation is regulated by c-di-GMP upon its combination with fleQ. This complex activates pel and psl operons to form exopolysaccharide [34]. In addition, c-di-GMP signaling affects the expression of type II secretion system, T3SS, and type IV pili, which are virulence factors of P. aeruginosa, thereby also regulating flagellar motility and the generation of lipopolysaccharide (LPS) [18]. Furthermore, the significant changes previously observed in the in vivo virulence of either DGC or PDE mutant strains in mice indicate that c-di-GMP signaling also has a major role in in vivo infections [32].

Vibrio cholera.

V. choleraeis usually transmitted through the consumption of contaminated water or food. In the natural environment, V. choleraeis in the form of biofilms, and therefore, it is resistant to nutrient-poor, harsh environments. When V. choleraereaches the stomach, it reacts to the low pH by producing cholera toxin and toxin-coregulated pili, i.e., the main virulence factors of V. cholerae. These virulence factors cause an imbalance in ion concentrations and the loss of water from host intestinal cells, resulting in diarrhea. In addition to cholera toxin, another important virulence factor is TCP, which contributes to the attack and colonization of the small intestine. Once V. choleraeexits the host, it again forms biofilms in order to survive in the external environment, and c-di-GMP signaling is involved in this transition [13]. For biofilm formation, expressions of vibrio polysaccharide (vps) and mannose-sensitive hemagglutinin (msh) operons are induced [4], whereas those of virulence genes and cholera toxin, required for host infection, decrease, along with flagella motility. c-di-GMP signaling acts, during the life cycle of V. cholerae, as a key regulator in the transition between the survival state, in the external environment, and the infectious state, in the host [62]. The MSH protein, a downstream effector of c-di-GMP, has a major role in in vivo infections, and an msh mutant strain displays strongly reduced virulence, compared to the wild-type (WT) strain, in which virulence is known to be associated with an escape mechanism from IgA-mediated immunity in the host [51].

Salmonella Typhimurium.

S. Typhimurium causes enteritis and septicemia and can infect multiple hosts. S. Typhimurium has two pathogenicity islands (SPI); SPI1 contains the genes needed for host infection and SPI2 is implicated in phagosomal survival. Both SPI1 and SPI2 are regulated by c-di-GMP signaling. The control of biofilm formation, requiring exopolysaccharide, cellulose, as well as curli fimbriae and flagellar motility, is affected by c-di-GMP signaling in S. Typhimurium [52]. For cellulose generation, c-di-GMP binds to BcsA, and this complex activates BcsB to synthesize cellulose [17]. Moreover, c-di-GMP signaling activates CsgD, a transcriptional activator, and stimulates the cgsABC operon to produce curli fimbriae [24]. The increase in c-di-GMP in DGC-overexpressing or PDE mutant strains of S. Typhimurium reduces adhesion to the cell surface and in vivo virulence [33]. In addition, c-di-GMP signaling increases in vivo virulence in bcs and csg mutant strains, compared to that of the WT strain; however, if the pga operon is activated, survival in the macrophage is reduced. As a result, c-di-GMP signaling in S. Typhimurium regulates the expression of genes associated with virulence and biofilm formation, thereby affecting survival and virulence during in vivo infection.

Yersinia pestis.

Y. pestis is a Gram-negative bacterium causing the plague, acute fever, and is primarily transmitted by fleas. Y. pestis hosts include mammals and fleas, and its life cycles between the flea and the mammalian host when the fleas suck host blood. Y. pestis uses T3SS and the Pla protease to escape the host immune system and the heme storage system (HMS) to form a biofilm in the digestive tract of the flea. The biofilm disrupts the digestive system, which in turn causes the fleas to starve. The surviving fleas may suck blood from other hosts, allowing for the propagation of Y. pestis in other hosts [25]. The life cycle of Y. pestis, carried out through the transition between the mammalian host and the flea, is controlled by c-di-GMP signaling. The formation of a biofilm, which has a major role in the life cycle of Y. pestis, is related to the expression of the hms gene and involves two DGC and one PDE protein isoforms. The hms gene product produces exopolysaccharide to form the biofilm, allowing for Y. pestis survival in the flea [41]. However, considering that the in vivo virulence is significantly decreased in the PDE mutant strain, it is likely that biofilm formation, based on exopolysaccharide, inhibits systemic interaction [5]. On the other hand, in an ingestion experiment performed in fleas and using a DGC mutant Y. pestis strain, bacterial clearance from the digestive system was higher than in the WT strain, indicating that DGC has a role in bacterial survival in the flea [5]. Therefore, c-di-GMP signaling in Y. pestis has a major role in the control of the bacterial life cycle allowing survival in the vector and infection in the host.

