Lactococcus lactis

L. lactis subsp. lactis (formerly Streptococcus lactis){{cite journal|vauthors=Schleifer KH, Kraus J, Dvorak C, Kilpper-Bälz R, Collins MD, Fischer W|date=1985|title=Transfer of Streptococcus lactis and Related Streptococci to the Genus Lactococcus gen. nov.|url=https://dx.doi.org/10.1016/S0723-2020%2885%2980052-7|format=PDF|journal=Systematic and Applied Microbiology|volume=6|issue=2|pages=183–195|doi=10.1016/S0723-2020(85)80052-7|bibcode=1985SyApM...6..183S |issn=0723-2020|via=Elsevier Science Direct|url-access=subscription}} is used in the early stages for the production of many cheeses, including brie, camembert, Cheddar, Colby, Gruyère, Parmesan, and Roquefort.{{cite journal |vauthors=Coffey A, Ross RP | title=Bacteriophage-resistance systems in dairy starter strains: molecular analysis to application | journal=Antonie van Leeuwenhoek | year=2002 | pages=303–21 | volume=82 | issue=1–4 | pmid=12369198 | doi=10.1023/A:1020639717181| s2cid=7217985 }} The use of L. lactis in dairy factories is not without issues. Bacteriophages specific to L. lactis cause significant economic losses each year by preventing the bacteria from fully metabolizing the milk substrate. Several epidemiologic studies showed the phages mainly responsible for these losses are from the species 936, c2, and P335 (all from the family Siphoviridae).{{cite journal |vauthors=Madera C, Monjardin C, Suarez JE | title=Milk contamination and resistance to processing conditions determine the fate of Lactococcus lactis bacteriophages in dairies | journal=Appl Environ Microbiol | year=2004 | pages=7365–71 | volume=70 | issue=12 | pmid=15574937 | doi=10.1128/AEM.70.12.7365-7371.2004 | pmc=535134| bibcode=2004ApEnM..70.7365M }}

The state Assembly of Wisconsin, also the number one cheese-producing state in the United States, voted in 2010 to name this bacterium as the official state microbe; it would have been the first and only such designation by a state legislature in the nation,{{cite news|url=https://www.nytimes.com/2010/04/16/us/16microbe.html|title=And Now, a State Microbe.|last=Davey|first=Monica|newspaper=New York Times|access-date=April 19, 2010 | date=April 15, 2010}} however the legislation was not adopted by the Senate.{{cite web|title=No State Microbe For Wisconsin| website=NPR.org |url=https://www.npr.org/templates/story/story.php?storyId=126370268|publisher=National Public Radio|access-date=28 October 2011}} The legislation was introduced in November 2009 as Assembly Bill 556 by Representatives Hebl, Vruwink, Williams, Pasch, Danou, and Fields; it was cosponsored by Senator Taylor.{{Cite web|url=http://docs.legis.wisconsin.gov/2009/proposals/ab556|title=2009 Assembly Bill 556|website=docs.legis.wisconsin.gov|language=en|access-date=2017-11-29}} The bill passed the Assembly on May 15, 2010, and was dropped by the Senate on April 28.

The feasibility of using lactic acid bacteria (LAB) as functional protein delivery vectors has been widely investigated.{{cite journal |vauthors=Wyszyńska A, Kobierecka P, Bardowski J, Jagusztyn-Krynicka EK |date= 2015|title= Lactic acid bacteria—20 years exploring their potential as live vectors for mucosal vaccination |journal=Appl Microbiol Biotechnol |volume= 99|issue= 7|pages= 2967–2977 |doi=10.1007/s00253-015-6498-0 |pmid= 25750046|pmc= 4365182 }} Lactococcus lactis has been demonstrated to be a promising candidate for the delivery of functional proteins because of its noninvasive and nonpathogenic characteristics.{{cite journal |vauthors=Varma NR, Toosa H, Foo HL, Alitheen NB, Nor Shamsudin M, Arbab AS, Yusoff K, Abdul Rahim R |date= 2013|title= Display of the viral epitopes on Lactococcus lactis: a model for food grade vaccine against EV71 |journal= Biotechnology Research International|volume= 2013|issue= 11|pages= 4032–4036|doi= 10.1155/2013/431315|pmid= 1069289|pmc= 431315|doi-access= free}} Many different expression systems of L. lactis have been developed and used for heterologous protein expression.{{cite journal |vauthors=Mierau I, Kleerebezem M |date= 2005|title= 10 years of the nisin-controlled gene expression system (NICE) in Lactococcus lactis |journal=Appl Microbiol Biotechnol |volume= 68|issue= 6|pages= 705–717 |doi=10.1007/s00253-005-0107-6 |pmid= 16088349|s2cid= 24151938}}{{cite journal |vauthors=Desmond C, Fitzgerald G, Stanton C, Ross R |date= 2004|title= Improved stress tolerance of GroESL-overproducing Lactococcus lactis and probiotic Lactobacillus paracasei NFBC 338|journal= Appl Environ Microbiol|volume= 70 |issue= 10|pages=5929–5936|doi= 10.1128/AEM.70.10.5929-5936.2004|pmid= 15466535|pmc= 522070|bibcode= 2004ApEnM..70.5929D}}{{cite journal |vauthors=Benbouziane B, Ribelles P, Aubry C, Martin R, Kharrat P, Riazi A, Langella P, Bermudez-Humaran LG|date= 2013|title= Development of a Stress-Inducible Controlled Expression (SICE) system in Lactococcus lactis for the production and delivery of therapeutic molecules at mucosal surfaces|journal= J. Biotechnol. |volume=168|issue= 2|pages= 120–129|doi=10.1016/j.jbiotec.2013.04.019 |pmid= 23664884}}

