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Review Article
Bacteriophages and Their Role in Food Safety
Copyright 2012 Sanna M. Sillankorva et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
The interest for natural antimicrobial compounds has increased due to alterations in consumer positions towards the use of
chemical preservatives in foodstu and food processing surfaces. Bacteriophages fit in the class of natural antimicrobial and their
eectiveness in controlling bacterial pathogens in agro-food industry has led to the development of dierent phage products
already approved by USFDA and USDA. The majority of these products are to be used in farm animals or animal products such
as carcasses, meats and also in agricultural and horticultural products. Treatment with specific phages in the food industry can
prevent the decay of products and the spread of bacterial diseases and ultimately promote safe environments in animal and plant
food production, processing, and handling. This is an overview of recent work carried out with phages as tools to promote food
safety, starting with a general introduction describing the prevalence of foodborne pathogens and bacteriophages and a more
detailed discussion on the use of phage therapy to prevent and treat experimentally induced infections of animals against the most
common foodborne pathogens, the use of phages as biocontrol agents in foods, and also their use as biosanitizers of food contact
surfaces.
of phages in 1915, they have been extensively used not or by spray to target avian pathogenic E. coli in poultry, and
only in human and veterinary medicine but also in various orally/rectally to control E. coli in ruminants.
agricultural settings. Being obligatory parasites, upon mul- Reduction of colonization on foods (biocontrol) during
tiplication by taking over host protein machinery, phages industrial food processing can be accomplished by applying
can either cause cell lysis to release the newly formed virus phages directly on food surfaces, for example, in case of
particles (lytic pathway) or lead to integration of the genetic meats, fresh produce, and processed foods or even mixed
information into the bacterial chromosome without cell onto raw milk. Experimental data reveals that phages are
death (lysogenic pathway). very eective against actively growing bacteria and lose
Towards a food safety perspective, strictly lytic phages are eectiveness in nongrowing bacteria [12]. In these cases,
possibly one of the most harmless antibacterial approaches eective control could be achieved, applying high titres
available. of phages to control pathogens by lysis from without
Phages oer advantages as biocontrol agents for several mechanisms [6, 13] or whenever phages start to replicate
reasons: (i) high specificity to target their host determined by immediately after the food begins to warm (i.e., during
bacterial cell wall receptors, leaving untouched the remain- preparation, handling, and/or consumption).
ing microbiota, a property that favors phages over other In food industry, biofilms are found on the surfaces of
antimicrobials that can cause microbiota collateral damage; equipment used, for example, in food handling, storage, or
(ii) self-replication and self-limiting, meaning that low or processing, especially in sites that are not easy to clean or
single dosages will multiply as long as there is still a host to sanitize. Some of the work using phages against in vitro
threshold present, multiplying their overall antimicrobial biofilms formed by spoilage and pathogenic bacteria show
impact; (iii) as bacteria develop phage defense mechanisms that under ideal conditions significant viable cell reductions
for their survival, phages continuously adapt to these altered are achieved and thus, their use for biosanitation is promising
host systems; (iv) low inherent toxicity, since they consist although very challenging due to the diversity of bacteria
mostly of nucleic acids and proteins; (v) phages are relatively found in dierent settings.
cheap and easy to isolate and propagate but may become time Phages are also excellent as food biopreservation agents
consuming when considering the development of a highly since they are reported to lyse hosts at temperatures as low
virulent, broad-spectrum, and nontransducing phage; (vi) as 1 C [14, 15], limiting growth of pathogenic and spoilage
they can generally withstand food processing environmental bacteria on refrigerated foods (specially psychrotrophic
stresses (including food physiochemical conditions); (vii) bacteria); once the foods are taken to room temperature,
they have proved to have prolonged shelf life. Phages are phages can further control their proliferation [16].
