Excerpt(s) from:
Silver nanoparticles interactions with the immune system:
Implications for Health and Disease
Rebecca Klippstein, Rafael Fernandez-Montesinos, Paula M. Castillo, Ana P. Zaderenko and David Pozo CABIMER-Andalusian Center for Molecular Biology & Regenerative Medicine CSIC-University of Seville-UPO-Junta de Andalucia, Seville, Spain Department of Physical, Chemical & Natural Systems, Pablo de Olavide University, Seville, Spain

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Recently, it has been suggested that nanoparticles bind with a viral envelope glycoprotein and inhibit the virus by binding to the disulfide bond regions of the CD4 binding domain within the gp120 glycoprotein, as demonstrated in vitro (Elechiguerraet al., 2005). Silver nanoparticles undergo a size-dependent interaction with HIV-1, nanoparticles ranging from 1 to 10 nm attached to the virus, and their surface chemistry can modify their interactions with viruses, tested with silver NPs that had three different surface chemistries: foamy carbon, poly (N-vinyl-2-pyrrolidone) (PVP), and bovine serum albumin (BSA). Differences have been observed in HIV-1 inhibition and can be justified because BSA and PVP are directly bounded to the nanoparticle surface and are totally encapsulated, while the foamy carbon silver nanoparticles have fundamentally a free surface area, which exhibit higher inhibitory effect and cytotoxicity as they are able to have stronger interactions (Elechiguerra et al., 2005).

Interaction of silver nanoparticles with bacteria – Bacteria are prokaryotic, microscopic, single-celled organisms that lack membrane bound organelle in the cytoplasm. They can inhabit all kinds of environments and exist either as independent (free-living) organisms or as parasites.

Silver has been used for at least six millennia in order to prevent microbial infections. It has been used to treat a wide variety of infections and has been effective against almost all organisms tested. Silver compounds were major weapons against wound infection in World War I until the advent of antibiotics and between 1900 and 1940, tens of thousands of patients consumed colloidal silver, and several million of doses were given intravenously. But it was shown that high doses of silver, when administered intravenously could cause convulsions or even death, and that oral administration of high doses could cause gastrointestinal disturbances (Alexander, 2009). For this reason the biomedical applications of silver can be effective by the use of biologically synthesized NPs, which minimize the factors such as toxicity and cost, and are found to be exceptionally stable and by virtue of extremely small size silver NPs exhibit unusual physicochemical properties and biological activities. Due to the large surface area (generally the diameter is smaller than 100nm and contains 20–15,000 silver atoms) for reaction of the NPs, the dose of silver used in medical applications can be reduced.

The mechanisms of action and binding of silver nanoparticles to microbes remain unclear but it is known that silver binds to the bacterial cell wall and cell membrane and inhibits the respiration process (Klasen, 2000) by which the chemical energy of molecules is released and partially captured in the form of ATP. Silver nanoparticles interact with sulfur-containing proteins of the bacterial membrane as well as with the phosphorus containing compounds like DNA to inhibit replication (Silveret al., 2006). Bactericidal effect of silver has also been attributed to inactivation of the enzyme phosphomannose isomerase (Bhattacharya & Mukherjee, 2008), that catalyzes the conversion of mannose-6-phosphate to fructose-6-phosphate which is an important intermediate of glycolysis, the most common pathway in bacteria for sugar catabolism.

The antimicrobial activity of silver nanoparticles has been investigated against yeast, gram negative and positive bacteria (Kimet al., 2007) (Sondi & Salopek-Sondi, 2004; Yu, 2007).

When silver nanoparticles were tested in yeast and Escherichia coli (Gram -), bacterial growth was inhibited (Sondi & Salopek-Sondi, 2004), but the inhibitory effect in Staphylococcus aureus(Gram +) was mild (Kimet al., 2007). Therefore, this suggests that the antimicrobial effects of silver nanoaparticles can be associated with different characteristics of the membrane structure, in order to the considerable differences between the membrane structures of Gram+ and Gram-. These differences mainly rely on the peptydoglycan layer thickness, the rigidity and extended cross linking that makes the penetration of nanoparticles very difficult.

Recently, due to the emergence of antibiotic-resistant bacteria and the use limitations of antibiotics that can cause serious diseases and is an important public health problem (Furuya & Lowy, 2006), the synergetic effect of silver nanoparticles with antibiotics has been studied combinating silver nanoparticles with different antibiotics like ampicillin, kanamycin, erythromycin and chloramphenicol against gram positive and gram negative bacteria. The antibacterial activities of these antibiotics increase in the presence of silver nanoparticles against gram positive and gram negative bacteria determined by the disk diffusion method. Different diameters of inhibition zones have been shown around the different antibiotic disk with or without AgNPs. The combination effect of nanosilver and ampicillin has more potential compared to the other antibiotics and may be caused by both, the cell wall lysis action of the ampicillin and the DNA binding action of the silver nanoparticles (Fayazet al., 2009). The antibiotic molecules contain many active groups such as hydroxyl and amido groups, which reacts easily with silver nanoparticles by chelation, for this reason, the synergistic effect may be caused by the bonding reaction with antibiotic and silver nanoparticles.

