Genetic Operation System of Lactic Acid Bacteria and Its Applications

  • Haiqin ChenEmail author
  • Chen Chen
  • Chunqing Ai
  • Chengcheng Ren
  • He Gao


Lactic acid bacteria (LAB), a class of commonly existing microorganisms in nature, are important components of gut commensal microflora in humans and animals. Previous studies suggested that LAB exerted specific physiological and biochemical functions on the host such as improving intestinal microbial balance, immunomodulation, inhibiting tumor growth, lowering cholesterol levels, as well as regulating blood pressure and are therefore widely used in food manufacturing and functional food development. Due to the continuous development of modern molecular biology techniques, studies regarding exploiting LAB as expression hosts in addition to fermentation starter cultures and probiotics have received increasing attention from both academia and industry. In the 1980s, some researchers initiated molecular genetic research for LAB. They characterized lactose metabolism-related genes and proteins in LAB and established preliminary DNA delivery systems for LAB. Over the past decades, owing to the advances in modern DNA sequencing and gene characterization techniques, structures and functions of LAB genomes and plasmid-related genes have been further elucidated, which lays a solid theoretical foundation for the further development of LAB-based gene expression systems (Bolotin et al. 2001; Altermann et al. 2005).


  1. Adel-Patient K, Ah-Leung S, Creminon C et al (2005) Oral administration of recombinant Lactococcus lactis expressing bovine β-lactoglobulin partially prevents mice from sensitization. Clin Exp Allergy 35(4):539–546PubMedCrossRefGoogle Scholar
  2. Ai CQ, Zhang QX et al (2015) Protective effect of Streptococcus thermophilus CCFM218 against house dust mite allergy in a mouse model. Food Control 50:283–290CrossRefGoogle Scholar
  3. Allison GE, Klaenhammer TR (1996) Functional analysis of the gene encoding immunity to lactacin F, laf I, and its use as a Lactobacillus-specific food-grade genetic marker. Appl Environ Microbiol 62:4450–4460PubMedPubMedCentralGoogle Scholar
  4. Altermann EWM, Russell MA, Azcarate-Peril R et al (2005) Complete genome sequence of the probiotic lactic acid bacterium Lactobacillus acidophilus NCFM. Proc Natl Acad Sci U S A 102(11):3906–3912PubMedPubMedCentralCrossRefGoogle Scholar
  5. Atiles MW, Dudley EG, Steele JL (2000) Gene cloning, sequencing, and inactivation of the branched-chain aminotransferase of Lactococcus lactis LM0230. Appl Environ Microbiol 66(6):2325–2329PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bahey-El-Din M (2012) Lactococcus lactis-based vaccines from laboratory bench to human use: an overview. Vaccine 30(4):685–690PubMedCrossRefGoogle Scholar
  7. Benbouziane B, Ribelles P (2013) Development of a stress-inducible controlled expression SICE system in Lactococcus lactis for the production and delivery of therapeutic molecules at mucosal surfaces. J Biotechnol 1682:120–129CrossRefGoogle Scholar
  8. Beninati C, Oggioni MR, Boccanera M et al (2000) Therapy of mucosal candidiasis by expression of an anti-idiotype in human commensal bacteria. Nat Biotechnol 18(10):1060–1064PubMedCrossRefGoogle Scholar
  9. Bermudez-Humaran LG, Langella P (2002) Production of human papillomavirus type 16 E7 protein in Lactococcus lactis. Appl Environ Microbiol 682:917–922CrossRefGoogle Scholar
  10. Bermudez-Humaran LG, Cortes-Perez NG, Le Loir Y et al (2003a) Fusion to a carrier protein and a synthetic propeptide enhances E7 HPV-16 production and secretion in Lactococcus lactis. Biotechnol Prog 19(3):1101–1104PubMedCrossRefGoogle Scholar
  11. Bermudez-Humaran LG, Langella P, Commissaire J et al (2003b) Controlled intra- or extracellular production of staphylococcal nuclease and ovine omega interferon in Lactococcus lactis. FEMS Microbiol Lett 224(2):307–313PubMedCrossRefGoogle Scholar
  12. Bermúdez-Humarán LG, Kharrat P, Chatel JM et al (2011) Lactococci and lactobacilli as mucosal delivery vectors for therapeutic proteins and DNA vaccines. Microb Cell Factories 10(1):1–10CrossRefGoogle Scholar
