Examples of bioparhamaceutical products of Saccharomyces.
Saccharomyces is a eukaryotic organism that possesses approximately 6,000 known genes since 1996. It has long been used for food, bakeries, drinks, and therapeutics due to its many ingredients and its role in several mechanisms. Saccharomyces can be used as an experimental organism for medicinal products in the pharmaceutical industry. Particularly in public health, the use of Saccharomyces in the production of vaccines is remarkable. It has been alleviated that this yeast helps clarify the function of individual proteins in pathogenic viruses. To clarify virus life and host interactions, virus replication systems in Saccharomyces were interested in scientists. The new antiviral strategies with yeasts suggest the biological mechanism of a pathogen virus. Due to the variety of diseases and current epidemic conditions, these organisms play an essential role in prevention and treatment. This chapter will try to update Saccharomyces’ scientific discoveries with the most recent and up-to-date literature.
- pandemic diseases
- experimental organisms
- public health
- antiviral strategies
Besides poor treatment and vaccination programs, a healthy immune system and antioxidant mechanism are the essential defenders considering the current viral diseases. The viral diseases hosted in a body has several impacts on organs and systems. Also, long-term drug use or vaccination programs can cause some acute side effects on the body, such as gut microbiota, immunity, lung tissue, etc. Therefore, probiotics, prebiotics, vitamins, natural antioxidants have been generally recommended over the years. Probiotics named live microorganisms have beneficial effects on systems, and they have been used successfully. Prebiotics are non-digestible foods that stimulate intestinal tissue growth and modulate immunity. Vitamins, minerals, and natural antioxidants have been used to enhance immune activity and health in viral diseases. It can be said that all these supplements are essential for adequate homeostasis.
Today, evaluate the most effective, economical, and safe vaccines is a significant challenge. Thus, some crucial organisms have been interested in vaccine production as well as nutrition. Among the different vaccination process, yeasts have a broad interest in the scientific area (Figure 1). These unicellular and saprotrophic fungi have been used as a biological model. They have also been accepted as critical models for experiments due to their cellular structure, components, and rapid growth. Yeast also can be cultured easily and manipulated genetically. These features showed that yeasts are beneficial to identify the cellular mechanism of virus and vaccine programs safely [1, 2].
The yeast Saccharomyces, the essential eukaryotic organism, have been used as a biological model. Nevertheless, there is a notable gene homology in this yeast with human genes. In this chapter, we try to identify the Saccharomyces yeast as a useful model for biological experiments and observe the importance of viruses, viral diseases, and vaccines.
Saccharomyces, which is a genus belonging to the Saccharomyces fungus kingdom, includes many yeast species. The name of Saccharomyces is derived from the Latin words saccharo- (sugar) and - Greek mikes (mushrooms). These yeasts were initially suggested in 1680, and named Saccharomyces in 1837. A successful systemic concept on these higher eukaryotes was designed by Mayr . Yeasts’ cultured forms have been used for thousands of years due to rapid reproduction and essential components. Typical features of Saccharomyces are the usage of nitrate and ability for the fermentation of carbohydrates. Saccharomyces have an excellent capacity for ethanol production, and they are suitable yeasts for large-scale fermentation . These important yeasts can be used for the food industry to produce several foods such as bread, beer, wine, distilled spirits, and industrial alcohols. The most knows are
Saccharomyces yeasts focus on the dietary field as a probiotic and the process of treating the disease. Belong the probiotic action; these yeasts have several vital roles on mechanisms such as bacterial adhesion, enhancement of immune cells and responses, modulation of the signaling pathways of the host, and improvement of the strengthening of enterocytes . Nevertheless, Saccharomyces are used as model organisms in biological studies, particularly chemicals and pharmaceuticals.
3. Experimental organism for pharmaceutical industry
Over the last fifty years, remarkable progress in our ability to produce advanced drugs has improved people’s health and longevity. Pharmaceutical proteins are one of the fastest-growing groups of medicines and are currently critical to treating many diseases .