Lactose fermentation

In one study that sought to prove that some fermentation produced by L. lactis can hinder motility in pathogenic bacteria, the motilities of Pseudomonas, Vibrio, and Leptospira strains were severely disrupted by lactose utilization on the part of L. lactis.{{cite journal |vauthors=Nakamura S, Morimoto YV, Kudo S |date= 2015|title= A lactose fermentation product produced by Lactococcus lactis subsp. lactis, acetate, inhibits the motility of flagellated pathogenic bacteria|journal= Microbiology|volume= 161|issue= 4|pages= 701–707|doi=10.1099/mic.0.000031|pmid= 25573770|s2cid= 109572|doi-access= free}} Using flagellar Salmonella as the experimental group, the research team found that a product of lactose fermentation is the cause of motility impairment in Salmonella. It is suggested that the L. lactis supernatant mainly affects Salmonella motility through disruption of flagellar rotation rather than through irreversible damage to morphology and physiology. Lactose fermentation by L. lactis produces acetate that reduces the intracellular pH of Salmonella, which in turn slows the rotation of their flagella.{{cite journal |vauthors=Kihara M, Macnab RM |date= 1981|title= Cytoplasmic pH mediates pH taxis and weak-acid repellent taxis of bacteria|journal= J Bacteriol |volume=145|issue= 3|pages= 1209–1221 |doi= 10.1128/JB.145.3.1209-1221.1981|pmid= 7009572|pmc= 217121}}{{cite journal |vauthors=Repaske DR, Adler J |date= 1981|title= Change in intracellular pH of Escherichia coli mediates the chemotactic response to certain attractants and repellents|journal= J Bacteriol |volume= 145|issue= 3|pages= 1196–1208 |doi= 10.1128/JB.145.3.1196-1208.1981|pmid= 7009571|pmc= 217120}} These results highlight the potential use of L. lactis for preventing infections by multiple bacterial species.

Secretion of Interleukin-10

Genetically engineered L. lactis can secrete the cytokine interleukin-10 (IL-10) for the treatment of inflammatory bowel diseases (IBD), since IL-10 has a central role in downregulating inflammatory cascades{{cite journal |vauthors=Stordeur P, Goldman M |title=Interleukin-10 as a regulatory cytokine induced by cellular stress: molecular aspects |date=1998 |journal=Int. Rev. Immunol. |volume=16|issue=5–6 |pages=501–522 |pmid=9646174|doi=10.3109/08830189809043006 }} and matrix metalloproteinases.{{cite journal |vauthors=Pender SL, etal |title=Suppression of T cell-mediated injury in human gut by interleukin 10: role of matrix metalloproteinases |date= 1998 |journal= Gastroenterology |volume= 115|issue=3 |pages=573–583 |pmid=9721154|doi=10.1016/S0016-5085(98)70136-2 |doi-access=free }} A study by Lothar Steidler and Wolfgang Hans{{cite journal |vauthors=Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, Fiers W, Remaut E |date= 2000 |title= Treatment of Murine Colitis by Lactococcus lactis Secreting Interleukin-10|journal= Science |volume= 289|issue= 5483|pages= 1352–1355|doi= 10.1126/science.289.5483.1352|pmid= 10958782 |bibcode= 2000Sci...289.1352S }} shows that in situ synthesis of IL-10 by genetically engineered L. lactis requires much lower doses than systemic treatments like antibodies to tumor necrosis factor (TNF) or recombinant IL-10.

The authors propose two possible routes by which IL-10 can reach its therapeutic target. Genetically engineered L. lactis may produce murine IL-10 in the lumen, and the protein may diffuse to responsive cells in the epithelium or the lamina propria. Another route involves L. lactis being taken up by M cells because of its bacterial size and shape, and the major part of the effect may be due to recombinant IL-10 production in situ in intestinal lymphoid tissue. Both routes may involve paracellular transport mechanisms that are enhanced in inflammation. After transport, IL-10 may directly downregulate inflammation. In principle, this method may be useful for intestinal delivery of other protein therapeutics that are unstable or difficult to produce in large quantities and an alternative to the systemic treatment of IBD.{{citation needed|date=February 2023}}

Tumor-suppressor through Tumor metastasis-inhibiting peptide KISS1

Another study, led by Zhang B, created a L. lactis strain that maintains a plasmid containing a tumor metastasis-inhibiting peptide known as KISS1.{{cite journal |vauthors=Zhang B, Li A, Zuo F, Yu R, Zeng Z, Ma H, Chen S |date= 2016 |title= Recombinant Lactococcus lactis NZ9000 secretes a bioactive kisspeptin that inhibits proliferation and migration of human colon carcinoma HT-29 cells|journal= Microbial Cell Factories|volume= 15|issue= 1|pages= 102|doi= 10.1186/s12934-016-0506-7|pmid= 27287327 |pmc= 4901401 |doi-access= free }} L. lactis NZ9000 was demonstrated to be a cell factory for the secretion of biologically active KiSS1 protein, exerting inhibition effects on human colorectal cancer HT-29 cells.

