Kevin B. Clark- Research and Development Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Introduction
Combined serendipitous and rational drug-design and -retasking approaches continue to identify many natural and synthetic substances with multipurpose therapeutic properties (Clark, 2013a). Among these substances are Ca2+ modulators capable of attenuating the transmission and severity of viral, bacterial, fungal, and protozoal infections (Clark and Eisenstein, 2013; Clark et al., 2013). The majority of purported Ca2+-modulating antiinfective compounds belong to the functional drug class termed Ca2+-channel blockers, including traditional synthetic 1,4-dihydropyridines, phenylalkylamines, and benzodiazepines long approved and marketed for various human and animal cardiovascular and neurological indications (Clark and Eisenstein, 2013; Clark et al., 2013). Additional Ca2+-modulating (putative) antiinfective substances, such as artemisinin, caloxin, dantrolene, cyclosporin A, and FK506, can be further categorized within a broader set of natural and synthetic compounds that affect operation of Ca2+ channels, transporters, exchangers, and/or protein sensors of both hosts and infectious agents (Clark and Eisenstein, 2013; Clark et al., 2013). Notably, depending on chemical structure, site, and mechanism of chemical action, and delivered chemical concentrations, these and other non-traditional antimicrobial and -viral compounds, many of which are expressed by pathogens themselves, may instead exert helpful trophic effects on hosts, their symbiotic microbiota, and harbored mutualistic copathogens. The reasons for such biphasic drug-response profiles partly derive from how pathogens evolved to parasitize host Ca2+-dependent functions and resources, yielding insights into devising better antiinfective treatment regimens and new valued probiotic medicines.
Pathogen Usurpation of Host Ca2+ Systems
Viruses, bacteria, fungi, and protozoa evolved the strong obligate parasitic strategy of hijacking host systems to augment their comparatively primitive genomic, epigenomic, and somatic capabilities, thereby facilitating infectious disease adaptation and propagation. Though infectious agents coopt many different host systems, few are more significant than host intracellular Ca2+ signaling pathways. Free intracellular Ca2+ serves as an intermediate between sensory input and response output for all known cellular life. Its ubiquitous presence within cells of diverse phylogeny and function makes Ca2+ an essential messenger for controlling host-cell stress responses, fate and death, synaptic plasticity, homeostasis, motility, bioenergetics, growth, morphogenesis, immunodefenses, protein modification and transport, cytoskeletal polymerization, endosome formation, and various other host processes (Clark and Eisenstein, 2013; Clark et al., 2013). Therefore, the ability of microbes to preferentially control host intracellular Ca2+ pathways enables them to optimize the timing and effectiveness of infection stages against barriers to invasion, pathogenesis, proliferation, and release (Moreno and Docampo, 2003; TranVan et al., 2004; Kozubowski et al., 2009; Zhou et al., 2009; Clark and Eisenstein, 2013; Clark et al., 2013).
Pathogens, mainly via toxic proteins and lipopolysaccharides, manipulate host intracellular Ca2+ systems by modulating (1) ligand- [e.g., N-methyl-D-aspartate receptors (NMDAr)] and voltage-gated (e.g., L-, N-, P/Q-, R-, and T-type receptors and Bsc1, Cch1, and NaChBac receptors) channels that permit Ca2+ entry from extracellular spaces, (2) upstream first or second messengers (e.g., inositol 1,4,5-trisphosphate (IP3), AMP-activated protein kinase, and mitogen-activated protein kinase pathways), (3) ion- (e.g., Ca2+/H+ and Na+/Ca2+ exchangers) and ATP-dependent (e.g., sarcoplasmic-endoplasmic-reticulum (SERCA) and plasma-membrane (PMCA) ATPases) Ca2+ pumps that sequester or extrude free cytosolic Ca2+, (4) ligand-gated channels (e.g., IP3 and ryanodine receptors) and peptidergic porins (e.g., amoebaporins, aquaporins, and PorB) responsible for store-operated Ca2+ mobilization and leakage, and (5) downstream host Ca2+ binding proteins and sensors (e.g., calmodulin, calrectulin, calcineurin, calnexin, and annexin) (Clark and Eisenstein, 2013; Clark et al., 2013). The wide range of host intracellular Ca2+ systems influenced by pathogen factors gives microbes remarkable control over the behavior and well-being of humans and animals, including, but not limited to, mental function and psychological state, voluntary and involuntary motor performance, and gastrointestinal absorption and metabolism. Yet, for microbes, the advantages of pathogen-mediated regulation of host intracellular Ca2+ systems extend beyond the impact on host health. In the case of viruses, increased host free cytosolic Ca2+ levels may promote viral adsorption, structural stability, capsid uncoating, enzymatic activity, replication, assembly, transport, and fusion (cf. Zhou et al., 2009; Clark and Eisenstein, 2013). Whereas, in cases of bacteria, fungi, and protozoa, alterations of host intracellular Ca2+ homeostasis is critical for pathogen sensory transduction, cell energetics, infection sequences, stress adaptation, gene expression, toxin biosynthesis and secretion, molecular biomimicry, conjugation and true sexual reproduction, cell motility and tropisms, growth, biofilm formation and cell aggregation, antigenic variation, and morphogenesis and lifecycle transitions (cf. Cyert, 2003; Moreno and Docampo, 2003; TranVan et al., 2004; Kozubowski et al., 2009; Clark et al., 2013).
