Bacteriophages in dairy products: Pros and cons

1 Bacteriophage

Bacteriophages (phages) are viruses that infect bacterialcells. In most of the cases, phages are exclusively com-posed of protein and nucleic acid and represent obligateparasites of their bacterial host cells, outside of whichthey have no intrinsic metabolism. The majority of phagesare members of the Siphoviridae, and their morphologythus consists of a head structure which contains the DNAgenome, and a connected tail structure, through which itspecifically recognizes its host. In order for a phage topropagate it must attach to specific receptor sites on itsbacterial host and deliver its DNA into the host cell cyto-plasm. Phages may be differentiated on the basis of theirlife cycle into one of two groups, being either temperateor lytic. Temperate phages are capable of integrating(lysogenizing) their genomes into that of the host bacteri-um. Host cell metabolism and phenotypic characteristicsare generally not at all or only minimally disrupted and thelysogenized prophage is replicated in situ with daughtercells of the host bacteria receiving a copy. This prophagemay, in response to environmental stimuli, be induced

into the lytic cycle at a later stage. When a temperatephage is induced into the lytic cycle, or when an obligatelytic phage infects a cell, the genetic instructions on thephage genome redirect the infected cell to produce newphage particles. From beginning to end this process cantake a matter of minutes and results in lysis and death ofthe host with the release of up to several hundreds of prog-eny phages, each capable of beginning the cycle again ona newly found susceptible host (for extensive reviews onbacteriophages, see [1]).

2 Bacteriophage and dairy fermentations

2.1 Cons

It has been claimed that phages are the most abundant bi-ological entities on earth with an estimated global popu-lation of 1031 individuals [2], which can be found in a va-riety of environments such as oceans [3], deserts [4],Antarctic lakes [5], hot springs [6], the human gut [7], anddairy plants [8]. These types of bactericidal agents haveobvious implications for the dairy industry, which relieson the metabolic capabilities of specific strains of lacticacid bacteria (LAB) on an industrial scale. Whitehead andCox [9] were the first to describe the detrimental effects ofphage infection in a dairy fermentation and despite hugescientific and technological advances over the last 70years, phages remain the largest single cause of fermen-

Review

Bacteriophages in dairy products: Pros and cons

Stephen Mc Grath1, Gerald F. Fitzgerald1, 2 and Douwe van Sinderen1, 2

1Department of Microbiology, National University of Ireland, Cork, Ireland2Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

Since the time bacteriophages were first identified as a major cause of fermentation failure in thedairy industry, researchers have been struggling to develop strategies to exclude them from thedairy environment. Over 70 years of research has led to huge improvements in the consistency andquality of fermented dairy products, while also facilitating an appreciation of the beneficial prop-erties of bacteriophages with respect to dairy product development. With specific reference to Lac-tococcus lactis and cheese production, this review outlines some recently reported novel methodsaimed at limiting the bacteriophage infection as well as highlighting some beneficial aspects ofbacteriophage activity.

Keywords: Bacteriophage · Dairy · Fermentation · Lactococcus

Correspondence: Dr. Douwe van Sinderen, Microbiology, UCC,Western Road, Cork 0001, IrelandE-mail: [email protected]: +353 21 4903101

Abbreviations: DHP, dynamic high pressure; LAB, lactic acid bacteria

Received 6 November 2006Revised 20 December 2006Accepted 9 January 2007

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tation failure in the dairy industry. In the most severe cas-es phage infection can cause a complete loss of starter ac-tivity resulting in dead vats and the associated problemsof disposing of large quantities of partly acidified milk.However, so-called slow vats are more common in whichstarter activity is impaired but not abolished with result-ant problems such as disruption to production schedulesdue to prolonged fermentation times and downgrading offinal product. Steps taken in the dairy industry to reducethe impact of phage infection on starter activity include:rotation of phage-unrelated strains, the use of mixedstrain cultures, separation of the bulk starter preparationarea from cheese production and whey handling areas,the use of phage inhibitory media for bulk starter prepa-ration, direct inoculation of cheese vats with frozen con-centrated starter cultures, sanitization regimes, air filtra-tion as well as many other strategies [10].