readily abundant in foods and have been isolated from a
wide variety of raw products (e.g., beef, chicken) [6, 7],
processed food (e.g., pies, biscuit dough, and roast turkey) 3. Phages Targeting Different Food Pathogens
[8], fermented products (e.g., cheese, yoghurt) [9], and
The global incidence of foodborne disease and costs associ-
seafood (e.g., mussels and oysters) [8, 10]. This suggests
ated are dicult to estimate, however cost at least $7 billion
that phages can be found in the same environments where
dollars each year in medical expenses and lost productivity in
their bacterial host(s) inhabit, or once were present and that
the United States according to the United States Department
phages are daily consumed by humans. Furthermore, the use
of Agricultures Economic Research Service [17]. The actual
of antibiotics prophylactically and therapeutically in farm
figure is higher since this estimate reflects illnesses caused
animals has become a major concern due to their possibility
only by the major foodborne pathogens. The most frequently
of contributing to the declining ecacy of the antibiotics
reported pathogens from animal origin, responsible for such
used to treat bacterial infections in humans and leading
impact, are separately discussed in this section, focusing on
to the alarming emergence of superbugs like Salmonella
their contamination sources and their harms for animals
DT104 and the methicillin-resistant and multidrug-resistant
and humans and furthermore summarizing the recent phage
Staphylococcus aureus. The use of phages to promote food
interventions and main outcomes. We also briefly address
safety can be basically done at four dierent stages along the
some of the common phytopathogens and discuss phage
food chain (Figure 1).
applications carried out in an attempt to decrease crop
Reduction of pathogens colonization in animals during
diseases and product loss.
primary production (phage therapy) is a strategy followed in
primary production just before slaughter or during animal
growth to reduce the probability of cross-contamination 4. Foodborne Pathogens from Animal Origin
with the animal feces during food processing. For example,
it is estimated that a reduction of 2 log on the Campylobacter The four main foodborne pathogens from animal origin
loads in poultry intestines is sucient to diminish 30- are accounted to be E. coli, Campylobacter, Salmonella, and
fold the incidence of campylobacteriosis associated with Listeria. These bacteria are all common contaminants of
consumption of chicken meals [11]. The proof of principle ruminants, poultry, and swine and are usually carried in
of phage therapy in animals was already established for their gastrointestinal tract asymptomatically. Research on
several pathogens (detailed description below). Phages can the use of phages against foodborne pathogens from animal
be administered orally, incorporated in drinking water or origin has mainly focused on the optimization of preharvest
food, to control Salmonella and Campylobacter in poultry, interventions where the phage administration routes and
International Journal of Microbiology 3
Therapy Sanitation
Phage applications
Control Preservation
Prevention of
Reduction of
contamination and
pathogen proliferation
colonization of foods on foods during
at industry food
storage and marketing
processing
of the final products
Figure 1: Feasible applications of phages along the food chain towards an increased food safety (adapted from Greer [18]).
delivery processes have received most attention and also of broiler chicken. Despite these results, phage adminis-
on the optimization of postharvest strategies. The usage tration via addition to bird drinking water proved to be
of phages as a preharvest strategy is made directly by inecient in protecting the birds from fatal E. coli respiratory
administering phages to livestock to prevent animal illness infections.
and/or also to minimize the pathogen carriage in the gastro- Although some successful results of phage therapy in
intestinal tract, thereby preventing pathogen entry to the ruminants have been reported using oral delivery of phages
food supply. Postharvest strategies are based on the use of via direct administration or addition to drinking water
phages directly on animal carcasses in an attempt to sanitize and/or feed, the majority of the recently published papers
the products. suggest that oral treatment is unsuccessful in reducing E. coli
Escherichia coli is a gram-negative bacterium. Serotype levels (see Table 1).
O157 : H7 in particular, classified as Shiga toxin-producing The main speculated causes for the failure of oral
E. coli, is a well-known food poisoning pathogen. Its major treatments have been reported to be (i) nonspecific binding
reservoir comprises ruminants and, as it can survive well of phages to food particles and other debris in the rumen
under intestinal conditions, if proper care is not taken during and gastrointestinal tract [25]; (ii) phage inactivation upon
slaughter, the contents of the intestines, fecal material, or contact with the acidic conditions of the abomasum [26];
dust on the hide may contaminate meats [19]. The most (iii) causing an insucient number of orally phages reaching
common route of E. coli transmission to humans is via the gastrointestinal tract [27]. An interesting approach
undercooked contaminated food, while water and raw milk to reduce coliphage inactivation has been described by
are assumed to be related to cross-contamination events, by Stanford and colleagues in 2010. These authors successfully
direct or indirect contact with feces. This microorganism is encapsulated phages in polymeric matrices which resisted
highly virulent and a public health threat because ingestion in vitro acidic conditions and furthermore, once delivered
orally to steers caused reduction of E. coli levels [28].
of a concentration as low as 10 cells is able to cause infection
Essentially, oral delivery of phages has reported to be
[1, 20, 21].
