By: Mary N. Wessling, Ph.D. ELS

In this blog we will unravel the terminology describing bacterial toxins. In general, there are at least three ways that bacterial toxins are described in the literature:

Below are examples of each:

Biological designation

When described by their biological designation a part of the genus or species name is used for the toxin. For example: Clostridium tetani produces Tetanus toxin and Corynebacterium diphtheriae produces Diphtheria toxin.

Origin of the toxin

Exotoxins (e.g. polypeptides) are toxins released by a cell, whereas endotoxins (e.g. lipopolysaccharides) are an integral part of the bacterial cell wall.

Body part damaged by the toxin

Bacteria may cause disease through their toxins that enter the body via the respiratory tract, gastrointestinal tract, genital tract, and the skin. Enterotoxins mostly affect the gastrointestinal tract. “Entero” comes from the Greek word “enteron” meaning intestine.

Bacterial enterotoxins include examples of exotoxins produced by some strains of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli).Staphylococcal enterotoxin acts on intestinal neurons to induce vomiting; E. coli producing Shiga toxin causes serious dysentery and can lead to hemorrhagic diarrhea and kidney failure.

You will also see other terms used to designate toxins…

Superantigens: toxins that cause over-reaction

Antigens are characterized by their ability to activate T-cells and other immune system cells; while the T-cell response is a normal part of the immune process, over-activation of T-cells can cause an inflammatory response that can result in shock and multiple organ failure.

Pore-forming toxins that open host cell membranes

Pore-forming toxins (PFT) are toxin proteins with the ability to spontaneously self-assemble forming transmembrane pores in the membrane of target cells. Staphylococcal alpha toxin, also known as alpha-haemolysin, makes specific pores in target cells which are part of the pathology of infection and a valuable tool in construction of nanopores. Tetanolysin is another pore forming toxin produced by C. tetani which can make cells permeable to materials for experimentation.

Intracellular toxins

These toxins have two-part structures and are termed AB toxins. The A stands for “active”, the B for “binding”, for the ways that the two structures cooperatively cause cell damage. In most cases, the B structural element attaches to the cell membrane and provides an entry point for the other part, the A-enzyme component that causes damage to the inside of the cell through its enzymatic activity.

Some AB toxins have more than one B moiety: for example, the cholera toxin has five B proteins that provide entry for the A moiety, so it is designated AB5. The A moiety is initially a coiled chain but once inside the cell it uncoils, where its enzymatic activity kills the enteric cell.

Ligand-receptor interactions

The actions of exotoxins and endotoxins depend on a process whereby a part of their molecular structure, a ligand, can bind or otherwise interact with a structure on the host cell being attacked, a receptor. Thus, this ligand–receptor interaction is crucial to most diseases produced by bacterial toxins.

Lethal dose 50%

Bacteria cause disease by toxin production, invasion and inflammation. All toxins damage or disrupt the functions of the host cells. The term that describes the level of danger presented to the host by a toxin is “Lethal Dose 50%”, abbreviated LD50; the lower the LD50, the lower the amount of toxin to cause death.

 

By: Mary N. Wessling, Ph.D. ELS

Bacterial Toxins used for Vaccine Research

List Biological Laboratories’ (List Labs) catalog of products is related to furthering research in human health and preventing disease, most commonly as the starting materials for vaccine research & development or production around the world. Vaccines are mainly identified for their capacity to prevent diseases that the body’s innate defensive mechanisms (the skin and specialized cells in the blood, for example) can’t resist unaided. However, there are many other uses for these purified materials in medical research, and you will likely encounter wording on our website that is not part of everyday vocabulary for non-scientists. This article is intended to provide a basic understanding of some of the more frequently used terms and aid you in selecting the products most essential to your projects.

Toxin vs. Toxoid

For starters, what is the difference between “toxin” and “toxoid”. Broadly defined, anything that can cause harm to an organism is a toxin. However, for List Labs’ products and in biological usage, a toxin refers to a bacterial or viral product that has harmful effects when it enters the body (List Labs’ toxins are in a highly purified form). A toxoid is a chemically altered toxin that has reduced or no toxicity and is used for its remaining antigenic activity, which can stimulate an immune response.