The study of the interactions between LAB, particu-larly the lactococci and their infecting bacteriophages hasbeen the focus of intensive research since bacteriophageswere first identified as a major cause of fermentation fail-ure in the dairy industries. In recent years, the applicationof molecular biology has yielded a much deeper under-standing of the molecular processes underlying these in-teractions. The discovery that many LAB possess naturaldefense mechanisms opened the door for the develop-ment of novel phage-resistant strains exhibiting desirablefermentation characteristics. The most extensively stud-ied of these natural defense mechanisms were thosefound in the lactococci, particularly because many suchsystems were encoded by conjugative plasmids. Theseresistance mechanisms have been divided into four maingroups on the basis of their mode of action: (a) adsorptioninterference, which prevents the adsorption of phage par-ticles to the cell surface; (b) DNA injection blocking,which prevents phages that have successfully attached tothe cell from injecting their DNA into the cell cytoplasm;(c) restriction/modification, causing intracellular degra-dation of incoming DNA molecules; and (d) abortive in-fection, which encompasses a range of mechanisms, anyof which may interfere with phage development at anytime following the injection of intact phage DNA into thecell and until the release of progeny phage [11].

The introduction of numerous technological advanceshas undoubtedly reduced the impact of phage infectionon dairy fermentations. However, the two key compo-nents of any dairy fermentation, namely the milk and thestarter represent the primary source of phages in the dairyplant. Phages capable of infecting LAB have been isolat-ed from raw milk and it has been proposed that their pres-ence is due to contamination of the milk with wild LABstrains in the farm upon which the phage propagates [12].In addition, it is now widely accepted that starter bacte-ria commonly harbor lysogenized prophages in theirgenomes which under certain environmental conditionsmay be triggered to propagate lytically with subsequent

bacteriocidal effects. Modern dairy processing generallyentails the heat treatment of milk prior to inoculation withthe starter, but sterilization is not achievable without de-stroying the physicochemical properties of the milk con-stituents essential for the development of finished prod-uct characteristics. Since limited heat treatment does noteliminate phage contamination, it follows that milk will bea continuous source of phage coming into a fermentationfacility irrespective of other measures taken to limit phagecontamination and spread.

Deveau et al. [13] have recently revised the originalclassification scheme for lactococcal phages proposed byJarvis et al. [14]. It was proposed that this highly diverseviral community be divided between eight groups ratherthan the previously accepted 12. However, members ofthree of these groups (c2, 936, and P335) are by far themost significant cause of problems encountered in dairyenvironments. The former two groups represent lyticphages while members of the latter may be either lytic ortemperate. Madera et al. [12] have studied the evolutiondynamics of phage populations in the dairy environmentwith specific reference to the presence of phages in theraw milk, the susceptibility of the phages to pasteuriza-tion, and the degree of resistance of the starter bacteria tophage infection. In this study, it was shown that approxi-mately 10% of the raw milk tested contained all of thethree main phage types, with members of the c2 grouprepresenting the majority. However, the population bal-ance was found to have swung in favor of the 936 groupswhen whey was tested. This shift in phage populationwas attributed to the ability of 936 phages to withstandpasteurization (members of the 936 species were report-ed to be 35 times more resistant than c2-type phage). In-triguingly, upon closer examination DNA restriction pro-file analysis revealed that the 936 phages in the wheywere genetically distinct to those in the raw milk. This ledthe authors to conclude that the continuous supply ofphage-contaminated milk, followed by pasteurization cre-ates a factory environment rich in diverse 936 phagetypes.

