June 5, 2017

By: douano@listlabs.com

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

 

Cholera Toxin has Two Faces

In 2010, Sanchez et al published an article with the puzzling title “Cholera toxin—A foe & a friend. ” The cholera toxin, a complex of two units produced by the pathogen Vibrio cholerae clearly plays the “foe” role [1]. The World Health Organization 2012 report estimated that it caused 2.8 million cases of cholera, which kills by attacking mucosal cells in the intestine, resulting in about 90,000 deaths [2]. To be sure, cholera’s devastating effect can be ameliorated by vaccination, but not completely overcome, given that outbreaks spread rapidly and that existing vaccines against cholera require conditions rarely available in endemic areas.

List Labs products belong to the “friend” aspect of cholera toxin; they are used in experimental research, sometimes alone and sometimes as an adjuvant for use with other chemical or biochemical entities. Among the many uses of List Labs’ Cholera toxin products, recent studies provide examples of the wide range of applications in various experimental fields. Once the crystallographic structure of the toxin was elucidated, the already established capacity of the subunits in experimental research became even more clearly understood. The friend aspect takes advantage of the elegant structure of the toxin complex of 6 protein subunits: the toxic “A” protein subunit embedded in a pentamer of 5 “B” protein subunits that can bind to the surface of mammalian target cells.

 

Cholera Toxin B products in Research

Studies are done using experimental animals to evaluate possible solutions to serious human health issues. For an example in behavioral research, Hervig et al [3] explored the structure of the serotonin 2A receptor in the prefrontal cortex as a target for treatment of neuropsychiatric disorders, including schizophrenia, obsessive-compulsive disorder, and borderline personality disorder. In a comparative murine study, the researchers related exposure to a ketaserin solution using List Labs’ Cholera toxin B (product #104) as a tracer for neuronal activity under different conditions. In neurology, List Labs’ Cholera toxin subunit B found further elegant application as a tracer: Bostan and colleagues [4] investigated basal ganglia and the cerebellum in cebus monkeys using injections into regions of the cerebellar cortex; their insights may at some future date provide further understanding of basal ganglia disorders with motor symptoms such as Parkinson disease and dystonia. Reichard et al [5] used List Labs’ Cholera B toxin in an exploration of systems in the temporal lobe that contribute to behavioral flexibility—the capacity for the organism to modify behavior in response to changing contingencies. Finally, chronic and acute pain continues to thwart efforts to provide long-term relief. In a study completed very recently by Lee and colleagues [6], List Labs’ Cholera B toxin was used to better understand the changes in the sensory pain process, or cutaneous nociception, by exploring in detail the changes in neural circuits after injury or disease. Exploring the mutagenic changes in a murine lung cancer cell line, Nogimori and colleagues [7], using the Cholera toxin B biotin conjugate, suggested that levels of the enzyme ppGalNAc-T13 could be a prognostic for human lung cancer.

 

Cholera Toxin from Vibrio Cholerae

Changes in long non-coding RNAs are involved in normal cellular process, but also participate in pathophysiological conditions—including cancer. List Labs’ Cholera toxin from Vibrio cholerae was used by Henry et al [8] to elucidate the molecular etiology of breast cancer. Lung cancer provides yet another example. Like most cancers, lung cancer involves inflammation and a concurrent mutagenic exposure. Shi et al [9] studied mutagenic changes through exposing cells from a specific pulmonary cell line to a chemical mutagen through levels of gene expression. In yet another field of research, List Labs’ Cholera toxin was used as an adjuvant to explore two major subtypes of respiratory syncytial virus (RSV). Against this virus, a major cause of serious illness, especially among infants, young children, and the elderly, Lee and colleagues proposed a vaccine that could be delivered intravenously as a universal preventive against both RSV A and B [10].

Much evidence has confirmed the symbiotic relationship between gut microbiota and the host. In mice that were immunized orally with List Labs’ cholera toxin, Nagashima et al explored the role of a subepithelial mesenchymal cell type that is involved in maintaining host–microbe interaction in the gut, especially important to the diversification of gut microbiota [11]. Disturbances in this homeostasis is involved in Crohn’s disease; this work provides a molecular basis for development of vaccines that provide a way to modulate the population of gut microbiota in inflammatory bowel disease and in infectious diseases.

These previous examples are only a few that emphasize the importance of List Labs’ Cholera toxin family of products in a broad range of experimental fields; many more can be easily found by searching the List Labs Citations Page. However, I can’t resist citing one more very important advance as a final source of joy per the study that inspired this blog entry, and that is a vital improvement in the current vaccine against anthrax caused by the deadly bacterial pathogen Bacillus anthracis. List Labs’ Cholera toxin is an important ally in the effort to improve the current vaccine against anthrax in humans, which is cumbersome to administer and does not provide complete immunity. Martin and colleagues in a murine study [12] have developed an experimental vaccine that could be administered mucosally and promotes broad immunity against anthrax toxins.

 

1. Sanchez J, Holmgren J. Cholera toxin – a foe & a friend. The Indian Journal of Medical Research. 2011;133:153-163. PMID: 21415489
   
2. Hervig ME, Jensen NCH, Rasmussen NB, et al. Involvement of serotonin 2A receptor activation in modulating medial prefrontal cortex and amygdala neuronal activation during novelty-exposure. Behavioural Brain Research. 2017;326:1-12. PMID: 28263831
   
3. Bostan AC, Dum RP, Strick PL. The basal ganglia communicate with the cerebellum. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(18):8452-8456. PMID: 20404184
   
4. Reichard RA, Subramanian S, Desta MT, et al. Abundant collateralization of temporal lobe projections to the accumbens, bed nucleus of stria terminalis, central amygdala and lateral septum. Brain Structure & Function. 2017;222(4):1971-1988. PMID: 27704219
   
5. Lee HJ, White JM, Chung J, Tansey KE. Peripheral and central anatomical organization of cutaneous afferent subtypes in a rat nociceptive intersegmental spinal reflex. The Journal of Comparative Neurology. 2017;525(9):2216-2234. PMID: 28295313
   
6. Nogimori K, Hori T, Kawaguchi K, et al. Increased expression levels of ppGalNAc-T13 in lung cancers: Significance in the prognostic diagnosis. International Journal of Oncology. 2016;49(4):1369-1376. PMID: 27499036
   
7. Henry WS, Hendrickson DG, Beca F, et al. LINC00520 is induced by Src, STAT3, and PI3K and plays a functional role in breast cancer. Oncotarget. 2016;7(50):81981-81994. PMID: 27626181
   
8. Shi Q, Boots AW, Maas L, et al. Effect of interleukin (IL)-8 on benzo[a]pyrene metabolism and DNA damage in human lung epithelial cells. Toxicology. 2017;381:64-74. PMID: 28238931
   
9. Lee JY, Chang J. Universal vaccine against respiratory syncytial virus A and B subtypes. PloS one. 2017;12(4):e0175384. PMID: 28384263
10. Nagashima K, Sawa S, Nitta T, et al. Identification of subepithelial mesenchymal cells that induce IgA and diversify gut microbiota. Nature Immunology. 2017;18(6):675-682. PMID: 28436956
    
11. Martin TL, Jee J, Kim E, Steiner HE, Cormet-Boyaka E, Boyaka PN. Sublingual targeting of STING with 3’3′-cGAMP promotes systemic and mucosal immunity against anthrax toxins. Vaccine. 2017;35(18):2511-2519. PMID: 28343781