Pathogen Selective Manipulation of Host Ca2+ Systems
To coordinate pathogen needs with operation of host cells, infectious agents must precisely change their host environment to maximize survival, proliferation, and spread with a repertoire of social-like (e.g., cell-cell communication, biofilm formation, cooperative, and competitive coinfection, etc.) and non-social (e.g., phenotypic variation, biomimicry, etc.) phenomena sometimes interpreted as pathogen intelligence (cf. Crespi, 2001; Casadesus and D'Ari, 2002; Ben-Jacob et al., 2004; Hellingwerf, 2005; Marijuán et al., 2010; Clark, 2013b). In regard to host intracellular Ca2+ homeostasis, pathogens rely on certain toxins that may either increase or decrease intracellular Ca2+ levels depending on stages of infection and host status. Such fine-tuned aptitude for altering host Ca2+ systems confers both advantages and disadvantages on hosts in relation to proper cell function and fate. Although most pathogens have evolved suites of toxins to manipulate host processes, including Ca2+-mediated ones, the selective fitness of surprisingly numerous single toxin molecules achieves multiplexed pathogen attacks on their host niche. This kind of pathogen intelligence conserves viral, bacterial, fungal, and protozoal resources for highly efficient and integrated host invasion and exploitation.
For example, overexpression of the multifunctional Hepatitus B Virus (HBV) protein HBx activates caspase-dependent cleavage of host Ca2+ PMCA, elevating free intracellular Ca2+ concentrations (Chami et al., 2003) as well as IP3 production and mitochondrial Ca2+ uptake during virus replication (Gearhart and Bouchard, 2010a,b; Yang and Bouchard, 2012). Unless competitively antagonized by IP3-receptor-inhibitors dantrolene and FK506 or other drug types, temporary stimulation of the endoplasmic reticulum/mitochondrial interface by IP3 boosts ATP synthesis and transport for energy-dependent cell processes required during early viral infection stages. However, when mitochondrial Ca2+ uptake subsequently exceeds buffering capacity, HBx advances mitochondrial swelling and fragmentation (Chami et al., 2003), making host cells more vulnerable to free radical generation, metabolic stress, and apoptosis prior to viral release. While sequalae are treatable with non-traditional compounds, including dual-active Beta Cell Lymphoma (Bcl)-related proteins (Clark and Eisenstein, 2013), HBV obviously evolved to carefully manage host-cell operation through well-timed, titrated levels of a single toxin, with lower concentrations of HBx causing long-term/short-term positive outcomes for virus/host and higher concentrations of HBx largely causing positive/negative outcomes for virus/host. This sort of versatility for single viral toxins to exploit host Ca2+ systems is observed for other viruses, including Human Immunodeficiency Virus type 1 (HIV-1). HIV-1, via the transcription factor Tat, for instance, potentiates Ca2+ influx through dihydropyridine-sensitive voltage-gated L-type Ca2+ (Lannuzel et al., 1995) and NMDAr channels (Prendergast et al., 2002; Self et al., 2004), leading to host-cell cytotoxicity. By means of the same Ca2+ channels, Tat also evokes production of the tumor necrosis factor (TNF)-alpha cytokine, an important compound for HIV-1 replication and pathogennesis (Contreras et al., 2005). Each harmful effect on host cells may be mitigated by voltage-gated L-type Ca2+ (e.g., nifedipine) and NMDAr channel antagonists (e.g., memantine). In contrast, Tat, similar to verapamil, inhibits cytotoxic release of serine esterases by blocking the phenylalkylamine-binding site of voltage-gated Ca2+ channels (Zocchi et al., 1998). As with protein HBx of HBV, Tat therefore affords HIV-1 with the ability to either