Traditionally the presence of phages in the dairy envi-ronment, presumably as a consequence of the constantsupply of wild phages carried in the raw milk, was ac-cepted as a fact of life and measures were taken to limittheir potential detrimental effect on fermentations. Inmore recent times, researchers have started to explore thepossibility of treating the milk to eliminate the phageswithout rendering the milk unsuitable for cheese making.Moroni et al. [15] have studied the possibility of inactivat-ing lactococcal bacteriophages in liquid media using dy-namic high pressure (DHP). In this article, the effect ofDHP on members of the c2, 936, and P335 species wasoutlined. It was demonstrated that inactivation of thephage was proportional to both the pressure applied andthe number of passages applied. Phage inactivation wasalso found to depend on the initial phage concentration,


while interestingly both 936 and P335 members werefound to be more resilient than c2 phages. This resilienceto pressure was proposed due to the isometric-shapedhead characteristic of the former two groups which waspresumably more robust than the elongated prolate-shaped head of c2-type phage.

More recently, Mueller-Merbach et al. [16] have pre-sented work outlining the application of thermal andhigh-pressure treatment for inactivating lactococcal bac-teriophages. These researchers reported that the isomet-ric-headed 936 phage, P008 was significantly more re-sistant to both heat and pressure treatment than its pro-late-headed c2-type counterpart, P001. This study wasmore an academic exercise in which the suspensionmedium used was a buffered nutrient broth in compari-son to the earlier report of Moroni et al. [15] in which PBS,whey permeate, and milk were used. Both these reportshighlight the potential application of DHP as a significantbarrier to the introduction of phages to the dairy environ-ment.

Tailed phages attach to their host cells by recognizingspecific receptors on the cell surface. This process usual-ly involves two stages. In the first stage, the phage re-versibly interacts with a specific component of the cellwall and this is followed by the second irreversible inter-action between the phage tail and a protein embedded inthe cell membrane. Using this knowledge as the basis fortheir rationale, Hicks et al. [17] examined the suitability ofusing a hydrolyzate of a lactococcal phage to impedephage infection of a starter strain in milk. They have ex-ploited this highly specific phage–host interaction in thedevelopment of a novel use for bacteriophage-derivedpeptides for inhibiting phage infection of lactococcalstarters. A highly specific irreversible interaction isknown to occur between phage c2 and the phage infec-tion protein (pip) of its lactococcal host [18], and Hicks etal. used this phage–host combination as a test case fortheir thesis. It was demonstrated that ficin-derived c2 hy-drolyzate prolonged the growth time of L. lactis C2 in milkwhen compared to controls not containing the phage-de-rived peptides. The authors concluded that although thisapproach did not completely inhibit phage infection, itmay delay it sufficiently to allow cheese fermentation inthe presence of otherwise prohibitive concentrations ofphage and therefore may represent an option for provid-ing additional barriers to phage infection of starters undermanufacturing conditions.

The possibility of immunizing cows with bacterio-phages was first investigated by Erskine [19] with twomore reports appearing subsequently [20, 21]. In all thecases, phage-neutralizing antibodies were identified inthe milk of immunized cows, but results were variable andother technological and financial considerations madethis an unrealistic approach for producing milk for dairyfermentations. Ledeboer et al. [22] have investigated an-other novel approach involving antibodies that circum-

vent some of the prohibitive technological and financialconsiderations of previous reports. In this article, the au-thors demonstrated that the addition of phage-neutraliz-ing antibody fragments could effectively be used to im-pede the phage-induced lysis during a cheese process.Heavy chain Camolidae antibody fragments were pro-duced in Saccharomyces cerevisae, an organism general-ly regarded as safe (GRAS), and prepared using estab-lished procedures for the production of food enzymes bymicroorganisms. These antibody fragments were shownto specifically target a phage structural protein located onthe base plate of the phage involved in host recognition.It was demonstrated that addition of nanomolar amountsof this antibody fragment to milk was sufficient to preventgrowth inhibition of the cheese starter culture even in thepresence of 105 pfu/mL of the 936 phage p2. Furthermore,a variety of neutralizing antibody fragments could be iso-lated that recognize different epitopes making it possibleto introduce a rotation system, thus enhancing the pro-tection and applicability of the system.