The bactericidal effects of silver nanoparticles are part of an extensive research field due to its potential translation for biomedical applications such as, wound-healing (Tianet al., 2007; Silver et al., 2006), clothes, coating for medical devices (Roe et al., 2008), antimicrobial gel (Jain et al., 2009), and orthopaedic implants (Nair & Laurencin, 2008).

It is well known that the use of central venous catheters is associated with bactericidal line infections, which is a usual problem (Stevens et al., 2009). Contaminated or infected catheters are a major source of nosocomial infections responsible for > 40% of all episodes of nosocomial sepsis in acute-care hospitals (Samuel & Guggenbichler, 2004). For this reason catheters coated with silver NPs are important to confer antimicrobial activity and play an essential part in the prevention of catheter-related infections.

In vivo studies have been performed to test the antimicrobial activity of catheters coated with silver NPs and it has been reported that the coating process is slowly reversible, yielding sustained release of silver for at least 10 days (Roe et al., 2008). Each animal (C57B1/6J male mice) was implanted with the equivalent of a 28 cm silver coated catheters and showed no sign of toxicity, inflammation or infection at the site of catheter implantation. The released silver is active against microorganisms with no risk of systemic toxicity and safety of use in animals. This suggests that catheters coated with this method could provide local protection against infections (Roe et al., 2008).