facilitate or guard against host-cell death depending on infection stage and location (e.g., molecule-binding site, cell type, and organ). Moreover, besides direct influence over host condition, both HBx and Tat may act synergistically on HBV and HIV-1 infections (Li et al., 2012) as well as provide opportunistic copathogens, such as mycobacteria (Pathak et al., 2010; Toossi et al., 2012), herpesviruses (Huang et al., 2001; Guo et al., 2004; Caselli et al., 2005), and commensal host fungi (Cassone and Cauda, 2012) and coliform bacteria (cf. Diniello et al., 1998; Mani et al., 2007), an (probiotic) enriched or (antiinfective) hostile host habitat affecting communicable disease progression.
Only two among many instances of viral proteins were discussed above to illustrate the powerful biphasic regulation of pathogen toxins in modifying host and infectious agent physiology (cf. Clark and Eisenstein, 2013). A large number of pathogen-associated Ca2+-modulating factors exist for bacteria, fungi, and protozoa as well (cf. Clark et al., 2013). These endo- and exotoxins, of which just a few exemplars will be described here for protists, often allow microbes to evade host defenses by usurping membrane repair systems, down-regulating redox immunological responses, mimicking proinflammatory chemokine and cytokine mobilization, and initiating ireversible host programmed cell death. In addition to purely selfish pathogen infective, survival, and reproductive strategies, such compounds may render trophic support and protective immunity for hosts and their microbiota. Prime examples, similar to those also reported for obligate parasitic Chlamydia, Rickettsia, and Toxoplasma species (cf. Romano et al., 2013), come from intracellular protozoan trypanosomes, etiogenic agents of Chagas' disease, sleeping sickness, and other human and animal illnesses. Several substances, a serine endopeptidase, also called a proteolytically generated trypomastigote factor, Tc-Tox, an acidic pore-forming protein, and acidic sphingomyelinase, synthesized and secreted by Trypanosoma cruzi induce host plasma-membrane damage, extracellular Ca2+ entry, IP3 formation, transient store-operated cytosolic Ca2+ liberation, and/or cytoskeletal reorganization to assist in parasite internalization and trafficking (Tardieux et al., 1994; Burleigh and Andrews, 1995; Rodríguez et al., 1995; Burleigh et al., 1997; Fernandes et al., 2011). These compounds are only produced during the infective stage of trypanosome lifecycles, when Ca2+-dependent, energy-expensive lysosome and endosome recruitment works to restore integrity of pathogen-injured host plasma membranes. To a limited extent, toxin activation of store-operated Ca2+ release can be decreased by IP3-receptor blockers. But by directly commandeering host membrane-repair systems and subverting intracellular innate immune-surveillance and potent inflammatory signaling pathways, trypomastigotes ensure successful host invasion and maintenance of host structural and biotic reliability for persistent cryptic and latent trypanosome and copathogen disease states, such as those involving multiple trypanosome strains, symbiotic enterobacteria and other Gram-negative bacteria, and entomopathic double-stranded DNA viruses (Peacock et al., 2007; Alam et al., 2012; Lowry et al., 2013). In turn, these processes, directed by identical toxin concentrations used for trypanosome benefit, can present formidable obstacles to other infectious agents, including convergent trypanosome strains (Ulrich and Schmid-Hempel, 2012) and possible Encephalitozoon (cf. Leitch et al., 2001) and Toxoplasma parasites (cf. Meirelles and De Souza, 1983), which compete for limited shared host resources and/or must overcome toxin-modified host immunoresponses.