In addition to elucidating and manipulating naturallyoccurring molecular interactions between phage andhost, researchers have harnessed the acquired knowl-edge on bacteriophages to develop novel genetic toolsthat utilize phage genes, promoters and DNA fragmentsfor use in many lactococcal, and other LAB strains. Thesegenetic tools may be grouped under the following head-ings; (i) engineered phage resistance systems, which uti-lize recombinant methods to interfere with specific stepsin the phage life cycle; (ii) cell lysis systems, which em-ploy phage lysis factors to improve starter strain autolysisduring cheese ripening; (iii) integration vectors, whichmake use of the enzymes encoded by temperate phage inthe development of systems for introducing recombinantDNA into bacterial genomes; (iv) transduction systems, inwhich phages are used to introduce plasmid DNA intospecific strains; and (v) gene expression systems, whichavail of phage promoter sequences to develop constitu-tive and inducible gene expression systems for use instarter strains [23].

2.2 Pros

One of the primary roles of starter bacteria in cheese man-ufacture is milk acidification which leads to curd forma-tion. The ability of lactococcal strains to lyse with con-comitant release of intracellular enzymes into the curd isalso a desirable trait and has been associated with accel-erated cheese ripening and improved flavors. This au-tolytic phenotype is strain dependent and is influenced bymany factors such as pH, temperature, carbon source,and salt concentration. Temperate bacteriophages en-code lytic functions that were first claimed to be associ-ated with autolysis by Feirtag and McKay [24], who sug-gested that the cooking temperatures used in cheddarcheese manufacture (38–40°C) could act as an environ-

BiotechnologyJournal Biotechnol. J. 2007, 2, 450–455





mental stimulus to effect temperate phage induction withsubsequent cell lysis in the cheese curd. Chapot-Chartieret al. [25] have compared autolysis of two starter bacteriain Saint-Paulin type cheese by measuring a variety of pa-rameters such as cell viability, changes in cell morpholo-gy, and release of intracellular peptidases. One of thestrains, L. lactis subsp. cremoris AM2 was found to un-dergo rapid autolysis in addition to being linked to a larg-er amount of amino nitrogen in the corresponding cheese.Lepeuple et al. [26] have studied the underlying molecu-lar mechanisms for this autolytic phenotype and have re-ported a major L. lactis-specific lytic activity encoded byan enzyme designated as A2, apparently different fromthe native AcmA. A2 was shown to be mitomycin C in-ducible and prophage encoded. Furthermore, analysis ofa prophage-cured derivative of L. lactis AM2 revealed asignificantly reduced autolytic activity. O’Sullivan et al.[27] investigated the relationship between lysogeny andautolysis of L. lactis in cheese. In this study, the authorsused a laboratory scale cheese manufacturing assay to as-sess the autolytic behavior of 31 strains. The genomes ofthese strains were also examined for the presence ofprophage sequences using PCR. The results demonstrat-ed that the lytic behavior of lactococcal starter strains cor-relates well with the presence of prophage sequences. Inaddition to highlighting the contribution of prophage tostarter cell lysis, this paper also underlines the potential ofPCR as a useful screening tool to assess strains for this im-portant industrial trait. de Ruyter et al. [28] described anovel recombinant food-grade system for controlled au-tolysis of starter strains. In this system, the lytic genes ofthe lactococcal bacteriophage US3 were placed under thecontrol of a nisin-inducible expression system in a lacto-coccal strain. Model cheese experiments demonstratedthat the resulting strain facilitated a four-fold increase inthe release of L-lactate dehydrogenase activity into thecurd relative to control strains, illustrating the suitabilityof the system for cheese applications.