Proteins have a catalyzer role in several metabolic reactions as well as an essential responsibility for cellular mechanisms. There are unique systems that can be used to produce proteins for the pharmaceutical industry from a single cell to multiple organisms, including eukaryotes, especially yeasts. Dozens of pharmaceutical proteins, including insulin, vaccines, and blood factors, produced by
The yeast Saccharomyces has been accepted as the significant organism for several metabolisms such as cell cycle, biogenesis, protein folding, genetic manipulation, recombination, etc. .
|Human serum albumin||Blood factors||Payne et al. |
|Recombinant proteins||Protein||Huang et al. , Ferrer-Millares et al. , Ma et al. , Cino |
|Insulin||Hormone||Martinez et al. |
|Glucagon||Hormone||Egel-Mitani et al. |
|Human parathyroid hormone||Hormone||Song et al. |
|Purified protein for vaccines||Protein||Hadiji-Abbes et al. , Zhang et al. , King et al. , Kaslow and Shiloach , Fazlalipour et al. .|
|Virus like particles||Protein||Jacobs et al. , Kim et al. , Kim et al. .|
|Gene expression systems||Gene||Malak et al. , van Ooyen et al. , Vierira Gomes et al. .|
Recombinant proteins are recognized as an important part of the drug industry. Among these proteins, Saccharomyces has greater attention than others due to their eukaryotic properties, easy genetic manipulation, and capable of modifications.
4. Antiviral strategies
While the vaccines currently available have proven invaluable in the fight against infectious diseases and eradicating viruses, there are many drawbacks to the current vaccine preparation or application regimen despite these successes. Certain limitations of conventional vaccines require multiple adjuvants and injections to induce a necessary or optimal immune response. Another reason is the constant increase in the number of post-vaccination allergic reactions or hypersensitivities in a specific group of people [47, 48].
Today, there are several critical viral diseases such as human hepatitis B and C, immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus (SARS), coronavirus-disease 2019 (COVID19), etc. Due to the inadequacy of treatment options for these infections, new antiviral strategies and model organisms, particularly yeast, were of interest to the researchers.
Yeasts have a delivery system for nucleic acids, and thus they can be an alternative for virus description. Besides, a humanized yeast system was identified for yeast/virus systems to study diseases . Yeasts are used for subunit vaccine formulations with producing antigens against viruses. It was reviewed that yeast can be used for vaccine development in such strategies; whole recombinant yeast, virus-like particles, yeast display, and purified protein immunogens . Among yeasts,
Rosenfeld and Racaniello  reported that hepatitis C virus (HCV) was demonstrated in
All things considered, the yeast-based carrier system can be a potential model to develop the vaccine insights of virus-host interactions. The yeast strategies can improve the recognition of pathogen antigens peptides, activate the immune response, and also modulate the yeast-based vaccines. Researchers for further pioneering findings have still endured the studies.
5. Future perspectives
There have been many illnesses that have not been controlled by vaccination and new ones as well. Mutation, genetic exchange, environmental and interspecific transference, or human contact are the most emerging diseases. However, new scientific technologies, model organisms and a number of researchers have proven beneficial to vaccination strategies. In this respect, it is possible to observe yeasts for the upcoming vaccines for several diseases.
Yeast engineered to the virus has been accepted as an ideal therapeutic approach. This vaccine’s strategy is improving humoral immunity due to the ability of yeast to the generation of immune responses.
There is a numerous increasing study to obtain the vaccine strategy of yeasts. Studies in yeast proteins and cell wall components, including beta-glucan, may become more critical for vaccine strategies under different phases of clinical trials on animals or humans. According to the essential features of yeast, the yeast-based vaccine strategy is being necessary for vaccine development. It has foreseen that diversity of yeast strains will improve in the future.
The yeast system provides invaluable antiviral strategies. Significant studies have been conducted on yeast progression in the identification of viral diseases and antiviral strategies. Based on a better understanding of yeast protein and viruses, the search for new vaccines and medications for viral or pandemic diseases is safer and more effective. However, experiments with animal models and human cells are still underway in many types of yeast. Knowledge of these new biological systems and technologies, models, and organisms will open up new science avenues.
Conflict of interest
The authors declare no conflict of interest.