Take, for example, cholera, a disease produced by Vibrio cholerae bacteria, possibly through contact with body fluids from a person ill with cholera or through contaminated water supply. Cholera causes severe diarrhea, and untreated, it can be fatal. However, the purified List Labs’ cholera toxin by chemical modification becomes a toxoid that lacks toxic activity but retains structures that make it useful for immunization of research animals or stimulation of immune cells in vitro.

How do Toxoids Impact the Immune Process? 

To understand how some List Labs products work, an overview of the immune process is helpful. During the course of a day, we frequently touch, ingest, or breathe in something that has potential to harm the body. Our cells react to this invader: is this a threat, or not, and if so, how serious is the threat?

What is the Innate Immune Response? 

The innate immune response is the first order of defense in the immune process. There are many different cell types in our body. Some of these cells are equipped by their structural and biochemical components to destroy dangerous microbial invaders–pathogens–quickly. The inflammation that we experience from minor infections is often a sign of this process as cells from the blood destroy the pathogen. This happens quickly, within hours.

What is the Adaptive Immune Response?

Another cellular response system requires a longer time to react to the threat. These cells react by changing from an inactive form to one that will start a more complex defensive process: this is the second step, the adaptive immune response. There are two different classes of cells that comprise the adaptive immune response; they differ by the structures that give them their ability to bind antigens– the invading bacteria and viruses. Both these cells are called lymphocytes; individually, they are the B-lymphocytes (B-cells) and T-lymphocytes (T-cells). Both originate from stem cells in the bone marrow; B and T refer to the place in the body where they mature. T-cells mature in the thymus into several subclasses of T-cells that circulate in the blood and lymph. “Killer” T-cells recognize foreign antigens on cell surfaces (e.g. from viral infection or malignancy). “Helper” T-cells induce B-cells to produce antibodies. “Suppressor” T-cells dampen or regulate the immune response to prevent over-reaction. B-cells mature in the bone marrow and migrate to secondary lymphoid tissues (e.g. spleen and lymph nodes). When they encounter foreign antigens and/or helper T-cells, they are stimulated to divide and expand clonally to produce antibodies and differentiate into plasma cells.

What is Immune Memory? 

After the B and T-lymphocytes react to an antigen, two results are possible. The first, and desirable result, is that the invader is identified and defeated, leaving behind what might be called its criminal record: immune memory. When the antigen comes creeping back in the future, the adaptive immune system recognizes it and attacks. The second possibility is an over-reaction and lack of cessation of the adaptive immune process that is harmful to the body: an autoimmune condition.

Antigens, Epitopes and Vaccines

Where do vaccines come into this process? An antigen is a substance that causes the body to mount an immune response against it. Antigens include toxins, bacteria, viruses, or other substances that the body recognizes as foreign or not “self”. Vaccines have structural features similar to structures of the toxin or invading pathogen that can elicit adaptive immunity.

An epitope is a specific molecular region on the surface of an antigen, typically one of many on the antigen, that elicits an immune response and is capable of binding with the specific antibody produced by the response. A toxin has many epitopes that can be recognized by the immune response. The epitopes that are required for toxicity have been altered chemically in toxoids or by specific genetic mutations in inactive mutants; however, many epitopes are retained and can stimulate an adaptive or memory immune response that will be effective against the toxin.

Toxins and Toxoid Products for Research

Below is a list of toxin and toxoid or inactive mutant pairs of products available to support your research.