Prospective Ca2+-Modulating Probiotic and other Treatment Strategies
Repurposed medications which target pathogen capacities to alter host Ca2+ homeostasis and vital cell functions, such as traditional Ca2+-channel blockers, SERCA-inhibitor artemisinins, PMCA-inhibitor caloxins, and the IP3-receptor-inhibitors dantrolene, FK506, and Bcl antiapoptotic compounds (Clark and Eisenstein, 2013; Clark et al., 2013), show efficacious antiinfective effects against both treatable and previous drug-resistant pathogens. Given examples of HBV, HIV-1, and trypanosome infections readily demonstrate how these drugs exert their chemotherapeutic properties through disruption of pathogen attack, reinforcement of compromised host immunity, and trophic support for host operation. Perhaps more significantly, toxins encoded by pathogens also show non-traditional antiinfective and probiotic traits, oftentimes in a concentration-dependent manner. Such highly adaptive cooperative and competitive traits evolved so pathogens can invade, inhabit, and abandon host niches. Many of these multipurpose pathogen toxins modulate Ca2+ systems of host cells and host microbiota, including aforementioned viral and protozoan toxins, HBx, Tat, and Tc-Tox, and different pathogen virulence factors, such as mycobacterial (macolide) mycolactone and lipoarabinomannan (Rojas et al., 2000; Snyder and Small, 2003; Vergne et al., 2003; Boulkroun et al., 2010), staphylococcal leukotoxins (Jover et al., 2013), coliform heat-stable enterotoxin B (Dreyfus et al., 1993), and saccharomycete and ascomycete gliotoxins (Niide et al., 2006), to name a few. In some cases, predictable antiinfective properties of pathogen toxins result from mechanisms known for antibiotic drugs, including the streptomycin-analogous (Diniello et al., 1998) polyamine-starving characteristics of Tat (Mani et al., 2007), or from entirely novel mechanisms. Regardless, pathogen toxins with combined antiinfective and biotic qualities provide exciting substrate to begin developing new medicines of broad therapeutic potential and lifespan.
References
Alam, U., Hyseni, C., Symula, R. E., Brelsfoard, C., Wu, Y., Kruglov, O., et al. (2012). Implications of microfauna-host interactions for trypanosome transmission dynamics in Glossina fuscipes in Uganda. Appl. Environ. Microbiol. 78, 4627–4637. doi: 10.1128/AEM.00806-12
Ben-Jacob, E., Becker, I., Shapira, Y., and Levine, H. (2004). Bacterial linguistic communication and social intelligence. Trends. Microbiol. 12, 366–372. doi: 10.1016/j.tim.2004.06.006
Boulkroun, S., Guenin-Macé, L., Thoulouze, M. I., Monot, M., Merckx, A., Langsley, G., et al. (2010). Mycolactone suppresses T cell rsponsiveness by altering both early signaling and posttranslational events. J. Immunol. 184, 1436–1444. doi: 10.4049/jimmunol.0902854
Burleigh, B. A., and Andrews, N. W. (1995). A 120-kDa alkaline peptidase from Trypanosoma cruzi is involved in the generation of a novel Ca(2+)-signaling factor for mammalian cells. J. Biol. Chem. 270, 5172–5180. doi: 10.1074/jbc.270.10.5172
Burleigh, B. A., Caler, E. V., Webster, P., and Andrews, N. W. (1997). A cytosolic serine endopeptidase from Trypanosoma cruzi is required for the generation of Ca2+ signaling in mammalian cells. J. Cell Biol. 136, 609–620. doi: 10.1083/jcb.136.3.609
Casadesus, J., and D'Ari, R. (2002). Memory in bacteria and phage. Bioessays 24, 512–518. doi: 10.1002/bies.10102
Caselli, E., Galvan, M., Cassai, E., Caruso, A., Sighinolfi, L., and Di Luca, D. (2005). Human herpesvirus 8 enhanvces immunodeficiency virus replication in acutely infected cells and indues reactivation in latently infected cells. Blood 106, 2790–2797. doi: 10.1182/blood-2005-04-1390
Cassone, A., and Cauda, R. (2012). Candida and candidiasis in HIV-infected patients: where commensalism, opportunistic behavior and frank pathogenicity lose their borders. AIDS 26, 1457–1472. doi: 10.1097/QAD.0b013e3283536ba8
Chami, M., Ferrari, D., Nicotera, P., Paterlini-Brechot, P., and Rizzuto, R. (2003). Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein. J. Biol. Chem. 278, 31745–31755. doi: 10.1074/jbc.M304202200
Clark, K. B. (2013a). Editorial: new therapeutic bearings for drug repositioning. Curr. Top. Med. Chem. 13, 2281–2282. doi: 10.2174/15680266113136660159
Clark, K. B. (2013b). “The mating judgments of microbes,” in Social Learning Theory: Phylogenetic Considerations across Animal, Plant, and Microbial Taxa, ed K. B. Clark (Hauppauge, NY: Nova Science Publishers Inc), 173–200.