  13. Bernaudat F, Frelet-Barrand A (2011) Heterologous expression of membrane proteins: choosing the appropriate host. PLoS One 612:e29191CrossRefGoogle Scholar
  14. Bhowmik T, Steele JL (1993) Development of an electroporation procedure for gene disruption in Lactobacillus helveticus CNRZ 32. J Gen Microbiol 139(7):1433–1439CrossRefGoogle Scholar
  15. Biswas I, Gruss A, Ehrlich SD et al (1993) High-efficiency gene inactivation and replacement system for gram-positive bacteria. J Bacteriol 175(11):3628–3635PubMedPubMedCentralCrossRefGoogle Scholar
  16. Boels IC, Van Kranenburg R, Kanning MW et al (2003) Increased exopoly- saccharide production in Lactococcus lactis due to increased levels of expression of the NIZO B40 eps gene cluster. Appl Environ Microbiol 69(8):5029–5031PubMedPubMedCentralCrossRefGoogle Scholar
  17. Bohle B (2006) T-cell epitopes of food allergens. Clin Rev Allergy Immunol 30(2):97–108PubMedCrossRefGoogle Scholar
  18. Bolotin A, Wincker P, Mauger S (2001) The complete genome sequence of the lactic acid bacterium Lactococcus lactis ssp. lactis IL1403. Genome Res 11(5):731–753PubMedPubMedCentralCrossRefGoogle Scholar
  19. Braat H, Rottiers P, Hommes DW et al (2006) A Phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin Gastroenterol Hepatol 4(6):754–759PubMedCrossRefGoogle Scholar
  20. Bron PA, Benchimol MG (2002) Use of the alr gene as a food-grade selection marker in lactic acid bacteria. Appl Environ Microbiol 6811:5663–5670CrossRefGoogle Scholar
  21. Carroll IM, Andrus JM, Bruno-Bárcena JM et al (2007) Anti-inflammatory properties of Lactobacillus gasseri expressing manganese superoxide dismutase using the interleukin 10-deficient mouse model of colitis. Am J Physiol Gastrointest Liver Physiol 293(4):G729–G738PubMedCrossRefGoogle Scholar
  22. Charng YC, Lin CC, Hsu CH (2006) Inhibition of allergen-induced airway inflammation and hyperreactivity by recombinant lactic-acid bacteria. Vaccine 24(33–34):5931–5936PubMedCrossRefGoogle Scholar
  23. Chassy BM, Flickinger JL (1987) Transformation of Lactobacillus casei by electroporation. FEMS Microbiol Lett 44(2):173–177CrossRefGoogle Scholar
  24. Chassy BM, Gibson EV, Giuffrida AL (1976) Evidence for extrachromosomal elements in Lactobacillus. J Bacteriol 127(3):1576–1578PubMedPubMedCentralGoogle Scholar
  25. Cheun HI, Kawamoto K, Hiramatsu M et al (2004) Protective immunity of SpaA-antigen producing Lactococcus lactis against Erysipelothrix rhusiopathiae infection. J Appl Microbiol 96(6):1347–1353PubMedCrossRefGoogle Scholar
  26. Cortes-Perez NG, Ah-Leung S (2007) Intranasal coadministration of live lactococci producing interleukin-12 and a major cow’s milk allergen inhibits allergic reaction in mice. Clin Vaccine Immunol 143:226–233PubMedPubMedCentralCrossRefGoogle Scholar
  27. Cortes-Perez NG, Lefèvre F, Corthier G et al (2007) Influence of the route of immunization and the nature of the bacterial vector on immunogenicity of mucosal vaccines based on lactic acid bacteria. Vaccine 25(36):6581–6588PubMedCrossRefGoogle Scholar
  28. Corthesy B, Boris S, Isler P et al (2005) Oral immunization of mice with lactic acid bacteria producing Helicobacter pylori Urease B subunit partially protects against challenge with Helicobacter felis. J Infect Dis 192(8):1441–1449PubMedCrossRefGoogle Scholar
  29. de Azevedo M, Karczewski J (2012) In vitro and in vivo characterization of DNA delivery using recombinant Lactococcus lactis expressing a mutated form of Listeria monocytogenes Internalin A. BMC Microbiol 12:299PubMedPubMedCentralCrossRefGoogle Scholar
  30. de Ruyter PG, Kuipers OP (1996) Controlled gene expression systems for Lactococcus lactis with the food-grade inducer nisin. Appl Environ Microbiol 6210:3662–3667Google Scholar
  31. Drouault S, Juste C, Marteau P et al (2002) Oral treatment with Lactococcus lactis expressing Staphylococcus hyicus lipase enhances lipid digestion in pigs with induced pancreatic insufficiency. Appl Environ Microbiol 68(6):3166–3168PubMedPubMedCentralCrossRefGoogle Scholar