Functional interactions of c-di-GMP with other signaling molecules

Pathogens may infect their hosts through a variety of pathways. To adapt to the environmental conditions inside the host, pathogens must adopt survival strategies and undergo a number of changes, including those that allow them to escape the host immune system. Many bacteria use nucleotide-based signaling molecules to sense and respond to environmental changes. These signaling molecules are closely related to the bacterial communication system referred to as quorum sensing (Fig. 1). If a high number of bacteria occupy a limited space, especially in the case of a nutrient shortage, they are able to estimate the surrounding population density by quorum sensing. Quorum sensing is reported to accompany the bacterial stringent response as poor-nutrient level stress increases ppGpp signaling. In addition, if glucose is lacking, the cAMP level also increases to start secondary carbon source metabolism. These observations indicate that signaling molecules do not work independently, but act in coordination and can influence each other. When E. coli growth reaches the stationary phase, amino acid starvation increases RelA-dependent ppGpp production and induces the expression of the stationary sigma factor [59]. This, in turn, regulates the expression of many DGC and PDE proteins, such as yedQ, ydaM, yegE, yciR, yaiC, and yoaD, that affect motility, adhesion, and biofilm formation by adjusting the concentration of c-di-GMP (Fig. 1). ppGpp also inhibits the expression of FlhDC, the motility master complex, whereas the cAMP-CRP complex activates FlhDC [60]. However, YcgR combining with c-di-GMP can function as a brake and inhibit flagellar motility [40]. The expression of mlrA is increased by the stationary sigma factor, whereas that of csgD is increased by c-di-GMP, inducing attachment via the expression of curli fimbriae [55]. Other signal transduction mechanisms associated with the stationary sigma factor regulate the c-di-GMP concentration through DGC YaiC and PDE YoaD, which leads to the expression of BcsA to produced cellulose, an important biofilm component in E. coli (Fig. 1). CsrA, a carbon storage receptor, is a protein involved in various signal transduction pathways in E. coli [28]. CsrA regulates motility and biofilm formation, as well as carbon metabolism, and has an important role in the motility-to-sessility transition. CsrA can stabilize the FlhDC transcript and increase PDE YhjH to activate motility [28]. Moreover, CsrA acts as a strong repressor of the DGCs YcdT and YdeH, thereby preventing the reduction in motility caused by these enzymes. In addition, CsrA is involved in PAG-mediated biofilm formation and can interfere with the action of the quorum-sensing receptor [6]. Although these signaling molecules perform their respective roles independently, they can also act in coordination and participate in complex mechanisms. However, much is still unknown about the relationships between these signaling molecules, and, in view of recent studies, further efforts are necessary to evaluate the role of cGMP and c-di-AMP and to integrate new findings with previously established information on known signaling factors.