Acronyms and abbreviations
Appendices and nomenclature
|Yeast||The most important eukaryote; Saccharomyces.|
|Single celled organism||Saccharomyces cerevisiae|
|Biopharmaceuticals||insulin and its analogs|
|Eukaryotes||The organisms whose cells have a nucleus enclosed within a nuclear envelope|
Wickner RB, Fujimura T, Esteban R. Viruses and prions of Saccharomyces cerevisiae. Adv Virus Res. 2013;86:1-36. doi:10.1016/B978-0-12-394315-6.00001-5
Walch B, Breinig T, Schmitt MJ, Breinig F. Delivery of functional DNA and messenger RNA to mammalian phagocytic cells by recombinant yeast. Gene Therapy.2012;19:237-245. DOI: 10.1038/gt.2011.121
Nielsen J, Keasling JD. Engineering cellular metabolism. Cell. 2016;164(6):1185-1197. DOI: 10.1016/j.cell.2016.02.004
Mayr E. Systematics and the Origin of Species. New York: Columbia University Press; 1942
Zhao XQ, Bai FW. Mechanisms of yeast stress tolerance and its manipulation for efficient fuel ethanol production. J Biotechnol. 2009;144:23-30. DOI: 10.1016/j.jbiotec.2009.05.001
Del Giudice L, Massardo DR, Pontieri P, Wolf K. Interaction between yeast mitochondrial and nuclear genomes: Null alleles of RTG genes affect resistance to the alkaloid lycorine in rho(0) petites of Saccharomyces cerevisiae. Gene. 2005;354:9-14. DOI: 10.1016/j.gene.2005.03.020
Galao RP, Scheller N, Alves-Rodrigues I, Breinig T, Meyerhans A, Diez J. Saccharomyces cerevisiae: a versatile eukaryotic system in virology. Microb Cell Fact. 2007;6:32. doi: 10.1186/1475-2859-6-32
Mcfarland LV, Bernasconi P. Saccharomyces boulardii: a review of an innovative biotherapeutic agent. Microbial Ecology in Health and Disease. 1993;6:157-171. DOI: 10.3109/08910609309141323
Pothoulakis C, Kelly CP, Joshi MA, Gao N, O'Keane CJ, Castagliuolo I, Lamont JT. Saccharomyces boulardiiinhibits Clostridium difficile toxin A binding and enterotoxicity in rat ileum. Gastroenterology. 1993;104:1108-1115. DOI: 10.1016/0016-5085(93)90280-p
Eser P, Wachutka L, Maier KC, Demel C, Boroni M, Iyer S, Cramer P, Gagneur J. Determinants of RNA metabolism in the Schizosaccharomyces pombegenome. Molecular Systems Biology. 2016;12(2):857. DOI: 10.15252/msb.20156526
Stewart GG. Saccharomyces, Introduction. In: Batt CA, Tortorello ML, editors. Encyclopedia of Food Microbiology. 2nd edition. Amsterdam: Elsevier; 2014. p.297-301
Boynton PJ, Greig D. The ecology and evolution of non-domesticated Saccharomyces species. Yeast. 2014: 31(12):449-462. DOI: 10.1002/yea.3040
Libkind D, Hittinger CT, Vale’rio E, Gonçalves C, Dover J, Johnston M, Gonçalves P, Sampaio JP. Microbe domestication and the identification of the wild genetic stock of lager-brewing yeast. Proc Natl Acad Sci USA. 2011;108:14539-14544
Guan Y, Dunham M, Caudy A, Troyanskaya O. Systematic planning of genome-scale experiments in poorly studied species. PLOS Computational Biology. 2010;6(3):e1000698. DOI: 10.1371/journal.pcbi.1000698
Guan Y, Yao V, Tsui K, Gebbia M, Dunham MJ, Nislow C, Troyanskaya OG. Nucleosome-coupled expression differences in closely-related species. BMC Genomics. 2011;12:466. DOI: 10.1186/1471-2164-12-466. PMC 3209474. PMID 21942931
Guan Y, Dunham MJ, Troyanskaya OG, Caudy AA. Comparative gene expression between two yeast species. BMC Genomics. 2013;14:33. doi:10.1186/1471-2164-14-33