  32. Eaton TJ, Shearman CA, Gasson MJ (1993) The use of bacterial luciferase genes as reporter genes in Lactococcus: regulation of the Lactococcus lactis subsp. lactis lactose genes. J Gen Microbiol 139:1495–1501PubMedCrossRefGoogle Scholar
  33. Emond E, Lavallée R, Drolet G, Moineau S, LaPointe G (2001) Molecular characterization of a theta replication plasmid and its use for development of a two-component food-grade cloning system for Lactococcus lactis. Appl Environ Microbiol 67(4):1700–1709PubMedPubMedCentralCrossRefGoogle Scholar
  34. Enouf V, Langella P, Commissaire J et al (2001) Bovine rotavirus nonstructural protein 4 produced by Lactococcus lactis is antigenic and immunogenic. Appl Environ Microbiol 67(4):1423–1428PubMedPubMedCentralCrossRefGoogle Scholar
  35. Ferain T, Hobbs JN Jr et al (1996) Knockout of the two ldh genes has a major impact on peptidoglycan precursor synthesis in Lactobacillus plantarum. J Bacteriol 178(18):5431–5437PubMedPubMedCentralCrossRefGoogle Scholar
  36. Foligne B, Dessein R, Marceau M et al (2007) Prevention and treatment of colitis with Lactococcus lactis secreting the immunomodulatory Yersinia LcrV protein. Gastroenterology 133(3):862–874PubMedCrossRefGoogle Scholar
  37. Fortina MG, Parini C, Rossi P et al (1993) Mapping of three plasmids from Lactobacillus helveticus ATCC 15009. Lett Appl Microbiol 17(6):303–306PubMedCrossRefGoogle Scholar
  38. Frossard CP, Steidler L, Eigenmann PA (2007) Oral administration of an IL-10–secreting Lactococcus lactis strain prevents food-induced IgE sensitization. J Allergy Clin Immunol 119(4):952–959PubMedCrossRefGoogle Scholar
  39. García-Mantrana I, Yebra MJ, Haros M et al (2016) Expression of bifidobacterial phytases in Lactobacillus casei and their application in a food model of whole-grain sourdough bread. Int J Food Microbiol 216:18PubMedCrossRefGoogle Scholar
  40. Goh YJ, Azcarate-Peril MA (2009) Development and application of a upp-based counterselective gene replacement system for the study of the S-layer protein SlpX of Lactobacillus acidophilus NCFM. Appl Environ Microbiol 7510:3093–3105CrossRefGoogle Scholar
  41. Grangette C, Muller-Alouf H (2001) Mucosal immune responses and protection against tetanus toxin after intranasal immunization with recombinant Lactobacillus plantarum. Infect Immun 693:1547–1553CrossRefGoogle Scholar
  42. Hanniffy SB, Carter AT, Hitchin E et al (2007) Mucosal delivery of a pneumococcal vaccine using Lactococcus lactis affords protection against respiratory infection. J Infect Dis 195(2):185–193PubMedCrossRefGoogle Scholar
  43. Ho PS, Kwang J, Lee YK (2005) Intragastric administration of Lactobacillus casei expressing transmissible gastroentritis coronavirus spike glycoprotein induced specific antibody production. Vaccine 23(11):1335–1342PubMedCrossRefGoogle Scholar
  44. Hols P, Kleerebezem M (1999) Conversion of Lactococcus lactis from homolactic to homoalanine fermentation through metabolic engineering. Nat Biotechnol 176:588–592CrossRefGoogle Scholar
  45. Hongying F, Xianbo W, Fang Y et al (2014) Oral Immunization with recombinant Lactobacillus acidophilus expressing the adhesin Hp0410 of Helicobacter pylori induces mucosal and systemic immune responses. Clin Vaccine Immunol 21(2):126–132PubMedPubMedCentralCrossRefGoogle Scholar
  46. Hu S, Kong J, Kong W, Guo T et al (2010) Characterization of a novel LysM domain from Lactobacillus fermentum bacteriophage endolysin and its use as an anchor to display heterologous proteins on the surfaces of lactic acid bacteria. Appl Environ Microbiol 76(8):2410–2418PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hugenholtz J, Kleerebezem M (2000) Lactococcus lactis as a cell factory for high-level diacetyl production. Appl Environ Microbiol 669:4112–4114CrossRefGoogle Scholar
  48. Hughes BF, Mc Kay LL (1992) Deriving phage-insensitive Lactococci using a food-grade vector encoding phage and nisin resistance. J Dairy Sci 75:914–923CrossRefGoogle Scholar
  49. Huibregtse IL, Snoeck V, de Creus A et al (2007) Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin. Gastroenterology 133(2):517–528PubMedCrossRefGoogle Scholar