Toxin and product numbers Toxoid Inactive Mutant
Botulinum Neurotoxin Type A from Clostridium botulinum130A, 130B, 9130A 133L
Botulinum Neurotoxin Type B, Nicked, from Clostridium botulinum136A, 136B 139
Toxin A from Clostridium difficile152C 153
Toxin B from Clostridium difficile 155A, 155B, 155L 154A
Diphtheria Toxin, Unnicked, from Corynebacterium diphtheriae150 151 149
Enterotoxin Type B from Staphylococcus aureus122 123
Tetanus Toxin from Clostridium tetani190A, 190B 191A, 191B

 

 

By: Mary N. Wessling, Ph.D. ELS

Tetanus ToxinTetanus Toxin’s Use as a Protein Carrier and Antigen

Tetanus toxin (TT) is the major virulence factor of the Gram-positive bacterium Clostridium tetani. Infection with this bacterium in unvaccinated persons produces muscle spasms by binding to nerve endings and moving throughout the nervous system in a specific way. Eventually, almost total paralysis results. The deactivated toxin is the basis for a vaccine, which can even be administered to pregnant women, usually as part of a combination vaccine also aimed at preventing neonatal pertussis.1 Worldwide, the mortality of infection among unvaccinated persons reaches 10%.2 It is the binding specificity of this dangerous toxin that makes it valuable as a research material. List Biological Laboratories (List Labs) offers inactivated tetanus toxin and six related products, used in intricate and fascinating ways in research as a model antigen and protein carrier.

 

List Labs’ Tetanus Toxoid in Immunosupression Research

Existing antibody treatments for rheumatic arthritis (RA), for example doses of rituximab every six months, suppress autoreactive B cells by killing them. The effects of the treatment fade over the 6-month period; this increases the inherent risk of infection and progressive multifocal leukoencephalopathy. Chu et al studied a treatment that characterized B-cell immunosuppression by an engineered antibody; List Labs’ tetanus toxoid (TTd)

was used in an elegant series of explorations of the mechanism of action of an engineered antibody (XmAb581) that enhanced the action of a B-cell antigen receptor complex currently under clinical development for treatment of RA, and enhanced both its safety and efficacy.3

 

Tetanus Toxoid in B Cell-Driven Autoimmune Disease Research

In a study with a broader purpose, Klose et al, expanding a previous murine study, developed a protein engineering strategy to selectively target and eradicate human memory B cells. These authors built a fusion protein that combined a model antigen TTd fragment C with a truncated version of exotoxin A derived from Pseudomonas aeruginosa. A fluorescein isocyanate-labelled TT fragment C produced by List Laboratories, used as a control in the binding analysis, played an important supporting role. This research offers a promising approach for the specific depletion of autoreactive B-lymphocytes in B cell-driven autoimmune diseases.4

 Prompted by the lower prevalence of these diseases in children who lived near farm animals and in unhygienic environments, Iwasaki et al studied the key role of intestinal infection in development of allergic respiratory disease in children. Their study used List Labs’ TTd antigen

to compare total antibody binding between asthmatic and non-asthmatic children. The authors found an association between lower antibody titers in asthmatic children to echovirus, and in a previous study, a heightened response to rhinovirus. These findings support a key role for intestinal infection in the development of allergic respiratory disease.5

 

Further Innovative Applications of List Labs’ Tetanus Toxin and Tetanus Toxoid

List Labs’ tetanus toxin (TT)

was used in a study that challenged an accepted mechanism for cell death in injured human retinal ganglion cells; Li Y et al showed that dysregulation of mobile zinc is to blame. In anesthetized animals, they used TTd to cleave the synaptic vesicle protein and then injected the zinc formulation. Fluorescent images showed that there was a rapid accumulation of Zn2+ in amacrine cell processes after optic nerve injury.6 Investigating yet another problem that affects injured persons, i.e., the necessity to keep an injured limb immobile, which results in muscle atrophy, Matthews et al reported that inactivity can result in 20% to 30% atrophy despite the use of exercise-based or neuromuscular electronic stimulation. They injected either saline or a very dilute solution of List Labs’ TT
in physiological saline in the tibialis anterior of rats and compared the health of muscle fibers after immobilization. They found that the TT prevented loss of size in all 3 myofiber types, and therefore was protective against muscle loss during immobility.7

Finally, animal studies are used to evaluate the efficacy of pharmaceutical and other products for human use; although there are stringent conditions that assure ethical treatment of animals, the process is often time-inefficient, inaccurate, and costly. Temann et al explored using precision-cut lung slices (PCLS) from lungs of donors that were not suitable for use in transplantation as an alternative to animal studies. They evaluated a culture system using PCLS stimulated by List Labs’ TTd

and found that these slices could be held in culture for up to 14 days to study cytotoxic, inflammatory, and immune responses.8

The studies we cite here are only a small sample of what can be accomplished using List Labs’ TT and related products. We invite you to visit our citations page to explore how TT and our other products can augment your experimental design.

