**6. Ca2+ signals during host-pathogen interactions**

Pathogenic bacteria have evolved various strategies to successfully colonize and cause infection in their hosts. Intracellular Ca2+ mobilization has been implicated as an important signaling event during bacterial adhesion, invasion and intracellular replication during infection [6]. Interestingly, some pathogens induce Ca2+ increases while others interfere with the Ca2+ signal to promote invasion [9, 94, 95]. However, despite the significant role of Ca2+ signaling during pathogenesis, the mechanisms underlying how bacterial cells and their virulent factors manipulate Ca2+ mobilization in host cells remains to be elucidated. This section will present some examples of the role of Ca2+ in host-pathogen interactions.

phagosmes or disrupt cell-cell junctions (Tran Van Nhieu [6]; Reboud et al. [102]). Interestingly, some pore-forming toxins such as *Listeria* listeriolysin O (LLO) induce Ca2+ oscillations as a result of a direct Ca2+ influx via the pore-forming toxin. An interesting feature of LLO is that pores open and close in a synchronized fashion leading to long lasting Ca2+ oscillating signaling provoking a broad spectrum of cellular responses during infection [6, 103]. Two other pore-forming toxins produced by the opportunistic pathogens *P. aeruginosa* (ExlA) and *Serratia marcescens* (ShlA), which share similar structural and functional aspects, have the capacity to trigger Ca2+ influx leading to disruption of cell-cell junctions of epithelial and endothelial cells. This influx of Ca2+ activates a metalloproteinase called 10(ADAM 10), which cleaves cadherin inducing cell-cell-junction breakdown and loss of tissue integrity [102].

Calcium Signaling in Prokaryotes

99

http://dx.doi.org/10.5772/intechopen.78546

There is a great diversity of Ca2+-dependent processes that pathogens utilize to cause infection. However, studies on bacterial induced Ca2+ signaling are limited. More research is needed in this filed to understand the mechanisms of how bacterial virulence factors regulate second

The role of Ca2+ in bacteria is a fascinating field that still remains unexplored. It is clear that evidence supporting the role of calcium as a regulator in prokaryotes is accumulating. However, the extent and significance remains unclear. A systematic assessment and careful

I thank Dr. Rossetta N. Reusch for agreeing to reproduce figures of her work and Samantha

Clinical Laboratory Science/Public Health, The University of Texas at El Paso, El Paso, Texas,

messengers such as Ca2+ and Ca2+-dependent events during the infectious processes.

analysis of the processes involving calcium warrants further analysis.

**7. Conclusion**

**Acknowledgements**

**Conflict of interest**

**Author details**

USA

Delfina C. Domínguez

Meza for assisting with the references.

The author has no conflict of interest.

Address all correspondence to: delfina@utep.edu

*Neisseria meningitidis* (meningococci) is the causative agent of bacterial meningitis. Pili are one of the major virulent factors of meningococci. Pili are bacterial structures that play an important role in adhesion to host cells. Analyzing the role of Ca2+ during *N. meningitides* infection, Asmat et al. [9] found that the meningococcal protein PilC1 triggered a significant increase of cytosolic Ca2+ in human brain microvascular endothelial cells (HBMEC), which was critical for adherence and subsequent internalization into host endothelial cells. Use of the Ca2+ chelator, BAPTA-AM, significantly reduced PilC1-mediated meningococcal adherence. Mutants deficient in PilC1 were not able to increase cytosolic Ca2+ in endothelial host cells. Pretreatment of host cells with the phospholipase inhibitor, U73122, indicated that the Ca2+ increase in endothelial cells was mediated by phospholipase C (PLC). Similar findings where Ca2+ mediated adherence to host cells occur through pili were reported in *P. aeruginosa* [96] and efficient internalization via PLC was reported in *Campylobacter jejuni* [97] and *Borrelia burgdorferi* [98].

*Shigella* is another pathogen that utilizes Ca2+ signaling during infection of epithelial cells. *Shigella* is the etiologic agent of bacillary dysentery. This pathogen invades the intestinal mucosa producing massive destruction of the colonic epithelium by eliciting a strong inflammatory response [6]. As early as 5 min after bacterial contact with epithelial cells *Shigella* induces local Ca2+ signals in the host cell, which remodel the cytoskeleton allowing bacterial entrance to the cells. Global Ca2+ signals are involved in later stages of infection promoting slow cell death as a result of plasma membrane permeabilization and increased cytosolic Ca2+. *Shigella* also manipulates the Ca2+ signal to interfere with immune responses and inflammation [99]. Global Ca2+ signals have also been associated with an induced decrease of sumoylation by *Shigella*. Sumoylation is a posttranslational modification by *S*mall *U*biquitin *Mo*difier (SUMO) proteins, which is an essential regulatory mechanism involved in several processes including protein stability, cell cycle, cell communication and gene expression [100]. At late time of postinfection, *Shigella* induces inhibition of sumoylation through activation of calpain proteases, which degrade SUMO proteins [101]. Inhibition of Ca2+ influx or calpain activity prevented shigella-induced loss of sumoylation. On the other hand Ca2+ treatment and inomycin resulted in sumoylation inhibition [101]. Knowledge of how pathogens interfere with SUMO enzymatic machinery is limited and remains to be characterized.

Several bacterial pathogens secrete potent virulence factors such as pore-forming toxins. These toxins perforate host cell membranes in order to deliver virulence factors, escape from phagosmes or disrupt cell-cell junctions (Tran Van Nhieu [6]; Reboud et al. [102]). Interestingly, some pore-forming toxins such as *Listeria* listeriolysin O (LLO) induce Ca2+ oscillations as a result of a direct Ca2+ influx via the pore-forming toxin. An interesting feature of LLO is that pores open and close in a synchronized fashion leading to long lasting Ca2+ oscillating signaling provoking a broad spectrum of cellular responses during infection [6, 103]. Two other pore-forming toxins produced by the opportunistic pathogens *P. aeruginosa* (ExlA) and *Serratia marcescens* (ShlA), which share similar structural and functional aspects, have the capacity to trigger Ca2+ influx leading to disruption of cell-cell junctions of epithelial and endothelial cells. This influx of Ca2+ activates a metalloproteinase called 10(ADAM 10), which cleaves cadherin inducing cell-cell-junction breakdown and loss of tissue integrity [102].

There is a great diversity of Ca2+-dependent processes that pathogens utilize to cause infection. However, studies on bacterial induced Ca2+ signaling are limited. More research is needed in this filed to understand the mechanisms of how bacterial virulence factors regulate second messengers such as Ca2+ and Ca2+-dependent events during the infectious processes.