  50. Jimenez JJ, Diep DB, Borrero J et al (2015) Cloning strategies for heterologous expression of the bacteriocin enterocin A by Lactobacillus sakei Lb790, Lb. plantarum NC8 and Lb. casei CECT475. Microb Cell Fact 14:166PubMedPubMedCentralCrossRefGoogle Scholar
  51. Jin Q, Li L (2014) Construction of a dextran-free Leuconostoc citreum mutant by targeted disruption of the dextransucrase gene. J Appl Microbiol 1174:1104–1112CrossRefGoogle Scholar
  52. Kahala M, Palva A (1999) The expression signals of the Lactobacillus brevis slpA gene direct efficient heterologous protein production in lactic acid bacteria. Appl Microbiol Biotechnol 51(1):71–78PubMedCrossRefGoogle Scholar
  53. Kajava AV, Zolov SN, Kalinin AE et al (2000) The net charge of the first 18 residues of the mature sequence affects protein translocation across the cytoplasmic membrane of gram-negative bacteria. J Bacteriol 182(8):2163–2169PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kandaswamy K, Liew TH, Wang CY et al (2013) Focal targeting by human beta-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis. Proc Natl Acad Sci U S A 110(50):20230–20235PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kanpiengjai A, Lumyong S, Wongputtisin P et al (2015) Efficient secretory expression of gene encoding a broad pH-stable maltose-forming amylase from Lactobacillus plantarum S21 in food-grade lactobacilli host. J Korean Soc Appl Biol Chem 58(6):901–908CrossRefGoogle Scholar
  56. Kleerebezem M, Beerthuyzen MM, Vaughan EE et al (1997) Controlled gene expression systems for lactic acid bacteria: transferable nisin-inducible expression cassettes for Lactococcus, Leuconostoc, and Lactobacillus spp. Appl Environ Microbiol 63(11):4581–4584PubMedPubMedCentralGoogle Scholar
  57. Kuczkowska K, Mathiesen G, Eijsink VG et al (2015) Lactobacillus plantarum displaying CCL3 chemokine in fusion with HIV-1 Gag derived antigen causes increased recruitment of T cells. Microb Cell Factories 14(1):1CrossRefGoogle Scholar
  58. Lambert JM, Bongers RS (2007) Cre-lox-based system for multiple gene deletions and selectable-marker removal in Lactobacillus plantarum. Appl Environ Microbiol 734:1126–1135CrossRefGoogle Scholar
  59. Langa S, Arqués JL (2015) Glycerol and cobalamin metabolism in lactobacilli: relevance of the propanediol dehydrogenase pdh30. Eur Food Res Technol 2412:173–184CrossRefGoogle Scholar
  60. Le Loir Y, Nouaille S, Commissaire J et al (2001) Signal peptide and propeptide optimization for heterologous protein secretion in Lactococcus lactis. Appl Environ Microbiol 67(9):4119–4127PubMedPubMedCentralCrossRefGoogle Scholar
  61. Le Loir Y, Azevedo V, Oliveira SC et al (2005) Protein secretion in Lactococcus lactis: an efficient way to increase the overall heterologous protein production. Microb Cell Factories 4(1):2CrossRefGoogle Scholar
  62. LeBlanc JG, del Carmen S, Miyoshi A et al (2011) Use of superoxide dismutase and catalase producing lactic acid bacteria in TNBS induced Crohn’s disease in mice. J Biotechnol 151(3):287–293PubMedCrossRefGoogle Scholar
  63. Lee MH, Roussel Y, Wilks M et al (2001) Expression of Helicobacter pylori urease subunit B gene in Lactococcus lactis MG1363 and its use as a vaccine delivery system against H-pylori infection in mice. Vaccine 19(28–29):3927–3935PubMedCrossRefGoogle Scholar
  64. Lee JS, Poo H, Han DP et al (2005) Mucosal immunization with surface-displayed severe acute respiratory syndrome coronavirus spike protein on Lactobacillus casei induces neutralizing antibodies in mice. J Virol 80(8):4079–4087CrossRefGoogle Scholar
  65. Lee P, Abdul-Wahid A, Faubert GM (2009) Comparison of the local immune response against Giardia lamblia cyst wall protein 2 induced by recombinant Lactococcus lactis and Streptococcus gordonii. Microbes Infect 11(1):20–28PubMedCrossRefGoogle Scholar
  66. Leenhouts K, Bolhuis A (1998) Construction of a food-grade multiple-copy integration system for Lactococcus lactis. Appl Microbiol Biotechnol 494:417–423CrossRefGoogle Scholar
  67. Lei H, Sheng Z, Ding Q et al (2011) Evaluation of oral immunization with recombinant avian influenza virus HA1 displayed on the Lactococcus lactis surface and combined with the mucosal adjuvant cholera toxin subunit B. Clin Vaccine Immunol 18(7):1046–1051PubMedPubMedCentralCrossRefGoogle Scholar