KiSS1 secreted from recombinant L. lactis strain effectively downregulated the expression of Matrix metalloproteinases (MMP-9), a crucial key in the invasion, metastasis, and regulation of the signaling pathways controlling tumor cell growth, survival, invasion, inflammation, and angiogenesis.{{cite journal |vauthors=Bauvois B |date= 2012|title= New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression|journal= Biochim Biophys Acta|volume= 1825|issue= 1|pages= 29–36|doi=10.1016/j.bbcan.2011.10.001|pmid= 22020293}}{{cite journal |vauthors=Kessenbrock K, Plaks V, Werb Z |date= 2010|title= Matrix metalloproteinases: regulators of the tumor microenvironment|journal= Cell|volume= 141|issue= 1|pages= 52–67|doi= 10.1016/j.cell.2010.03.015|pmid= 20371345|pmc= 2862057}}{{cite journal |vauthors=Klein T, Bischoff R |date= 2011|title= Physiology and pathophysiology of matrix metalloproteases |journal= Amino Acids |volume= 41 |issue= 2|pages= 271–290 |doi= 10.1007/s00726-010-0689-x|pmid= 20640864|pmc= 3102199}} The reason for this is that KiSS1 expressed in L. lactis activates the MAPK pathway via GPR54 signaling, suppressing NFκB binding to the MMP-9 promoter and thus downregulating MMP-9 expression.{{cite journal |vauthors=Nash KT, Welch DR |date= 2006|title= The KISS1 metastasis suppressor: mechanistic insights and clinical utility|journal= Frontiers in Bioscience|volume= 11 |pages= 647–659|doi= 10.2741/1824|pmid= 16146758|pmc= 1343480}} This, in turn, reduces the survival rate, inhibits metastasis, and induces dormancy of cancer cells.

In addition, it was demonstrated that tumor growth can be inhibited by the LAB strain itself,{{cite journal |vauthors=Gorbach SL |date= 1990|title= Lactic acid bacteria and human health |journal=Annals of Medicine |volume= 22 |issue= 1|pages= 37–41|doi= 10.3109/07853899009147239|pmid= 2109988}}{{cite book |vauthors=Hirayama K, Rafter J |chapter= The role of lactic acid bacteria in colon cancer prevention: Mechanistic considerations|date= 1999|title= Lactic Acid Bacteria: Genetics, Metabolism and Applications |journal= Antonie van Leeuwenhoek|volume= 76|issue= 1–4|pages= 391–394|doi= 10.1007/978-94-017-2027-4_25|pmid= 10532395|isbn= 978-90-481-5312-1}} due to the ability of LAB to produce exopolysaccharides.{{cite journal |vauthors=Ruas-Madiedo P, Hugenholtz J, Zoon P |date= 2002|title= An overview of the functionality of exopolysaccharides produced by lactic acid bacteria|journal= Int Dairy J|volume= 12|issue= 2–3|pages= 163–171|doi= 10.1016/S0958-6946(01)00160-1}}{{cite journal |vauthors=Looijesteijn PJ, Trapet L, de Vries E, Abee T, Hugenholtz J |date= 2001|title= Physiological function of exopolysaccharides produced by Lactococcus lactis|journal=International Journal of Food Microbiology |volume= 64|issue= 1–2|pages= 71–80|doi= 10.1016/S0168-1605(00)00437-2|pmid= 11252513}} This study shows that L. lactis NZ9000 can inhibit HT-29 proliferation and induce cell apoptosis by itself. The success of this strain's construction helped to inhibit migration and expansion of cancer cells, showing that the secretion properties of L. lactis of this particular peptide may serve as a new tool for cancer therapy in the future.{{cite journal |vauthors=Ji K, Ye L, Ruge F, Hargest R, Mason MD, Jiang WG |date= 2014|title= Implication of metastasis suppressor gene, Kiss-1 and its receptor Kiss-1R in colorectal cancer|journal= BMC Cancer |volume= 14 |pages= 723|doi= 10.1186/1471-2407-14-723|pmid= 25260785|pmc= 4190326|doi-access= free}}

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• [http://bacdive.dsmz.de/index.php?search=14702&submit=Search Type strain of Lactococcus lactis at BacDive - the Bacterial Diversity Metadatabase]

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Category:Streptococcaceae

Category:Bacteria used in dairy products

Category:Bacteria described in 1873

Category:Gram-positive bacteria