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Eming, S. A.; Krieg, T. & Davidson, J. M. (2007). Inflammation in wound repair: molecular and cellular mechanisms.
J Invest Dermatol, 127, (3), 514-525
Fayaz, M.; Balaji, K.; Girilal, M.; Yadav, R.; Kalaichelvan, P. T. & Venketesan, R. (2009). Biogenic synthesis of silver nanoparticles and its synergetic effect with antibiotics: A study against Gram positive and Gram negative bacteria. Nanomedicine, Furuya, E. Y. & Lowy, F. D. (2006). Antimicrobial-resistant bacteria in the community setting.
Nat Rev Microbiol, 4, (1), 36-45
Greulich, C.; Kittler, S.; Epple, M.; Muhr, G. & Koller, M. (2009). Studies on the biocompatibility and the interaction of silver nanoparticles with human  mesenchymal stem cells (hMSCs). Langenbecks Arch Surg, 394, (3), 495-502
Hussain, S. M.; Hess, K. L.; Gearhart, J. M.; Geiss, K. T. & Schlager, J. J. (2005). In vitro toxicity of nanoparticles in BRL 3A rat liver cells. Toxicol In Vitro, 19, (7), 975-983
Jain, J.; Arora, S.; Rajwade, J.; Khandelwal, S. & Paknikar, K. M. (2009). Silver nanoparticles in therapeutics: development of an antimicrobial gel formulation for topical use. Mol Pharm, Kim, J. S.; Kuk, E.; Yu, K. N.; Kim, J. H.; Park, S. J.; Lee, H. J.; Kim, S. H.; Park, Y. K.; Park, Y.
H.; Hwang, C. Y.; Kim, Y. K.; Lee, Y. S.; Jeong, D. H. & Cho, M. H. (2007).
Antimicrobial effects of silver nanoparticles. Nanomedicine, 3, (1), 95-101
Kim, S.; Choi, J. E.; Choi, J.; Chung, K. H.; Park, K.; Yi, J. & Ryu, D. Y. (2009). Oxidative stress-dependent toxicity of silver nanoparticles in human hepatoma cells. Toxicol In Vitro, Klasen, H. J. (2000). A historical review of the use of silver in the treatment of burns. II. Renewed interest for silver. Burns, 26, (2), 131-138
Lu, L.; Sun, R. W.; Chen, R.; Hui, C. K.; Ho, C. M.; Luk, J. M.; Lau, G. K. & Che, C. M. (2008).
Silver nanoparticles inhibit hepatitis B virus replication. Antivir Ther, 13, (2), 253-262
Lucarelli, M.; Gatti, A. M.; Savarino, G.; Quattroni, P.; Martinelli, L.; Monari, E. & Boraschi, D. (2004). Innate defence functions of macrophages can be biased by nano-sized  ceramic and metallic particles. Eur Cytokine Netw, 15, (4), 339-346
Makkouk, A. & Abdelnoor, A. M. (2009). The potential use of toll-like receptor (TLR) agonists and antagonists as prophylactic and/or therapeutic agents. Immunopharmacol Immunotoxicol, Nair, L. S. & Laurencin, C. T. (2008). Nanofibers and nanoparticles for orthopaedic surgery applications.
J Bone Joint Surg Am, 90 Suppl 1, 128-131 Pozo, D. (2008). Immune-based disorders: the challenges for translational immunology.
J Cell Mol Med, 12, (4), 1085-1086 Rai, M.; Yadav, A. & Gade, A. (2009). Silver nanoparticles as a new generation of antimicrobials. Biotechnol Adv, 27, (1), 76-83
Rasmussen, S. B.; Reinert, L. S. & Paludan, S. R. (2009). Innate recognition of intracellular pathogens: detection and activation of the first line of defense. APMIS, 117, (5-6), 323-337
Roe, D.; Karandikar, B.; Bonn-Savage, N.; Gibbins, B. & Roullet, J. B. (2008). Antimicrobial surface functionalization of plastic catheters by silver nanoparticles. J Antimicrob Chemother, 61, (4), 869-876
Samuel, U. & Guggenbichler, J. P. (2004). Prevention of catheter-related infections: the potential of a new nano-silver impregnated catheter. Int J Antimicrob Agents, 23 Suppl 1, S75-78
Shin, S. H.; Ye, M. K.; Kim, H. S. & Kang, H. S. (2007). The effects of nano-silver on the proliferation and cytokine expression by peripheral blood mononuclear cells. Int Immunopharmacol, 7, (13), 1813-1818
Silver, S.; Phung, L. T. & Silver, G. (2006). Silver as biocides in burn and wound dressings and bacterial resistance to silver compounds. J. Ind. Microbiol. Biotechonol. , Singh, A. V.; Patil, R.; Kasture, M. B.; Gade, W. N. & Prasad, B. L. (2009). Synthesis of Ag-Pt alloy nanoparticles in aqueous bovine serum albumin foam and their cytocompatibility against human gingival fibroblasts.
Colloids Surf B Biointerfaces, 69, (2), 239-245 Sondi, I. & Salopek-Sondi, B. (2004). Silver nanoparticles as antimicrobial agent: a case study on E. coli as a model for Gram-negative bacteria.
J Colloid Interface Sci, 275, 177-182
Stevens, K. N.; Crespo-Biel, O.; van den Bosch, E. E.; Dias, A. A.; Knetsch, M. L.; Aldenhoff, Y. B.; van der Veen, F. H.; Maessen, J. G.; Stobberingh, E. E. & Koole, L. H. (2009).
The relationship between the antimicrobial effect of catheter coatings containing silver nanoparticles and the coagulation of contacting blood. Biomaterials, 30, (22), 3682-3690
Tian, J.; Wong, K. K.; Ho, C. M.; Lok, C. N.; Yu, W. Y.; Che, C. M.; Chiu, J. F. & Tam, P. K. (2007). Topical delivery of silver nanoparticles promotes wound healing. ChemMedChem, 2, (1), 129-136
Tsirogianni, A. K.; Moutsopoulos, N. M. & Moutsopoulos, H. M. (2006). Wound healing: immunological aspects.
Injury, 37 Suppl 1, S5-12 Uematsu, S. & Akira, S. (2006). The role of Toll-like receptors in immune disorders.
Expert Opin Biol Ther, 6, (3), 203-214
Venier, C.; Guthmann, M. D.; Fernandez, L. E. & Fainboim, L. (2007). Innate-immunity cytokines induced by very small size proteoliposomes, a Neisseria-derived immunological adjuvant.
Clin Exp Immunol, 147, (2), 379-388
Weyermann, J.; Lochmann, D. & Zimmer, A. (2005). A practical note on the use of cytotoxicity assays. Int J Pharm, 288, (2), 369-376
Wong, K. K.; Cheung, S. O.; Huang, L.; Niu, J.; Tao, C.; Ho, C. M.; Che, C. M. & Tam, P. K. (2009). Further evidence of the anti-inflammatory effects of silver nanoparticles. ChemMedChem, 4, (7), 1129-1135
Yen, H. J.; Hsu, S. H. & Tsai, C. L. (2009). Cytotoxicity and Immunological Response of Gold and Silver Nanoparticles of Different Sizes. Small, Yu, D. G. (2007). Formation of colloidal silver nanoparticles stabilized by Na+-poly(gamma-glutamic acid)-silver nitrate complex via chemical reduction process. Colloids Surf B Biointerfaces, 59, (2), 171-178
Zolnik, B. S. & Sadrieh, N. (2009). Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs. Adv Drug Deliv Rev, 61, (6), 422-427
Zuany-Amorim, C.; Hastewell, J. & Walker, C. (2002). Toll-like receptors as potential therapeutic targets for multiple diseases. Nat Rev Drug Discov, 1, (10), 797-807

Silver nanoparticles interactions with the immune system:
Implications for Health and Disease
COMPLETE PDF DOCUMENT

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Spectrum of antimicrobial activity associated with ionic colloidal silver.

http://www.ncbi.nlm.nih.gov/pubmed/23017226

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Additional …

Research Communications:
Bactericidal Activity of Silver-Water Dispersion(Full PDF)
Department of Microbiology/Molecular Biology
Brigham Young University, Provost, Utah

Silver Enhances Antibiotic Activity Against Gram-Negative Bacteria
http://stm.sciencemag.org/content/5/190/190ra81