 

  1. Chu HY, Englund JA. Maternal immunization. Birth Defects Research. 2017;109(5):379-386. PMID: 28398678
  2. da Silva Antunes R, Paul S, Sidney J, et al. Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses. PloS One. 2017;12(1):e0169086. PMID: 28081174
  3. Chu SY, Yeter K, Kotha R, et al. Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcgamma receptor IIb inhibitory receptor. Arthritis & Rheumatology (Hoboken, NJ). 2014;66(5):1153-1164. PMID: 24782179
  4. Klose D, Saunders U, Barth S, Fischer R, Jacobi AM, Nachreiner T. Novel fusion proteins for the antigen-specific staining and elimination of B cell receptor-positive cell populations demonstrated by a tetanus toxoid fragment C (TTC) model antigen. BMC Biotechnology. 2016;16:18. PMCID: PMC4756516
  5. Iwasaki J, Chai LY, Khoo SK, et al. Lower anti-echovirus antibody responses in children presenting to hospital with asthma exacerbations. Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2015;45(10):1523-1530. PMID: 25640320
  6. Li Y, Andereggen L, Yuki K, et al. Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(2):E209-e218. PMCID: PMC5240690
  7. Matthews CC, Lovering RM, Bowen TG, Fishman PS. Tetanus toxin preserves skeletal muscle contractile force and size during limb immobilization. Muscle & Nerve. 2014;50(5):759-766. PMID: 24590678
  8. Temann A, Golovina T, Neuhaus V, et al. Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices. Human Vaccines & Immunotherapeutics. 2017;13(2):351-358. PMID: 27929748

By: Md. Elias, Ph.D, Senior Scientist

List Labs is one of the leading manufacturers of high quality adjuvants from bacterial sources. Our highly purified adjuvants for research and development are Tetanus Toxoid (Product #191), Cholera Toxin B Subunit (Product #104), Diphtheria Toxin CRM197 Mutant (Product #149), Adenylate Cyclase Mutant, Cya-AC (Product #198L), Pertusis Toxin Mutant (Product #184), and LPS and its derivatives (Products #400, #401, #421, #423, #433, #434). GMP grade material is available by custom order.

In immunology, an adjuvant is a component that enhances and/or potentiates the immune responses (humoral and /or cell mediated) to an antigen and modulates it to achieve the desired immune responses. Adjuvants can be used for various reasons: (i) to enhance the immunogenicity of antigens; (ii) to reduce the amount of antigen or the number of immunizations needed for protective immunity; (iii) to improve the efficacy of vaccines in immune-compromised persons; (iv) to increase functional antibody titer; or (v) as antigen delivery systems for the uptake of antigens by the mucosa (1-3). Brief descriptions of List Labs products that have potential uses as vaccine adjuvants or immune modulators are provided below. For more details, please visit www.ListLabs.com.

Tetanus Toxoid (Product #191): Tetanus toxoid is prepared by formaldehyde inactivation of pure neurotoxin (Product #190). There are FDA approved vaccines that use a tetanus toxoid antigen to protect children and adult against tetanus such as DAPTACEL and Tripedia, and others that use it as a carrier in conjugate vaccines against various pathogens. For example, MenHibrix® is an FDA approved vaccine where tetanus toxoid has been conjugated to Neisseria meningitidis serogroup C and Y capsular polysaccharides and Hib capsular polysaccharide. Several other tetanus toxoid conjugated vaccines are in research and investigation stages such as Type III group B streptococcal polysaccharide-tetanus toxoid conjugate vaccine (4). Information on our entire family of Tetanus products can be found at https://www.listlabs.com/products/tetanus-toxins-&-related-products/.