Clark, K. B., and Eisenstein, E. M. (2013). Targeting host store-operated Ca2+ release to attenuate viral infections. Curr. Top. Med. Chem. 13, 1916–1932. doi: 10.2174/15680266113139990128
Clark, K. B., Eisenstein, E. M., and Krahl, S. E. (2013). Calcium antagonists: a ready prescription for treating infectious diseases? Curr. Top. Med. Chem. 13, 2291–2305. doi: 10.2174/15680266113136660161
Contreras, X., Bennasser, Y., Chazal, N., Moreau, M., Leclerc, C., Tkaczuk, J., et al. (2005). Human immunodeficiency virus type 1 Tat protein induces an intracellular calcium increase in human monocytes that requires DHP receptors: Involvement in TNF-alpha production. Virology 332, 316–328. doi: 10.1016/j.virol.2004.11.032
Crespi, B. J. (2001). The evolution of social behavior in microorganisms. Trends Ecol. Evol. 16, 178–183. doi: 10.1016/S0169-5347(01)02115-2
Cyert, M. S. (2003). Calcineurin signaling in Saccharomyces cerevisiae: how yeast go crazy in response to stress. Biochem. Biophys. Res. Commun. 311, 1143–1150. doi: 10.1016/S0006-291X(03)01552-3
Diniello, G. B., Algranati, I. D., and Goldemberg, S. H. (1998). Streptomycin bacterial action is dependent on polyamine endogenous levels in E. coli. Cell Mol. Biol. 44, 521–526.
Dreyfus, L. A., Harville, B., Howard, D. E., Shaban, R., Beatty, D. M., and Morris, S. J. (1993). Calcium influx mediated by the Escherichia coli heat-stable enterotoxin B (STB). Proc. Natl. Acad. Sci. U. S. A. 90, 3202–3206. doi: 10.1073/pnas.90.8.3202
Fernandes, M. C., Cortez, M., Flannery, A. R., Tam, C., Mortara, R. A., and Andrews, N. W. (2011). Trypanosoma cruzi subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion. J. Exp. Med. 208, 909–921. doi: 10.1084/jem.20102518
Gearhart, T. L., and Bouchard, M. J. (2010a). Replication of the hepatitis B virus requires a calcium-dependent HBx-induced G1 phase arrest of hepatocytes. Virology 407, 14–25. doi: 10.1016/j.virol.2010.07.042
Gearhart, T. L., and Bouchard, M. J. (2010b). The hepatitis B virus X protein modulates hepatocyte proliferation pathways to stimulate viral replication. J. Virol. 84, 2675–2686. doi: 10.1128/JVI.02196-09
Guo, H. G., Pati, S., Sadowska, M., Charurat, M., and Reitz, M. (2004). Tumorigenesis by human herpesvirus 8 vGPCR is accelerated by human immunodeficiency virus type 1 Tat. J. Virol. 78, 9336–9342. doi: 10.1128/JVI.78.17.9336-9342.2004
Hellingwerf, K. J. (2005). Bacterial observations: a rudimentary form of intelligence? Trends Microbiol. 13, 152–158. doi: 10.1016/j.tim.2005.02.001
Huang, L. M., Chao, M. F., Chen, M. Y., Shih, H. M., Chiang, Y. P., Chuang, C. Y., et al. (2001). Reciprocal regulatory interaction between human herpesvirus 8 and human immunodeficiency virus type 1. J. Biol. Chem. 276, 13427–13432. doi: 10.1074/jbc.M011314200
Jover, E., Tawk, M. Y., Laventie, B. J., Poulain, B., and Prévost, G. (2013). Staphylococcal leukotoxins trigger free intracellular Ca(2+) rise in neurons, signaling trough acidic stores and activation of store-operated channels. Cell Microbiol. 15, 742–758. doi: 10.1111/cmi.12069
Kozubowski, L., Lee, S. C., and Heitman, J. (2009). Signaling pathways in the pathogenesis of Cryptococcus. Cell Microbiol. 11, 370–380. doi: 10.1111/j.1462-5822.2008.01273.x