As outlined above, the ability of phages to rapidlyeradicate specific bacterial populations is a major con-cern of the dairy industries. Conversely, this bacteriolyticactivity also marks phages as a suitable tool to be har-nessed for the elimination of undesirable bacteria in food,environmental, and medical applications. In this respect,phages possess a number of amenable characteristicssuch as: (i) specificity, i.e., they only kill their specific hostbacteria leaving other species unharmed in contrast toantibiotics and/or other chemical treatments; (ii) they areself-multiplying, i.e., successful lytic infection of a singlehost cell by a single phage results in the release of multi-ple progeny phage; and (iii) they are already present in theenvironment in significant amounts and are composed ofproteins and nucleic acids and consequently may be con-sidered for an environmental treatment. Recent studieshave highlighted the efficacy of phages in the treatmentof food-borne pathogens. Modi et al. [29] have studied the

effect that the addition of the SJ2 phage has on the sur-vival of its host Salmonella enteritidis during manufactureand storage of cheddar cheese. In this study, S. enteritidisand SJ2 were added to raw and pasteurized milk prior tocheese manufacture and processing. The counts of S. en-teritidis were found to have decreased by 1–2 log cyclesin cheeses made with milk to which the phage had alsobeen added in contrast to an increase by a factor of 1 login cheeses untreated with SJ2. Furthermore, S. enteritidiswas undetectable in SJ2-treated cheeses after 99 d stor-age, in contrast to the significant levels of this bacteriumfound in untreated cheeses, after the same period.

Pathogens such as Listeria monocytogenes can adaptto survive and grow in a wide range of environmental con-ditions and cause the severe disease listeriosis with re-sultant high hospitalization and fatality rates. L. monocy-togenes can be found in a wide variety of raw andprocessed foods, including milk and dairy products, andfoods such as soft cheeses have been implicated in sev-eral outbreaks of human listeriosis. Carlton et al. [30] haverecently published a comprehensive article outlining thesuitability of the Listeria phage P100 for the control of L.monocytogenes in soft cheese. This study goes beyondprevious efforts at assessing the suitability of phages forfood sanitization as it includes the complete genome se-quence of the phage as well as an oral toxicity study.Bioinformatic analysis of the genome sequence revealedthat none of the P100 ORFs displayed similarity to genesor proteins of listeria or any other bacteria which are ei-ther known or suspected toxins, pathogenicity factors,antibiotic resistance determinants, or any known aller-gens. The oral toxicity study demonstrated that rats re-peatedly dosed with high levels of P100 phage (5 × 1011)did not significantly differ from untreated controls with re-spect to morbidity, mortality, or histology. The cheese tri-al was designed to simulate a commercial productionprocess for surface ripened red-smear soft cheese (type“Munster”). Cheeses were made according to standardprotocols, from pasteurized cow’s milk, using a meso-philic starter culture and calf rennet. Cheeses were con-taminated with low levels of L. monocytogenes at the be-ginning of the ripening process and P100 phages were ap-plied to the surface during the rind washings. The in-hibitory effect of P100 was found to be dose-dependentwith repeated washes of higher concentrations of phagesolution sufficient to completely eradicate L. monocyto-genes from the cheese rind. In a subsequent experiment,a single dose of phage applied to the cheeses shortly afterListeria contamination resulted in complete elimination ofthis bacterium, in comparison to L. monocytogenescounts of 107 colony forming units (cfu)/cm2 on the sur-face of untreated cheeses. It is also noteworthy that noneof the Listeria isolates from cheeses that received lowerconcentrations of P100 were found to have developed re-sistance to the phage.


A P100 phage preparation is currently being market-ed under the brand name “Listex P100” by the Dutch com-pany EBI Food Safety and has recently been grantedGRAS status for the control of L. monocytogenes incheese by the US Food and Drug Administration (FDA)(www.ebifoodsafety.com). FDA has also recently granteda license to the US based company Intralytix for the sell-ing of another anti-L. monocytogenes phage preparationcalled LMP102 for use in ready to eat meats (www.intra-lytix.com).

3 Outlook

The myriad technological advances in plant design,starter strain development, and production processeshave obviously led to a drastic reduction in the incidenceof serious detrimental effects caused by phage infectionsin the dairy industry. However, phages represent a realand persistent threat and the authors are aware of recentunpublished cases where phage infection actually limitedthe fermentation process and/or causing product down-grading. The consumer driven demand for artisanal-typeand niche cheeses is certainly putting pressure on alreadyexisting phage protection systems and is driving their fur-ther development. One positive spin-off from phage re-search in the dairy industry and elsewhere has been thedevelopment of phage-derived tools for starter strain ma-nipulation and study, as well as the recently reported cas-es of the successful application of phage to cheese for theeradication of pathogenic bacteria. Further research willundoubtedly refine these already existing technologieswhile also resulting in the development of novel phage-based technologies.