Cholera Toxin B subunit (Products #103B and #104): Cholera toxin B subunit (CTB) is the cell binding domain of cholera toxin protein complex. The holotoxin consists of a single A subunit bearing ADP-ribosyl-transferase activity surrounded by five B subunits that bind to GM1 ganglioside receptors on mammalian cell surfaces and facilitate entrance of the A subunit into cells. The non-toxic CTB has been shown to be an efficient mucosal adjuvant and carrier molecule for the generation of mucosal antibody responses and/or induction of systemic T-cell tolerance to linked antigens. Due to the ubiquitous presence of the GM1 ganglioside receptor on eukaryotic cell membranes, CTB has been extensively used as a conjugate and non-conjugate vaccine adjuvant in a wide variety of model systems.

A CTB-urease conjugated vaccine has been shown to prevent infection by Helicobacter pylori, a bacterium that infects greater than 50% of world population and can cause a variety of gastrointestinal diseases (5). A series of studies have been carried out to develop CTB carrier based vaccines to prevent HIV-1 (6) and West Nile Virus infections (7). CTB has been used as a component of a skin patch for transcutaneous immunization against hepatitis B virus in a mouse model (8). Besides the adjuvant activity, recent studies show that CTB can suppress immunopathological reactions in allergy and autoimmune diseases such as Crohn’s disease (9). Information on our entire family of Cholera products can be found at https://www.listlabs.com/products/cholera-toxins/.

Diphtheria Toxin CRM197 Mutant (Product #149): CRM197 is a non-toxic mutant of diphtheria toxin lacking the ADP-ribosylation activity (10). CRM197 results from a naturally occuringsingle base change (glutamic acid to glycine) in the toxin gene which is immunologically indistinguishable from the native diphtheria toxin. CRM197 functions as a carrier for polysaccharides and haptens making them immunogenic (11, 12). It is utilized as a carrier to develop conjugate vaccines for diseases such as pneumococcal and meningococcal infections. MenACWY-CRM is an approved vaccine to protect adults and adolescents against disease caused by meningococcal serogroups A, C, W-135 and Y. Information on our entire family of Diphtheria products can be found at https://www.listlabs.com/products/diphtheria-toxins/.

Adenylate Cyclase Toxoid, Cya-AC (Product #198L): A genetically modified adenylate cyclase toxin (ACT) lacking adenylate cyclase activity (CyaA-AC) has been produced (13). Although the catalytic activity is destroyed, CyaA-AC is still cell invasive and able to induce an immune response to co-administered pertussis antigens (14, 15).  CyaA-AC has been shown to promote delivering of vaccine antigens into the cytosol of major histocompatibility complex (MHC) class I antigen-presenting cells (16). CyaA-AC has been used as a tool to deliver antigens to T-cells in anti-cancer immunotherapeutic vaccines (17, 18).

Pertussis Toxin Mutant (Product #184): List Labs produces Pertussis Toxin Mutant, a genetically inactivated form of pertussis toxin where mutations were introduced to abolish the catalytic activity of the S1 subunit while the toxin complex still retains the cell binding ability (19). A pertusis toxin mutant has been used as an adjuvant or as a carrier to promote an immune response. These studies indicated that pertussis toxin mutant possesses adjuvant properties with the ability to encourage both local and systemic responses, to promote T helper cell responses to co-administered antigens and to favor the production of Th1/Th17 cells, important in mediating host immunity to infectious pathogens (20). Pertusis toxin binds to the cell receptor, TLR4 which activates Rac and subsequently causes various effects depending on the type of cell treated (21). The toxin or binding oligomer induces dendritic cell maturation in a TLR4-dependent manner (22). Information on our entire family of Pertussis products can be found at https://www.listlabs.com/products/pertussis-toxins-&-virulence-factors/.