Chen X, Kelly CP. Saccharomyces. In Versalovic J, Wilson M, editors. Therapeutic microbiology. Washington: ASM Press; 2008. p. 51-60 DOI: 10.1128/9781555815462.ch5
Huang M, Bao J, Nielsen J. Biopharmaceutical protein production by Saccharomyces cerevisiae: current state and future prospects. Pharmaceutical Bioprocessing. 2014;2(2):167-182. DOI: 10.4155/pbp.14.8
Ferrer-Miralles N, Domingo-Espin J, Corchero JL, Vazquez E, Villaverde A. Microbial factories for recombinant pharmaceuticals. Microb Cell Fact. 2009;8:17. DOI: 10.1186/1475-2859-8-17
Pereira C, Countinho I, Soares J, Bessa C, Lea˜o M, Saraiva L. New insights into cancer-related proteins provided by theyeast model. FEBS Journal. 2012;279:697-712. DOI: 10.1111/j.1742-4658.2012.08477.x
Botstein D, Fink GR. Yeast: an experimental organism for modern biology. Science. 1988;240:1439-1443. DOI: 10.1126/science.3287619
Smith MG, Snyder M. Yeast as a model for human disease. In: Curr Protoc Hum Genet. 2006. Chapter 15:Unit 15.6. DOI: 10.1002/0471142905.hg1506s48
Nielsen J. Production of biopharmaceutical proteins by yeast: advances through metabolic engineering. Bioengineered. 2013;4(4):207-211. DOI: 10.4161/bioe.22856
Payne T, Finnis C, Evans LR, Mead DJ, Avery SV, Archer DB, Sleep D. Modulation of chaperone gene expression in mutagenized Saccharomyces cerevisiaestrains developed for recombinant human albumin production results in increased production of multiple heterologous proteins. Appl Environ Microbiol. 2008;74(24):7759-7766. DOI: 10.1128/AEM.01178-08
Ma JK, Drake PM, Christou P. The production of recombinant pharmaceutical proteins in plants. Nat Rev Genet. 2003;4(10):794-805. DOI: 10.1038/nrg1177
Cino J. High-yield protein production from Pichia pastoris yeast: a protocol for benchtop fermentation. Am Biotechnol Lab. 1999;17:10-21
Martinez JL, Liu LF, Petranovic D, Nielsen J. Pharmaceutical protein production by yeast: towards production of human blood proteins by microbial fermentation. Curr Opin Biotechnol. 2012;23(6):965-971. DOI: 10.1016/j.copbio.2012.03.011
Egel-Mitani M, Andersen AS, Diers II, Hach M, Thim L, Hastrup S, Vad K. Yield improvement of heterologous peptides expressed in yps1-disrupted Saccharomyces cerevisiaestrains. Enzyme Microb Technol. 2000;26(9-10):671-677. DOI: 10.1016/s0141-0229(00)00158-7
Song GY, Chung BH. Overproduction of human parathyroid hormone by fed-batch culture of a Saccharomyces cerevisiaemutant lacking yeast aspartic protease 3. Process Biochem. 1999;35(5):503-508. DOI: 10.1016/S0032-9592(99)00097-7
Hadiji-Abbes N, Martin M, Benzina W, Karray-Hakim H, Gergely C, Gargouri A, Mokhad-Gargouri R. Extraction and purification of hepatitis B virus-like M particles from a recombinant Saccharomyces cerevisiaestrain using alumina powder. J Virol Methods. 2013;187:132-137. DOI: 10.1016/j.jviromet.2012.09.023
Zhang L, Liu J, Lu J, Yan B, Song L, Li, L, Cui F, Zhang G, Wang F, Liang X, Xu A. Antibody response to revaccination among adult non-responders to primary Hepatitis B vaccination in China. Hum Vaccin Immunother. 2015a;11:2716-2722. DOI: 10.1080/21645515.2015.1045172
King TH, Shanley CA, Guo Z, Bellgrau D, Rodell T, Furney S, Henao-Tamayo M, Orme IM. GI-19007, a novel Saccharomyces cerevisiae-based therapeutic vaccine against tuberculosis. Clin Vaccine Immunol. 2017;24:e00245–e00217. DOI: 10.1128/CVI.00245-17