successful either using a cocktail of phages or combined
Recent pre- and postharvest phage research targeting E. with rectal treatment. For instance, a combined oral/rectal
coli is listed in Table 1. treatment using phages KH1, SH1 was able to reduce
Recent phage therapy to decrease E. coli levels on farm E. coli levels compared to oral treatment alone or to
animals has focused mainly on poultry and ruminants. individual phage administration, but still this combined
Application of phages to poultry has been successful to oral/rectal treatment using a phage cocktail did not cause
prevent fatal respiratory infections in broiler chickens [22 total eradication of the pathogen from cattle [32]. Also, a
24]. Several dierent approaches have been used; however, cocktail of phages CEV1 and CEV2 were reported to lead to
aerosol spraying and intramuscular (i.m.) injection have more than 99.9% of reduction of E. coli in sheep guts [36].
given the best results and reduced significantly the mortality However, although reductions of E. coli levels in dierent
4 International Journal of Microbiology
organs have been described, phages still fail in reducing phage and that prudence must be taken to validate phage
fecal shedding [29, 35], and only in one published work therapy for E. coli O157 : H7 control [42].
the authors managed to reduce fecal shedding duration All postharvest interventions reported since 2000 have
by 14 days [28]. In 2008, Niu and colleagues investigated been eective in reducing E. coli levels from fresh produce
two dierent sampling techniques: fecal grab and rectoanal and meats. Also, phage application to E. coli contaminated
mucosal swab for surveillance of E. coli O157 : H7 [42] food contact surfaces has led to significant reductions
and to study the role of phage as a mitigation strategy. proving that phage can be used safely for equipment and
Their study showed discrepancy between fecal and rectoanal food contact surface sanitation.
mucosal swab sampling in 63 of the 213 positive samples The successful use of coliphages has led to the devel-
from experimentally inoculated feedlot steer. This shows that opment of a phage-product (EcoShield (Intralytix)) which
sampling procedures can significantly influence the merit of received regulatory approval from the Food and Drug
International Journal of Microbiology 5
Administration (FDA) in 2011. This product can be used disinfectants, and acidic conditions frequently encountered
on red meat parts and trims intended to be ground (Food in food environments [52]; however, to date, we were
Contact Notification no. 1018) and has proved to eliminate only able to find one report evaluating the ecacy of
from 95 to 100% of E. coli O157 : H7. Finalyse (Elanco Food Campylobacter phages of disrupting biofilm formed on glass.
Solutions) is another product on the market using naturally In this study, phages were able to reduce by 1 to 3 log the
occurring phages specific for E. coli O157 : H7. Finalyse is viable cell counts under microaerobic conditions; however,
sprayed on cattle to reduce the load of E. coli, prior to its after treatment above 84% of the surviving bacteria were
entering the beef packing facility (preharvest strategy). resistant to the two phages applied [53].
Campylobacter is a genus of gram-negative, spiral, Salmonella, is a genus of gram-negative facultative intra-
motile, and microaerophilic bacteria with an optimal growth cellular species, is considered to be one of the principal
temperature around 41 C. C. jejuni and C. coli members causes of zoonotic diseases reported worldwide. Salmonella
are considered to be major aetiological agents of enteric serovars can colonize and persist within the gastrointestinal
diseases worldwide. Campylobacter is the most commonly tract, and so human salmonellosis is commonly associated
reported zoonosis in Europe (EFSA 2011), and C. jejuni, with consumption of contaminated foods of animal origin.
in particular, is estimated to cause approximately 845,000 Salmonella infections cost nearly 3 million euros in EU per
illnesses, 8,400 hospitalizations, and 76 deaths each year annum in health care systems [17, 54]. Salmonella enterica
in the USA [1]. This widespread infection is explained serovars, Enteritidis and Typhimurium, are responsible for
because ingestion of low doses (400500 cells) [43] can cause the majority of Salmonella outbreaks, and most events are
campylobacteriosis typically characterized by fever, bloody reported to be due to consumption of contaminated eggs and
diarrhea, and acute abdominal pain [44]. Campylobacter is poultry, pig, and bovine meats, respectively [55]. Salmonella
capable of colonizing the intestine of poultry and cattle, is also a known spoilage bacterium in processed foods.
and thus infection is mostly acquired by fecal-oral contact, Once ingested, this microorganism can cause fever, diarrhea,
ingestion of contaminated foods (i.e., raw meat and milk abdominal cramps, and even life-threatening infections [56].