LPS and its derivatives: List Labs provides LPS and various derivatives: highly purified HPTTM LPS from Escherichia coli O113 (Product #433); Ultar Pure Escherichia coli O111:B4 LPS (Product #421); Escherichia coli O55:B5 LPS (Product #423); Ultra pure LPS from Salmonella Minnesota R595 (Product #434); Lipid A Monophosphoryl from Salmonella Minnesota R595 (Product #401) and highly purified HPTTM LPS from Bordetella pertusis strain 165 (Product #400). For other LPS products please go to our product website. These LPS products are widely used as vaccine adjuvants and immune stimulators.

LPS is a potent stimulator of the vertebrate innate immune system mediated by macrophages and dendritic cells and generates a rapid response to infectious agents. Structural patterns common to diverse LPS molecules are recognized by Toll-like receptors (TLR) and accessory proteins in serum.  LPS released from bacterial membranes is bound to LPS binding protein (LBP) in serum, transferred to CD-14, an LPS receptor glycoprotein, and presented to the TLR-4-MD-2 complex, stimulating production of cytokines. LPS has a wide range of uses in research and drug development.  It may be used to stimulate immune cells and investigate the innate immune responses.  In drug development, structurally modified LPS forms, such as monophophoryl lipid A (MPLA) have been used as adjuvants in a wide range of vaccine formulations. MPLA, a TLR4 agonist has been formulated with liposomes, oil emulsions, or aluminium salts for several vaccines such as malaria vaccine (known as RTS,S) that is comprised of MPLA and a detoxified saponin derivative, QS-21 (3). Information on our entire family of Lipopolysaccharides can be found at https://www.listlabs.com/products/lipopolysaccharides/.

List Labs specializes in producing high quality adjuvants for vaccine development and is interested in partnering with others on new projects.  See some of our special projects or contact us for more information.