Kaslow DC, Shiloach J. Production, purification and immunogenicity of a malaria transmission-blocking vaccine candidate: TBV25H expressed in yeast and purified using nickel-NTA agarose. Biotechnology (N Y). 1994;12:494-499. DOI: 10.1038/nbt0594-494
Fazlalipour M, Keyvani H, Monavari SH, Mollaie HR. Expression, purification and immunogenic description of a hepatitis C virus recombinant CoreE1E2 protein expressed by yeast Pichia pastoris. Jundishapur J Microbiol. 2015;8:e17157. DOI: 10.5812/jjm.8(4)2015.17157
Jacobs E, Rutgers T, Voet P, Dewerchin M, Cabezon T, de Wilde M. Simultaneous synthesis and assembly of various hepatitis B surface proteins in Saccharomyces cerevisiae. Gene 1989;80:279-291. DOI: 10.1016/0378-1119(89)90292-8
Kim HJ, Kim SY, Lim SJ, Kim JY, Lee SJ, Kim HJ. One-step chromatographic purification of human papillomavirus type 16 L1 protein from Saccharomyces cerevisiae. Protein Expression Purif. 2010;70:68-74. DOI: 10.1016/j.pep.2009.08.005
Kim HJ, Lee JY, Kang HA,Lee Y, Park EJ, Kim HJ. Oral immunization with whole yeast producing viral capsid antigen provokes a stronger humoral immune response than purified viral capsid antigen. Lett Appl Microbiol. 2014;58:285-291. DOI: 10.1111/lam.12188
Malak A, Baronian K, Kunze G. Blastobotrys (Arxula) adeninivorans: a promising alternative yeast for biotechnology and basic research. Yeast. 2016;33:535-547. DOI: 10.1002/yea.3180
van Ooyen AJ, Dekker P, Huang M, Olsthoorn MMA, Jacobs DI, Colussi PA, Taron CH. Heterologous protein production in the yeast Kluyveromyces lactis. FEMS Yeast Res. 2006;6:381-392. DOI: 10.1111/j.1567-1364.2006.00049.x
Vieira Gomes AM, Souza Carmo T, Silva Carvalho L, Mendonça Bahia F, Skorupa Parachin N. Comparison of yeasts as hosts for recombinant protein production. Microorganisms. 2018;6(2):38. OI: 10.3390/microorganisms6020038
Goffeau A, Barrell BG, Bussey H, Davis RW, Dujon B, Feldmann H, Galibert F, Hoheisel JD, Jacq C, Johnston M, Louis EJ, Mewes HW, Murakami Y, Philippsen P, Tettelin H, Oliver SG. Life with 6000 genes. Science. 1996;274(5287):546, 563-547. DOI: 10.1126/science.274.5287.546
Giga-Hama Y, Kumagai H. Expression system for forein genes using the fission yeast Schizosaccharomyces pombe. Biotechnology and Applied Biochemistry. 2000;30(3):235-244. DOI: 10.1111/j.1470-8744.1999.tb00776.x
Drăgan CA, Buchheit D, Bischoff D, Ebner T, Bureik M. Glucuronide production by whole-cell biotransformation using genetically engineered fission yeast Schizosaccharomyces pombe. Drug Metab Dispos. 2010;38(3):509-515. doi: 10.1124/dmd.109.030965
Wood V, Gwilliam R, Rajandream MA, Lyne M, Lyne R, Stewart A, Sgouros J, Peat N, Hayles J, Baker S, Basham D, Bowman S, Brooks K, Brown D, Brown S, Chillingworth T, Churcher C, Collins M, Connor R, Cronin A, Davis P, Feltwell T, Fraser A, Gentles S, Goble A, Hamlin N, Harris D, Hidalgo J, Hodgson G, Holroyd S, Hornsby T, Howarth S, Huckle EJ, Hunt S, Jagels K, James K, Jones L, Jones M, Leather S, McDonald S, McLean J, Mooney P, Moule S, Mungall K, Murphy L, Niblett D, Odell C, Oliver K, O'Neil S, Pearson D, Quail MA, Rabbinowitsch E, Rutherford K, Rutter S, Saunders D, Seeger K, Sharp S, Skelton J, Simmonds M, Squares R, Squares S, Stevens K, Taylor K, Taylor RG, Tivey A, Walsh S, Warren T, Whitehead