contaminated through feces), and waterborne through con- To prevent such infections, a number of studies on animal
taminated drinking water [4547]. The widespread disease phage therapy have been reported where phages were used to
and economic impact on agriculture and food industries has prevent or reduce colonization and diseases in livestock. All
led to the development of various approaches to contain this recent studies are summarized in Table 3.
infection using bacteriophages (Table 2). Phage therapy of experimentally Salmonella-infected
Phage preharvest interventions reported so far have been poultry and swine animals has been successful and sig-
successful in reducing Campylobacter numbers in the cecal nificantly decreased Salmonella in major tissues such as
content and feces of experimentally infected broilers and ileum and cecal tonsils. Although these results have been
have not caused any adverse health eects. However, some mostly obtained within contrived laboratory conditions, the
degree of resistant phenotypes, recovered from phage-treated success of postslaughter phage employment, to lower the
chickens, has been reported [4850], of which some were risk of cross-contamination, will only be determined after
found to display clear evidence of genomic rearrangements extending these studies to poultry farms.
[51]. Scott and colleagues demonstrated that Campylobacter Apart from one report in 2001, where the multivalent
virulent phages have the potential to activate dormant Felix01 phage was used, all other in vivo experiments
prophages, leading to rapid pathogen evolution towards the performed recently were carried out using cocktails of two
development of phage-resistant phenotypes. These authors to six phages. Furthermore, Ma and colleagues (2008) have
also showed that whilst pathogen evolution can be rapid, encapsulated phage Felix01 in a chitosan-coated Ca-alginate
resistance to the therapeutic bacteriophage is associated with spheres [57] and have found in in vitro studies that this
a decreased fitness to environment, specifically meaning technique preserves phage viability upon exposure to acidic
that phage-resistant phenotypes exhibited a decreased ability conditions; however, to our knowledge, these encapsulated
to colonize the gastrointestinal tract [51]. These genomic phages have not yet been tested in vivo. Valuable outputs
instability findings suggest that C. jejuni adopt this strategy to have been made in the last couple of years in terms of
temporarily survive local environmental pressures, including using phages for Salmonella biocontrol. Today, two phage-
phage predation and competition for resources. The key ele- products are available: (1) BacWash from OmniLytics Inc.
ments for the success of phage therapy against Campylobacter which received, in 2007, USDAs Food Safety and Inspection
in broiler chickens are a proper selection of phage, the dose Services approval to be commercialized and applied as a mist,
of phage applied, and the time elapsed after administration spray, or wash on live animals prior to slaughter; (2) BIO-
[48]. TECTOR S1 phage product from CheilJedang Corporation
As for postharvest strategies, two studies have been that is to be applied on animal feed to control Salmonella in
reported (see Table 2) in which phages reduced Campy- poultry.
lobacter contamination following a lysis from without Unlike phage preharvest strategies on animals, several
mechanism. This suggests that Campylobacter phages can be postharvest strategies have adopted the use of only one phage
used as a tool for biocontrol purposes. and not a cocktail. All Salmonella phages reported have
It is known that Campylobacter attaches and forms been able to decrease the number of viable cells present
biofilms on surfaces as a measure to overcome environmental on raw meats, processed and ready-to-eat foods, and fresh
stresses, such as aerobic conditions, desiccation, heating, produce. Furthermore, the combined treatment of phage
6 International Journal of Microbiology
and Enterobacter asburiae, a strain exhibiting antagonistic of phage-nisin mixture was however significantly reduced in
activity against Salmonella, to control this pathogen on apples on the account of a decline of phage numbers possibly
tomatoes, mung bean sprouts, and alfalfa seeds, represents a due to the low pH. Phage biocontrol should therefore be
highly promising, chemical-free approach. However, in some optimized separately for each food matrices under study.
settings phages were found to be readily immobilized by the Four other studies have used phage P100, which was highly
food matrix and, although retaining infectivity, they lost the eective in inhibiting Listeria growth at storage temperatures
ability to diuse and infect target cells [59]. for several days (see Table 4). Like in Campylobacter, only one
Listeria monocytogenes is a gram-positive, motile, and article, by Soni and Nannapaneni (2010), on the ecacy of
facultative intracellular bacterium, that can grow under phages against biofilms was found for Listeria monocytogenes.
several food matrices and storing conditions (e.g., high These authors evaluated the ability of P100 against 21 L.