c-di-GMP and bacterial persistence

Since the discovery of the first antibiotic drug, penicillin, in the late 1920s, antibiotics have been used to treat numerous bacterial infectious diseases. However, in recent years, the risk of infectious diseases that are untreatable with antibiotics, due to antibiotic resistance, is increasing. There are many diseases caused by antibiotic resistance, and one mechanism associated with the development of antibiotic resistance is bacterial persistence. Persistence occurs when a bacterium, exposed to severe stress or antibiotics, acquires a dormant state to survive. In this state, its growth rate is decreased, reducing the effects of the drugs. The systems involved in bacterial persistence include SOS responses, which are general stress responses, toxin-antitoxin (TA) modules associated with the second messenger ppGpp, and c-di-GMP-regulated biofilm formation [36]. The TisB/IstR TA modules are activated by the SOS response and RecA as a consequence of DNA damage [22]. TisB is a protein present in the inner membrane that inhibits proton-motile force (PMF), thus disrupting ATP synthesis and maintaining the dormancy state. ppGpp, a stress response alarmone, is involved in the regulation of HipA/HipB TA modules. HipA is an mRNA endonuclease, which inhibits Glu-tRNA synthetase to increase uncharged tRNA (Glu) generation and induces a RelA-dependent ppGpp increase [20]. ppGpp activates the Lon protease, which degrades HipB, an antitoxin, and consequently activates HipA [19]. HipA acts as a translocation inhibitor, slowing growth and promoting the dormancy state. A biofilm induced by c-di-GMP not only confers high resistance in the external environment but also hinders the penetration of drugs, including antibiotics, and slows down cell growth and metabolism. By preventing drugs from reaching their effective concentrations and by decreasing their metabolism, bacteria adopt a persistence phenotype. Recent studies, combining ppGpp or c-di-GMP analogs to selectively disrupt the relevant signals and to enhance antibiotic efficiency, have shown that persistence is involved in the development of bacterial resistance to antibiotics [54].

Concluding remarks

Many bacteria use signaling molecules to adapt to and survive in the natural environment. Besides nucleotide-based signal molecules, such as c-di-GMP, and quorum-sensing molecules, such as AI-1, AI-2, and PQS, cell-cell communication also has an important role in signaling. c-di-GMP and other signaling molecules not only promote growth and survival but also enhance the effectiveness of an infection through the regulation of virulence factors, which is necessary for infection by pathogenic bacteria. However, there is still a lack of information on the implicated signaling molecules, especially in relation to their close involvement in the phenomena of antibiotic resistance that has emerged in recent years. Therefore, we strongly suggest that additional studies focusing on anti-bacterial and anti-biofilm drugs are needed. Future research should focus on the overall interactions between various signals by initiating studies that approach this subject with a broad perspective, one that goes beyond the characterization of individual signaling molecules.

ACKNOWLEDGMENTS

The study was supported by grants from National Research Foundation (NRF-2011-0010224 and NRF-2017R1A2B4013056), Republic of Korea.

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Fig.Β 1.
Functional interactions of c-di-GMP with other signaling molecules
jpvm-2019-43-1-38f1.tif
TableΒ 1.
Role of c-di-GMP signaling in bacteria
Phenotype c-di-GMP Protein Organism References
Cellulose synthesis or inhibition Variable AxDGC2, AxPDEA1 A. xylinus [9, 46]
High BcsA G. xylinus [49]
High YdaM E. coli [59]
Biofilm formation for inhibition High BpeGReg B. pertussis [57]
Low PvrR P. aeruginosa [32]
High SwDGC S. woodyi [37]
High LapD P. fluorescens [39]
High VpsT, PlzB V. cholerea [31, 44]
High Bcam1349 B. cenocepacia [15]
Motility regulation Variable DgcA, DgrA C. crescentus [10, 11]
Variable DgcK, DgcL V. cholera [7]
Variable ScrC V. parahaemolyticus [16]
Variable PilZ, FimX P. aeruginosa [2, 45]
Flagella activity High PleD C. crescentus [8]
High YcgR E. coli [49]
Variable FleQ P. aerugenosa [53]
Curli fimbriae Low RocR P. aerugenosa [59]
Low YciR E. coli [27]
Variable MrKI K. pneumoniae
Host infection Variable STM3615, STM2672 S. Typhimurium [1]
Low BpdA, CgsB B. melitensis [42]
Low YhjH, YaiC E. coli [12]
Low DGCs L. pneumophila [35]
Variable DGCs, PDEs P. aeruginosa [32]
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