This work was funded by Science Foundation Irelandthrough an investigator grant awarded to Douwe vanSinderen.

4 References

[1] Calendar, R. L. (Ed.), The Bacteriophages. Oxford University Press,Oxford 2005.

[2] Breitbart, M., Rohwer, F., Here a virus, there a virus, everywhere thesame virus? Trends Microbiol. 2005, 13, 278–284.

[3] Breitbart, M., Salamon, P., Andresen, B., Mahaffy, J. M. et al., Ge-nomic analysis of uncultured marine viral communities. Proc. Natl.Acad. Sci. USA 2002, 99, 14250–14255.

[4] Prigent, M., Leroy, M., Confalonieri, F., Dutertre, M., DuBow, M. S., Adiversity of bacteriophage forms and genomes can be isolated fromthe surface sands of the Sahara Desert. Extremophiles 2005, 9,289–296.

[5] Kepner, R. L., Robert, A., Wharton, J. R., Suttle, C. A., Viruses inAntarctic lakes. Limnol. Oceanogr. 1998, 13, 1754–1761.

[6] Yu, M. X., Slater, M. R., Ackermann, H. W., Isolation and characteri-sation of Thermus bacteriophage. Arch. Virol. 2005, 151, 663–679.

[7] Breitbart, M., Hewson, I., Felts, B., Mahaffy, J. M. et al., Metage-nomic analyses of an uncultured viral community from human feces.J. Bacteriol. 2003, 185, 6220–6223.

[8] Casey, C. N., Morgan, E., Daly, C., Fitzgerald, G. F., Characterisationand classification of virulent bacteriophages isolated from a cheddarcheese plant. J. Appl. Bacteriol. 1993, 74, 268–275.

[9] Whitehead, H. R., Cox, G. A., The occurrence of bacteriophages instarter cultures of lactic streptococci. N. Z. J. Sci. Technol. 1935, 16,319–320.

[10] Cogan, T. M., Hill, C., Cheese Starter Cultures, in: Fox, P. F. (Ed.),Cheese: Chemistry, Physics and Microbiology. Chapman & Hall,London, 1993, pp. 193–255.

[11] Forde, A., Fitzgerald, G. F., Bacteriophage defence systems in lacticacid bacteria. Antonie Van Leeuwenhoek 1999, 76, 89–113.

[12] Madera, C., Garcia, P., Janzen, T., Rodriguez, A., Suarez, J. E., Char-acterisation of technologically proficient wild Lactococcus lactisstrains resistant to phage infection. Int. J. Food. Microbiol. 2003, 86,213–222.

[13] Deveau, H., Labrie, S. J., Chopin, M. C., Moineau, S., Biodiversityand classification of lactococcal phages. Appl. Environ. Microbiol.2006, 72, 4338–4346.

[14] Jarvis, A. W., Fitzgerald, G. F., Mata, M., Mercenier, A. et al., Speciesand type phages of lactococcal bacteriophages. Intervirology 1991,32, 2–9.

[15] Moroni, O., Jean, J., Autret, J., Fliss, I., Inactivation of lactococcalbacteriophages in liquid media using dynamic high pressure. Int.Dairy J. 2002, 12, 907–913.

[16] Mueller-Merbach, M., Rauscher, T., Hinrichs, J., Inactivation of bac-teriophages by thermal and high-pressure treatment. Int. Dairy J.2005, 15, 777–784.

[17] Hicks, C. L., Clark-Safko, P. A., Surjawan, I., O’Leary, J., Use of bac-teriophage-derived peptides to delay phage infections. Food Res.Int. 2004, 37, 115–122.

[18] Geller, B. L., Ivey, R. G., Trempy, J. E., Hettinger-Smith, B., Cloningof a chromosomal gene required for phage infection of Lactococcuslactis subsp. lactis C2. J. Bacteriol. 1993, 175, 5510–5519.