  68. Levander F, Svensson M (2002) Enhanced exopolysaccharide production by metabolic engineering of Streptococcus thermophilus. Appl Environ Microbiol 682:784–790CrossRefGoogle Scholar
  69. Limaye SA, Haddad RI, Cilli F et al (2013) Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer 119(24):4268–4276PubMedCrossRefGoogle Scholar
  70. Lin XB, Lohans CT (2015) Genetic determinants of reutericyclin biosynthesis in Lactobacillus reuteri. Appl Environ Microbiol 816:2032–2041CrossRefGoogle Scholar
  71. Liu B, Xu H (2015) CRISPR/Cas: a faster and more efficient gene editing system. J Nanosci Nanotechnol 153:1946–1959CrossRefGoogle Scholar
  72. Liu CQ, Leelawatcharamas V, Harvey ML et al (1996) Cloning vectors for lactococcus based on a plasmid encoding resistance to cadmium. Curr Microbiol 33:35–39PubMedCrossRefGoogle Scholar
  73. Liu DQ, Qiao XY, Ge JW et al (2011) Construction and characterization of Lactobacillus pentosus expressing the D antigenic site of the spike protein of transmissible gastroenteritis virus. Can J Microbiol 57(5):392–397CrossRefGoogle Scholar
  74. Llull D, Poquet I (2004) New expression system tightly controlled by zinc availability in Lactococcus lactis. Appl Environ Microbiol 70(9):5398–5406PubMedPubMedCentralCrossRefGoogle Scholar
  75. Lokman BC, Santen PV, Verdoes JC et al (1991) Organization and characterization of three genes involved in d -xylose catabolism in Lactobacillus pentosus. Mol Gen Genomics 230(1):161–169CrossRefGoogle Scholar
  76. Maassen CB, Laman JD, den Bak-Glashouwer MJ et al (1999) Instruments for oral disease-intervention strategies: recombinant Lactobacillus casei expressing tetanus toxin fragment C for vaccination or myelin proteins for oral tolerance induction in multiple sclerosis. Vaccine 17(17):2117–2128PubMedCrossRefGoogle Scholar
  77. Madsen SM, Arnau J, Vrang A et al (1999) Molecular characterization of the pH-inducible and growth phase-dependent promoter P170 of Lactococcus lactis. Mol Microbiol 32(1):75–87PubMedCrossRefGoogle Scholar
  78. Maguin E, Duwat P, Hege T et al (1992) New thermosensitive plasmid for gram-positive bacteria. J Bacteriol 174(17):5633–5638PubMedPubMedCentralCrossRefGoogle Scholar
  79. Mahmoud KT, Sameh EM (2011) Heterologous expression of pctA gene expressing propionicin T1 by some lactic acid bacterial strains using pINT125. Alexandria University, NetherlandsGoogle Scholar
  80. Mannam P, Jones KF, Geller BL (2004) Mucosal vaccine made from live, recombinant Lactococcus lactis protects mice against pharyngeal infection with Streptococcus pyogenes. Infect Immun 72(6):3444–3450PubMedPubMedCentralCrossRefGoogle Scholar
  81. McKay LL, Baldwin KA (1990) Applications for biotechnology: present and future improvements in lactic acid bacteria. FEMS Microbiol Rev 7(1–2):3–14PubMedCrossRefGoogle Scholar
  82. Meazza R, Gaggero A, Neglia F et al (1997) Expression of two interleukin-15 mRNA isoforms in human tumors does not correlate with secretion: role of different signal peptides. Eur J Immunol 27(5):1049–1054PubMedCrossRefGoogle Scholar
  83. Meijerink M, Wells JM, Taverne N et al (2012) Immunomodulatory effects of potential probiotics in a mouse peanut sensitization model. FEMS Immunol Med Microbiol 65(3):488–496PubMedCrossRefGoogle Scholar
  84. Murphy KC (1998) Use of bacteriophage lambda recombination functions to promote gene replacement in Escherichia coli. J Bacteriol 180(8):2063–2071PubMedPubMedCentralGoogle Scholar
  85. Narita J, Okano K, Kitao T et al (2006) Display of alpha-amylase on the surface of Lactobacillus casei cells by use of the PgsA anchor protein, and production of lactic acid from starch. Appl Environ Microbiol 72(1):269–275PubMedPubMedCentralCrossRefGoogle Scholar
  86. Nauta A, van den Burg B, Karsens H et al (1997) Design of thermolabile bacteriophage repressor mutants by comparative molecular modeling. Nat Biotechnol 15(10):980–983PubMedCrossRefGoogle Scholar
  87. Nguyen HA, Nguyen TH (2012a) Chitinase from Bacillus licheniformis DSM13: expression in Lactobacillus plantarum WCFS1 and biochemical characterisation. Protein Expr Purif 812:166–174CrossRefGoogle Scholar