Lannuzel, A., Lledo, P. M., Lamghitnia, H. O., Vincent, J. D., and Tardieu, M. (1995). HIV-1 envelope proteins gp 120 and gp160 potentiate NMDA-induced [Ca2+]i increase, alter [Ca2+]i homeostasis and induce neurotoxicity in human embryonic neurons. Eur. J. Neurosci. 7, 2285–2293. doi: 10.1111/j.1460-9568.1995.tb00649.x
Leitch, G. J., Scanlon, M., Shaw, A., and Visvesvara, G. S. (2001). Role of glygoprotein in the course and treatment of Encephalitozoon microsporidiosis. Antimicrob. Agents Chemother. 45, 73–78. doi: 10.1128/AAC.45.1.73-78.2001
Li, Y. J., Wang, H. L., and Li, T. S. (2012). Hepatitis B virus/human imunodeficiency virus coinfection: interaction among human immunodeficiency virus infection, chronic hepatitis B virus infection, and host immunity. Chin. Med. J. 125, 2371–2377.
Lowry, J. E., Leonhardt, J. A., Yao, C., Belden, E. L., and Andrews, G. P. (2013). Infection of C57BL/6 mice by Trypanosoma musculi modulates host immune responses during Brucella abortus cocolonization. J. Wildl. Dis. doi: 10.7589/2013-03-008. [Epub ahead of print].
Mani, K., Sandgren, S., Lilja, J., cheng, F., Svensson, K., Persson, L., and Belting, M. (2007). HIV-Tat protein transduction domain specifically attenuates growth of polyamine deprived tumor cells. Mol. Cancer Ther. 6, 782–788. doi: 10.1158/1535-7163.MCT-06-0370
Marijuán, P. C., Navarro, J., and del Moral, R. (2010). On prokaryotic intelligence: strategies for sensing the environment. Biosystems 99, 94–103. doi: 10.1016/j.biosystems.2009.09.004
Meirelles, M. N., and De Souza, W. (1983). Interaction of lysosomes with endocytic vacuoles in macrophages simultaneously infected with Trypanosoma cruzi and Toxoplasma gondii. J. Submicrosc. Cytol. 15, 889–896.
Moreno, S. N., and Docampo, R. (2003). Calcium regulation in protozoan parasites. Curr. Opin. Microbiol. 6, 359–364. doi: 10.1016/S1369-5274(03)00091-2
Niide, O., Suzuki, Y., Yoshimaru, T., Inoue, T., Takayama, T., and Ra, C. (2006). Fungal metabolite gliotoxin blocks mast cell activation by a calcium- and superoxide-dependent mechanism: implications for immunosuppressive activities. Clin. Immunol. 118, 108–116. doi: 10.1016/j.clim.2005.08.012
Pathak, S., Wentzel-Larsen, T., and Asjö, B. (2010). Effects of in vitro HIV-1 infection on mycobaterial growth in peripheral blood monocyte-derived macrophages. Infect. Immun. 78, 4022–4032. doi: 10.1128/IAI.00106-10
Peacock, L., Ferris, V., Bailey, M., and Gibson, W. (2007). Dynamics of infection and competition between two strains of Trypanosoma brucei brucei in the tsetse fly observed using fluorescent markers. Kinetoplastid Biol. Dis. 6, 4. doi: 10.1186/1475-9292-6-4
Prendergast, M. A., Rogers, D. T., Mulholland, P. J., Littelton, J. M., Wilkins, L. H. Jr., Self, R. L., et al. (2002). Neurotoxic effects of the human immunodeficiency virus type-1 transcription factor Tat require function of a polyamine sensitive-site on the N-meythl-D-aspartate receptor. Brain Res. 954, 300–307. doi: 10.1016/S0006-8993(02)03360-7
Rodríguez, A., Rioult, M. G., Ora, A., and Andrews, N. W. (1995). A trypanosome-soluble factor induces IP3 formation, intracellular Ca2+ mobilization and microfilament rearrangement in host cells. J. Cell Biol. 129, 1263–1273. doi: 10.1083/jcb.129.5.1263