  1. Lee S.,Nguyen M.T. Recent advances of vaccine adjuvants for infectious diseases. Immune Netw. 2015, 15(2): 51-7. PMID: 25922593
  2. Petrovsky N., Aguilar J.C. Vaccine adjuvants: current state and future trends. Immunol Cell Biol.2004, 82(5): 488-96. PMID: 15479434 
  3. Alving C.R., Peachman K.K.,Rao M., Reed S.G. Adjuvants for human vaccines. Curr Opin Immunol. 2012, 24 (3):310-5. PMID: 22521140 
  4. Baker C.J., Rench M.A., McInnes P. Immunization of pregnant women with group B streptococcal type III capsular polysaccharide-tetanus toxoid conjugate vaccine. 2003. 21(24)3468-72. PMID: 12850362
  5. Guo L., Li X., Tang F., He Y., Xing Y., Deng X., Xi T. Immunological features and the ability of inhibitory effects on enzymatic activity of an epitope vaccine composed of cholera toxin B subunit and B cell epitope from Helicobacter pylori urease A subunit. Appl Microbiol Biotechnol. 2012, 93(5):1937-45. PMID: 22134639
  6. Matoba N., Kajiura H., Cherni I., Doran J.D., Bomsel M., Fujiyama K., Mor T.S. Biochemical and immunological characterization of the plant-derived candidate human immunodeficiency virus type 1 mucosal vaccine CTB-MPR. Plant Biotechnol J.2009, 7(2):129-45. PMID: 19037902
  7. Tinker J.K., Yan J., Knippel R.J., Anayiotou P., Ornell K.A. Immunogenicity of a West Nile virus DIII-cholera toxin A2/B chimera after intranasal delivery. Toxins (Basel).2014, 6(4):1397-418. PMID: 24759174
  8. Anjuere F., George-Chandy A., Audant F., Rousseau D., Holmgren J., Czerkinsky C. Transcutaneous immunization with cholera toxin B subunit adjuvant suppresses IgE antibody responses via selective induction of Th1 immune responses. J Immunol.2003, 170(3):1586-92. PMID: 12538724
  9. Sun J.B., Czerkinsky C.,Holmgren J. Mucosally induced immunological tolerance, regulatory T cells and the adjuvant effect by cholera toxin B subunit. Scand J Immunol. 2010, 71(1):1-11. PMID: 20017804
  10. Pappenheimer Jr. A.M., Uchida T., Harper A.A. An immunological study of the diphtheria toxin molecule. 1972, 9(9):891-906. PMID: 4116339
  11. Gupta R.K., Siber G.R. Reappraisal of existing methods for potency testing of vaccines against tetanus and diphtheria. 1995, 13(11): 965-6. PMID: 8525688
  12. Benaissa-Trouw B., Lefeber D.J, Kamerling J.P., Vliegenthart J.F., Kraaijeveld K., Snippe H. Synthetic polysaccharide type 3-related di-, tri-, and tetrasaccharide-CRM (197) conjugates induce protection against Streptococcus pneumoniae type 3 in mice. Infect Immun.2001, 69(7):4698-701. PMID: 11402020
  13. Simsova M., Sebo P., Leclerc C. The adenylate cyclase toxin from Bordetella pertussis–a novel promising vehicle for antigen delivery to dendritic cells. Int J Med Microbiol. 2004, 293(7-8):571-6. PMID: 15149033
  14. Macdonald-Fyall J., Xing D., Corbel M., Baillie S., Parton R., Coote J. Adjuvanticity of native and detoxified adenylate cyclase toxin of Bordetella pertussistowards co-administered antigens. 2004, 22(31-32):4270-81. PMID: 15474718
  15. Cheung G.Y., Xing D., Prior S., Corbel M.J., Parton R., Coote J.G. Effect of different forms of adenylate cyclase toxin of Bordetella pertussis on protection afforded by an acellular pertussis vaccine in a murine model. Infect Immun.2006, 74(12):6797-805. PMID: 16982827
  16. Osicka R., Osicková A., Basar T., Guermonprez P., Rojas M., Leclerc C., Sebo P. Delivery of CD8(+) T-cell epitopes into major histocompatibility complex class I antigen presentation pathway by Bordetella pertussis adenylate cyclase: delineation of cell invasive structures and permissive insertion sites. Infection Immunity, 2000, 68(1): 247-256. PMID: 10603395
  17. Dadaglio G., Morel S., Bauche C.,  Moukrim Z., Lemonnier F.A., Van Den Eynde B.J., Ladant D., Leclerc C.  Recombinant adenylate cyclase toxin of Bordetella pertussisinduces cytotoxic T lymphocyte responses against HLA*0201-restricted melanoma epitopes. Int Immunol. 2003 15(12):1423-30. PMID: 14645151
  18. Fayolle C., Ladant D., Karimova G., Ullmann A., Leclerc C. Therapy of murine tumors with recombinant  Bordetella pertussisadenylate cyclase carrying a cytotoxic T cell epitope. J Immunol. 1999, 162(7):4157-62. PMID: 10201941
  19. Brown D.R.,Keith J.M., Sato H., Sato Y. Construction and characterization of genetically inactivated pertussis toxin. Dev Biol Stand. 1991, 73:63-73. PMID: 1778335
  20. Nasso M., Fedele G., Spensieri F., Palazzo R., Costantino P., Rappuoli R., Ausiello C.M. Genetically detoxified pertussis toxin induces Th1/Th17 immune response through MAPKs and IL-10-dependent mechanisms. J Immunol. 2009, 183(3):1892-9. PMID: 19596995
  21. Nishida M.,Suda R., Nagamatsu Y., Tanabe S., Onohara N., Nakaya M., Kanaho Y., Shibata T., Uchida K., Sumimoto H., Sato Y., Kurose H. Pertussis toxin up-regulates angiotensin type 1 receptors through Toll-like receptor 4-mediated Rac activation. J Biol Chem. 2010, 285(20):15268-77. PMID: 20231290
  22. Wang ZY., Yang D., Chen Q., Leifer C.A., Segal D.M., Su S.B., Caspi R.R., Howard Z.O., Oppenheim J.J. Induction of dendritic cell maturation by pertussis toxin and its B subunit differentially initiate Toll-like receptor 4-dependent signal transduction pathways. Exp Hematol. 2006, 34(8):1115-24. PMID: 16863919