  88. Nguyen TT, Nguyen HA (2012b) Homodimeric beta-galactosidase from Lactobacillus delbrueckii subsp. bulgaricus DSM 20081: expression in Lactobacillus plantarum and biochemical characterization. J Agric Food Chem 607:1713–1721CrossRefGoogle Scholar
  89. Nielsen H, Engelbrecht J, Brunak S et al (1997) Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Eng 10(1):1–6PubMedCrossRefGoogle Scholar
  90. Norton PM, Wells JM, Brown HW et al (1997) Protection against tetanus toxin in mice nasally immunized with recombinant Lactococcus lactis expressing tetanus toxin fragment C. Vaccine 15(6–7):616–619PubMedCrossRefGoogle Scholar
  91. Oh JH, van Pijkeren JP (2014) CRISPR-Cas9-assisted recombineering in Lactobacillus reuteri. Nucleic Acids Res 4217:e131PubMedPubMedCentralCrossRefGoogle Scholar
  92. Oliveira MLS, Areas APM, Campos IB et al (2006) Induction of systemic and mucosal immune response and decrease in Streptococcus pneumoniae colonization by nasal inoculation of mice with recombinant lactic acid bacteria expressing pneumococcal surface antigen A. Microbes Infect 8(4):1016–1024PubMedCrossRefGoogle Scholar
  93. Payne J, MacCormick CA (1996) Exploitation of a chromosomally integrated lactose operon for controlled gene expression in Lactococcus lactis. FEMS Microbiol Lett 1361:19–24CrossRefGoogle Scholar
  94. Perez CA, Eichwald C, Burrone O et al (2005) Rotavirus vp7 antigen produced by Lactococcus lactis induces neutralizing antibodies in mice. J Appl Microbiol 99(5):1158–1164PubMedCrossRefGoogle Scholar
  95. Petersen KV, Martinussen J (2013) Repetitive, marker-free, site-specific integration as a novel tool for multiple chromosomal integration of DNA. Appl Environ Microbiol 7912:3563–3569CrossRefGoogle Scholar
  96. Platteeuw C, Hugenholtz J (1995) Metabolic engineering of Lactococcus lactis: influence of the overproduction of alpha-acetolactate synthase in strains deficient in lactate dehydrogenase as a function of culture conditions. Appl Environ Microbiol 6111:3967–3971Google Scholar
  97. Platteeuw C, van Alen-Boerrigter I et al (1996) Food-grade cloning and expression system for Lactococcus lactis. Appl Environ Microbiol 623:1008–1013Google Scholar
  98. Poo H, Pyo HM, Lee TY et al (2006) Oral administration of human papillomavirus type 16 E7 displayed on Lactobacillus casei induces E7-specific antitumor effects in C57/BL6 mice. Int J Cancer 119(7):1702–1709PubMedCrossRefGoogle Scholar
  99. Posno M, Heuvelmans PT (1991) Complementation of the inability of lactobacillus strains to utilize D-xylose with D-xylose catabolism-encoding genes of Lactobacillus pentosus. Appl Environ Microbiol 579:2764–2766Google Scholar
  100. Ramasamy R, Yasawardena S, Zomer A et al (2006) Immunogenicity of a malaria parasite antigen displayed by Lactococcus lactis in oral immunisations. Vaccine 24(18):3900–3908PubMedCrossRefGoogle Scholar
  101. Ravnikar M, Štrukelj B, Obermajer N et al (2010) Engineered lactic acid bacterium Lactococcus lactis capable of binding antibodies and tumor necrosis factor alpha. Appl Environ Microbiol 76(20):6928–6932PubMedPubMedCentralCrossRefGoogle Scholar
  102. Remus DM, Kranenburg R (2012) Impact of 4 Lactobacillus plantarum capsular polysaccharide clusters on surface glycan composition and host cell signaling. Microb Cell Factories 111:149CrossRefGoogle Scholar
  103. Ribeiro LA, Azevedo V, Le Loir Y et al (2002) Production and targeting of the Brucella abortus antigen L7/L12 in Lactococcus lactis: a first step towards food-grade live vaccines against brucellosis. Appl Environ Microbiol 68(2):910–916PubMedPubMedCentralCrossRefGoogle Scholar
  104. Rigaux P, Daniel C, Isbergues M et al (2009) Immunomodulatory properties of Lactobacillus plantarum and its use as a recombinant vaccine against mite allergy. Allergy 64(3):406–414PubMedCrossRefGoogle Scholar
  105. Robinson K, Chamberlain LM, Schofield KM et al (1997) Oral vaccination of mice against tetanus with recombinant Lactococcus lactis. Nat Biotechnol 15(7):653–657PubMedCrossRefGoogle Scholar