[19] Erskine, J. M., A new laboratory method for preventing bacterio-phage attack on cheese starter streptococci. J. Dairy Res. 1964, 31,95–104.

[20] Duitschaever, C. L., Quinn, P. J., Antibody response of cows to Strep-tococcus lactis bacteriophage. J. Dairy Sci. 1970, 53, 1363–1366.

[21] Geller, B. L., Kraus, J., Schell, M. D., Hornsby, M. J., Neal, J. J., Hightiter, phage-neutralizing antibodies in bovine colostrum that pre-

BiotechnologyJournal Biotechnol. J. 2007, 2, 450–455


Dr. Stephen Mc Grath is a native of

Waterford City, Ireland. He completed

his undergraduate degree in Biotech-

nology at Waterford Institute of Tech-

nology and his PhD in Bacteriophage

genetics at the Department of Microbi-

ology, University College Cork. After a

brief postdoctoral stint at the Universi-

ty of North Carolina, USA, he returned

to UCC as a senior researcher in the

bacteriophage group at the Department of Microbiology. His interests

include the genetics and physiology of bacteriophage infecting lactic

acid bacteria as well as the development of bacteriophage and bacte-

riophage-derived products as therapeutic and biocontrol agents.




vent lytic infection of Lactococcus lactis in fermentations of phage-contaminated milk. J. Dairy Sci. 1998, 81, 895–900.

[22] Ledeboer, A. M., Bezemer, S., de Hiaard, J. J., Schaffers, I. M. et al.,Preventing phage lysis of Lactococcus lactis in cheese productionusing a neutralizing heavy-chain antibody fragment from llama. J.Dairy Sci. 2002, 85, 1376–1382.

[23] Mc Grath, S., Van Sinderen, D., Fitzgerald, G. F., Bacteriophage-de-rived genetic tools for use in lactic acid bacteria. Int. Dairy J. 2002,12, 3–15.

[24] Feirtag, J. M., McKay, L. L., Thermoinducible lysis of temperature-sensitive Streptococcus cremoris strains. J. Dairy Sci. 1987, 70,1779–1784.

[25] Chapot-Chartier, M. P., Deniel, C., Rousseau, L., Vassal, L., Gripon, J.C., Autolysis of two strains of Lactococcus lactis during cheeseripening. Int. Dairy J. 1994, 4, 251–269.

[26] Lepeuple, A. S., Van Gemert, E., Chapot-Chartier, M. P., Analysis ofthe bacteriolytic enzymes of the autolytic Lactococcus lactis subsp.cremoris strain AM2 by renaturing polyacrylamide gel electrophore-sis: Identification of a prophage-encoded enzyme. Appl. Environ.Microbiol. 1998, 64, 4142–4148.

[27] O’Sullivan, D., Ross, R. P., Fitzgerald, G. F., Coffey, A., Investigationof the relationship between lysogeny and lysis of Lactococcus lactisin cheese using prophage-targeted PCR. Appl. Environ. Microbiol.2000, 66, 2192–2198.

[28] de Ruyter, P. G., Kuipers, O. P., Meijer, W. C., de Vos, W. M., Food-grade controlled lysis of Lactococcus lactis for accelerated cheeseripening. Nat. Biotechnol. 1997, 15, 976–979.

[29] Modi, R., Hirvi, Y., Hill, A., Griffiths, M. W., Effect of phage on sur-vival of Salmonella enteritidis during manufacture and storage ofcheddar cheese made from raw and pasteurized milk. J. Food. Prot.2001, 64, 927–933.

[30] Carlton, R. M., Noordman, W. H., Biswas, B., de Meester, E. D., Loess-ner, M. J., Bacteriophage P100 for control of Listeria monocytogenesin foods: Genome sequence, bioinformatic analyses, oral toxicitystudy, and application. Reg. Toxicol. Pharmacol. 2005, 43, 301–312.


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Bacteriophages in dairy products: Pros and cons