S, Woodward J, Volckaert G, Aert R, Robben J, Grymonprez B, Weltjens I, Vanstreels E, Rieger M, Schäfer M, Müller-Auer S, Gabel C, Fuchs M, Düsterhöft A, Fritzc C, Holzer E, Moestl D, Hilbert H, Borzym K, Langer I, Beck A, Lehrach H, Reinhardt R, Pohl TM, Eger P, Zimmermann W, Wedler H, Wambutt R, Purnelle B, Goffeau A, Cadieu E, Dréano S, Gloux S, Lelaure V, Mottier S, Galibert F, Aves SJ, Xiang Z, Hunt C, Moore K, Hurst SM, Lucas M, Rochet M, Gaillardin C, Tallada VA, Garzon A, Thode G, Daga RR, Cruzado L, Jimenez J, Sánchez M, del Rey F, Benito J, Domínguez A, Revuelta JL, Moreno S, Armstrong J, Forsburg SL, Cerutti L, Lowe T, McCombie WR, Paulsen I, Potashkin J, Shpakovski GV, Ussery D, Barrell BG, Nurse P. The genome sequence of Schizosaccharomyces pombe. Nature. 2002;415:871-880. DOI: 10.1038/nature724
Hoffman CS, Wood V, Fantes PA. An ancient yeast for young geneticists: A primer on the Schizosaccharomyces pombemodel system. Genetics. 2015;201:403-423. DOI: 10.1534/genetics.115.181503
Darby RA, Cartwright SP, Dilworth MV, Bill RM. Which yeast species shall I choose? Saccharomyces cerevisiaeversus Pichia pastoris (review). Methods Mol Biol. 2012;866:11-23. DOI: 10.1007/978-1-61779-770-5_2
Shams H. Recent developments in veterinary vaccinology. Vet J. 2005;170(3):289-299. DOI: 10.1016/j.tvjl.2004.07.004
Fang Y, Liu MQ, Chen L, Zhu ZG, Zhu RZ, Hu Q. Rabies post-exposure prophylaxis for a child with severe allergic reaction to rabies vaccine. Hum Vaccin Immunother 2016;12:1802-1804. DOI: 10.1080/21645515.2016.1143158
Mager WH, Winderickx J. Yeast as a model for medical and medicinal research. Trends Pharmacol Sci. 2005;26:265-273. DOI: 10.1016/j.tips.2005.03.004
Kumar R, Kumar P. Yeast-based vaccines: New perspective in vaccine development and application. FEMS Yeast Research. 2019;19. DOI: 10.1093/femsyr/foz007
Rosenfeld AB, Racaniello VR. Hepatitis C virus internal ribosome entry site-dependent translation in Saccharomyces cerevisiae is independent of polypyrimidine tract-binding protein, poly(rC)-binding protein 2, and La protein 1. J Virol. 2005;79:10126-10137. DOI: 10.1128/JVI.79.16.10126-10137.2005
Valenzuela P, Medina A, Rutter WJ, Ammerer G, Hall BD. Synthesis and assembly of hepatitis B virus surface antigen particles in yeast. Nature. 1982;298:347-350. DOI: 10.1038/298347a0
Blanco R, Carrasco L, Ventoso I. Cell killing by HIV-1 protease. J Biol Chem. 2003;278:1086-1093. DOI: 10.1074/jbc.M205636200
Kapoor P, Lavoie BD, Frappier L. EBP2 plays a key role in Epstein-Barr virus mitotic segregation and is regulated by aurora family kinases. Mol Cell Biol. 2005;25:4934-4945. DOI: 10.1128/MCB.25.12.4934-4945.2005
Zhang X, Xin L, Li S, Fang M, Zhang J, Xia N, Zhao Q. Lessons learned from successful human vaccines: delineating key epitopes by dissecting the capsid proteins. Hum Vaccine Immunotherapeutics 2015;11:1277-1292. DOI: 10.1080/21645515.2015.1016675
Nussenzweig V, Barr P, inventors; New York University, Chiron Corporation, assignee. Vaccine against the sporozoite stage of malaria. Patent US4997647A. 1991
Karumuthil-Melethil S, Gudi R, Johnson BM, Perez N, Vasu C. Fungal βglucan, a Dectin-1 ligand, promotes protection from type 1 diabetes by inducing regulatory innate immune response. J Immunol 2014;193:3308-3321. DOI: 10.4049/jimmunol.1400186