  106. Robinson K, Chamberlain LM, Lopez MC et al (2004) Mucosal and cellular immune responses elicited by recombinant Lactococcus lactis strains expressing tetanus toxin fragment C. Infect Immun 72(5):2753–2761PubMedPubMedCentralCrossRefGoogle Scholar
  107. Rochat T, Bermúdez-Humarán L, Gratadoux JJ et al (2007) Anti-inflammatory effects of Lactobacillus casei BL23 producing or not a manganese-dependant catalase on DSS-induced colitis in mice. Microb Cell Factories 6(1):1–10CrossRefGoogle Scholar
  108. Rolain T, Bernard E (2012) Identification of key peptidoglycan hydrolases for morphogenesis, autolysis, and peptidoglycan composition of Lactobacillus plantarum WCFS1. Microb Cell Factories 111:137CrossRefGoogle Scholar
  109. Ross P, O’Gara F (1990) Thymidylate synthase gene from Lactococcus lactis as a genetic marker: an alternative to antibiotic resistance genes. Appl Environ Microbiol 567:2164–2169Google Scholar
  110. Scheppler L, Vogel M, Zuercher AW et al (2002) Recombinant Lactobacillus johnsonii as a mucosal vaccine delivery vehicle. Vaccine 20(23–24):2913–2920PubMedCrossRefGoogle Scholar
  111. Scheppler L, Vogel M, Marti P et al (2005) Intranasal immunisation using recombinant Lactobacillus johnsonii as a new strategy to prevent allergic disease. Vaccine 23(9):1126–1134PubMedCrossRefGoogle Scholar
  112. Schwarzer M, Repa A, Daniel C et al (2011) Neonatal colonization of mice with Lactobacillus plantarum producing the aeroallergen Bet v 1 biases towards Th1 and T-regulatory responses upon systemic sensitization. Allergy 66(3):368–375PubMedCrossRefGoogle Scholar
  113. Sibakov M, Koivula T, von Wright A, Palva I (1991) Secretion of TEM beta-lactamase with signal sequence isolated from the chromosome of Lactococcus lactis subsp. lactis. Appl Environ Microbiol 57(2):341–348PubMedPubMedCentralGoogle Scholar
  114. Smiley MB, Fryder V (1978) Plasmids, lactic acid production, and N-acetyl-D-glucosamine fermentation in Lactobacillus helveticus subsp. Appl Environ Microbiol 35(4):777–781PubMedPubMedCentralGoogle Scholar
  115. Smith GP (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228(4705):1315–1317PubMedCrossRefGoogle Scholar
  116. Solem C, Defoor E (2008) Plasmid pCS1966, a new selection/counterselection tool for lactic acid bacterium strain construction based on the oroP gene, encoding an orotate transporter from Lactococcus lactis. Appl Environ Microbiol 7415:4772–4775CrossRefGoogle Scholar
  117. Song L, Cui H (2014) Construction of upp deletion mutant strains of Lactobacillus casei and Lactococcus lactis based on counterselective system using temperature-sensitive plasmid. J Microbiol Methods 102:37–44PubMedCrossRefGoogle Scholar
  118. Sorensen KI, Larsen R (2000) A food-grade cloning system for industrial strains of Lactococcus lactis. Appl Environ Microbiol 664:1253–1258CrossRefGoogle Scholar
  119. Sorvig E, Gronqvist S (2003) Construction of vectors for inducible gene expression in Lactobacillus sakei and L plantarum. FEMS Microbiol Lett 2291:119–126CrossRefGoogle Scholar
  120. Sorvig E, Mathiesen G (2005) High-level, inducible gene expression in Lactobacillus sakei and Lactobacillus plantarum using versatile expression vectors. Microbiology 151(Pt 7):2439–2449PubMedCrossRefGoogle Scholar
  121. Steidler L, Hans W (2000) Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2895483:1352–1355CrossRefGoogle Scholar
  122. Svensson M, Waak E, Svensson U et al (2005) Metabolically improved exopoly- saccharide production by Streptococcus thermophilus and its influence on the rheological properties of fermented milk. Appl Environ Microbiol 71(10):6398–6400PubMedPubMedCentralCrossRefGoogle Scholar
  123. Takala TM, Saris PE (2002) A food-grade cloning vector for lactic acid bacteria based on the nisin immunity gene nisI. Appl Microbiol Biotechnol 594–5:467–471Google Scholar
  124. van Asseldonk M, Rutten G, Oteman M et al (1990) Cloning of usp45, a gene encoding a secreted protein from Lactococcus lactis subsp. lactis MG1363. Gene 95(1):155–160PubMedCrossRefGoogle Scholar
  125. van Pijkeren JP, Britton RA (2012) High efficiency recombineering in lactic acid bacteria. Nucleic Acids Res 4010:e76CrossRefGoogle Scholar