Rojas, M., García, L. F., Nigou, J., Puzo, G., and Olivier, M. (2000). Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca2+-dependent cell signaling. J. Infect. Dis. 182, 240–251. doi: 10.1086/315676
Romano, J. D., de Beaumont, C., Carrasco, J. A., Ehrenman, K., Bavoil, P. M., and Coppens, I. (2013). Fierce competition between Toxoplasma and Chlamydia for host cell structures in dually infected cells. Eukaryot. Cell 12, 265. doi: 10.1128/EC.00313-12
Self, R. L., Mulholland, P. J., Nath, A., Harris, B. R., and Prendergast, M. A. (2004). The human immunodeficiency virus type-1 transcription factor Tat produces elevations in intracellular Ca2+ that require function of an N-methyl-D-aspartate receptor polyamine-sensitive site. Brain Res. 995, 39–45. doi: 10.1016/j.brainres.2003.09.052
Snyder, D. S., and Small, P. L. (2003). Uptake and cellular actions of mycolactone, a virulence determinant for Mycobacterium ulcerans. Microb. Pathog. 34, 91–101. doi: 10.1016/S0882-4010(02)00210-3
Tardieux, I., Nathanson, M. H., and Andrews, N. W. (1994). Role in host cell invasion of Trypanosoma cruzi-induced cytosolic-free Ca2+ transients. J. Exp. Med. 179, 1017–1022. doi: 10.1084/jem.179.3.1017
Toossi, Z., Wu., M., Hirsch, C. S., Mayanja-Kizza, H., Baseke, J., Aung, H., et al. (2012). Activation of P-TEFb at sites of dual HIV/TB infection, and inhibition of MTB-induced HIV transcription activation by the inhibitor of CDK9, Indirubin-3′-monoxime. AIDS Res. Hum. Retroviruses 28, 182–187. doi: 10.1089/aid.2010.0211
TranVan, N. G., Clair, C., Grompone, G., and Sansonetti, P. (2004). Calcium signalling during cell interactions with bacterial pathogens. Biol. Cell 96, 93–101. doi: 10.1016/j.biolcel.2003.10.006
Ulrich, Y., and Schmid-Hempel, P. (2012). Host modulation of parasite competition in multiple infections. Proc. Biol. Sci. 279, 2982–2989. doi: 10.1098/rspb.2012.0474
Vergne, I., Chua, J., and Deretic, V. (2003). Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin-P13K hVPS34 cascade. J. Exp. Med. 198, 653–659. doi: 10.1084/jem.20030527
Yang, B., and Bouchard, M. J. (2012). The hepatitis B virus X protein elevates cytosolic calcium signals by modulating mitochondrial calcium uptake. J. Virol. 86, 313–327. doi: 10.1128/JVI.06442-11
Zhou, Y., Frey, T. K., and Yang, J. J. (2009). Viral calciomics: interplays between Ca2+ and virus. Cell Calcium 46, 1–17. doi: 10.1016/j.ceca.2009.05.005
Keywords: antiifective, bacteria, calcium channel blockers, drug design and development, pathogen toxins, probiotic, protozoa, viruses
Citation: Clark KB (2013) Biotic activity of Ca2+-modulating non-traditional antimicrobial and -viral agents. Front. Microbiol. 4:381. doi: 10.3389/fmicb.2013.00381
Received: 02 November 2013; Accepted: 24 November 2013;
Published online: 12 December 2013.
Edited by:
Joshua D. Nosanchuk, Albert Einstein College of Medicine, USAReviewed by:
Mircea R. Mihu, Montefiore Medical Center - Albert Einstein College of Medicine, USACopyright © 2013 Clark. 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.
*Correspondence: Kevin B. Clark, 4229 SE Harney Street, Portland, OR 9720-0941, USA e-mail: kbclarkphd@yahoo.com