  126. Vandenbroucke K, Hans W, Van Huysse J et al (2004) Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice. Gastroenterology 127(2):502–513PubMedCrossRefGoogle Scholar
  127. Vandenbroucke K, de Haard H, Beirnaert E et al (2009) Orally administered L. lactis secreting an anti-TNF nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol 3(1):49–56PubMedCrossRefGoogle Scholar
  128. Vescovo M, Bottazzi V, Sarra PG et al (1981) Evidence of plasmid deoxyribonucleic acid in Lactobacillus. Microbiologica (Bologna) 4(4):413–419Google Scholar
  129. von Wright A, Wessels S, Tynkkynen S et al (1990) Isolation of a replication region of a large lactococcal plasmid and use in cloning of a nisin resistance determinant. Appl Environ Microbiol 56:2029–2035Google Scholar
  130. Watterlot L, Rochat T, Sokol H et al (2010) Intragastric administration of a superoxide dismutase-producing recombinant Lactobacillus casei BL23 strain attenuates DSS colitis in mice. Int J Food Microbiol 144(1):35–41PubMedCrossRefGoogle Scholar
  131. Wei CH, Liu JK, Hou XL et al (2010) Immunogenicity and protective efficacy of orally or intranasally administered recombinant Lactobacillus casei expressing ETEC K99. Vaccine 28(24):4113–4118PubMedCrossRefGoogle Scholar
  132. Wells JM, Wilson PW, Norton PM et al (1993) Lactococcus lactis: high-level expression of tetanus toxin fragment C and protection against lethal challenge. Mol Microbiol 8(6):1155–1162PubMedCrossRefGoogle Scholar
  133. Wong WY, Su P, Allison GE et al (2003) A potential food-grade cloning vector for Streptococcus thermophilus that uses cadmium resistance as the selectable marker. Appl Environ Microbiol 69(69):5767–5771PubMedPubMedCentralCrossRefGoogle Scholar
  134. Wu CM, Chung TC (2007) Mice protected by oral immunization with Lactobacillus reuteri secreting fusion protein of Escherichia coli enterotoxin subunit protein. FEMS Immunol Med Microbiol 50(3):354–365PubMedCrossRefGoogle Scholar
  135. Xin KQ, Hoshino Y, Toda Y et al (2003) Immunogenicity and protective efficacy of orally administered recombinant Lactococcus lactis expressing surface-bound HIV Env. Blood 102(1):223–228PubMedCrossRefGoogle Scholar
  136. Yam KK, Hugentobler F, Pouliot P et al (2011) Generation and evaluation of A2-expressing Lactococcus lactis live vaccines against Leishmania donovani in BALB/c mice. J Med Microbiol 60(9):1248–1260PubMedCrossRefGoogle Scholar
  137. Yao LY, Man CX, Zhao F et al (2010) Expression of bovine trypsin in Lactococcus lactis. Int Dairy J 20(11):806–809CrossRefGoogle Scholar
  138. Ye W, Huo G, Chen J et al (2010) Heterologous expression of the Bacillus subtilis (natto) alanine dehydrogenase in Escherichia coli and Lactococcus lactis. Microbiol Res 165(4):268–275PubMedCrossRefGoogle Scholar
  139. Yoon SW, Lee CH, Kim JY et al (2008) Lactobacillus casei secreting alpha-MSH induces the therapeutic effect on DSS-induced acute colitis in Balb/c Mice. J Microbiol Biotechnol 18(12):1975–1983PubMedGoogle Scholar
  140. Zhang ZH, Jiang PH, Li NJ et al (2005) Oral vaccination of mice against rodent malaria with recombinant Lactococcus lactis expressing MSP-119. World J Gastroenterol 11(44):6975–6980PubMedPubMedCentralCrossRefGoogle Scholar
  141. Zhang Q, Zhong J, Liang X et al (2010) Improvement of human interferon alpha secretion by Lactococcus lactis. Biotechnol Lett 32(9):1271–1277PubMedCrossRefGoogle Scholar
  142. Zhang Q, Zhong J, Huan L (2011) Expression of hepatitis B virus surface antigen determinants in Lactococcus lactis for oral vaccination. Microbiol Res 166(2):111–120PubMedCrossRefGoogle Scholar
  143. Zhu D, Zhao K (2014) Construction of thyA deficient Lactococcus lactis using the cre-loxp recombination system. Ann Microbiol 653:1–7Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. and Science Press 2019

Authors and Affiliations

  • Haiqin Chen
    • 1
    Email author
  • Chen Chen
    • 2
  • Chunqing Ai
    • 3
  • Chengcheng Ren
    • 1
  • He Gao
    • 1
  1. 1.Jiangnan UniversityWuxiChina
  2. 2.Shanghai Institute of TechnologyShanghaiChina
  3. 3.Dalian Polytechnic UniversityDalianChina

Personalised recommendations