salt levels, low pH, lack of oxygen, and low temperatures) monocytogenes strains belonging to 13 serotypes and found
[60]. Invasive infection by L. monocytogenes causes listeriosis that P100 reduced by 3.5 to 5.4 log/cm2 the viable cells
and is transmitted to humans with 103 CFU/mL levels. It present in stainless steel surfaces [64]. Nonetheless, studies
is often associated with contaminated minimally processed carried out on a variety of experimentally contaminated
food such as ready-to-eat (RTE) products, poultry, and dairy meats, fresh produce, and processed food among others
products or related to cross-contamination after the heat show that biocontrol is influenced by phage contact time
treatment process of foods stored at low temperatures [61, and phage dose, regardless of higher or lower temperature.
62]. Despite its low incidence, estimated to be in order of 2 Despite this fact, the results conducted on RTE foods
of 10 reported cases per million per year in Europe [63], its and meats using LMP-102 phage preparation (six-phage
pathogenicity causes a high mortality rate of approximately cocktail) allowed the commercialization of ListShield phage
255 deaths each year in the USA alone according to the product from Intralytix. Also, LISTEX P100 phage-based-
Centers for Disease Control and Prevention (CDC) [1]. As product (from EBI Food Safety) is being commercialized
so, contingency measures have led to the establishment of a with a GRAS status (generally recognized as safe) to prevent
limit for common RTE foods of 100 CFU per gram in EU and Listeria contamination on food products and food processing
a zero tolerance policy in the USA. facilities.
Considering the sources of Listeria outbreaks, phage Staphylococcus aureus is a gram-positive bacterium, is
research has focused on postharvest applications (Table 4). considered to be a major threat to food safety [1, 90], and
The first two studies in Table 4 were carried out using a also is the most common agent of mastitis in dairy cows [91].
combination of phage and a nisin, a broad spectrum antibac- CDC estimates that staphylococcal food poisoning, which
teria peptide used during production to extend shelf life by results from the consumption of foods containing sucient
suppressing gram-positive spoilage and pathogenic bacteria. amounts of one or more preformed enterotoxins [91, 92],
While in ground beef the phage-nisin combination revealed is 242.148 cases annually in the USA [1]. The mechanisms
to be ineective, this strategy had a synergistic eect once described for the contamination of foods with S. aureus can
added to melon and apple resulting in an improved reduc- be of animal or human origin, such as due to the infection
tion of Listeria compared to phage or nisin alone. The ecacy and colonization of livestock or farm workers and even
International Journal of Microbiology 7
due to the human handling of the food products [93]. S. that the activity in milk of the phages used in their work was
aureus can cause toxin-mediated diseases within 1 to 6 h after due to their dairy origin.
consumption of contaminated foods; nevertheless the symp- Postharvest applications in pasteurized milk show that
toms are usually mild and most people recover within 13 the use of combined phage treatments with nisin and high
days [94]. The annual estimated loss worldwide due to mas- hydrostatic pressure could synergistically be used to reduce
titis in adult dairy cows is of 35 billion US dollars [95]. Phage staphylococcal contamination compared to each treatment
research has focused on the treatment of mastitis in lactating alone [101, 102]. Nevertheless, care should be taken in
dairy cows and mostly in dairy food products (Table 5). regard to combined phage-nisin application since nisin-
The experimental work of phage therapy on dairy cattle adapted strains can seriously compromise phage activity
to control S. aureus on teats shows that, although there was [101]. Inactivation of S. aureus has also been accomplished
no increase in somatic cell counts in milk samples indicating in both fresh and hard-type cheese using a phage cocktail
that the phages did not irritate the animal [96, 97], there were during cheese manufacturing [103]. While for fresh cheese
no statistically dierent outcomes between phage-treated staphylococcal cells could not be detectable until the end
and placebo groups [97]. This suggests that the use of phage of the curdling process (after 24 h), in hard cheeses, the
as teat washes or sanitizers will not reduce the incidence presence of staphylococcal strains continuously dropped to
of S. aureus mostly due to the barriers to phage-mediated 1.24 log CFU per gram at the end of ripening [103] providing
bacteria lysis which are present in the bovine mammary evidence that phages can be successfully used to control S.
gland. The suggested reasons for the inecacy of phage K are aureus in dairy food products.
the degradation or inactivation of the phage particles within
Today, there are phage-based diagnostic tools available to
the gland and the inhibitory eects of raw milk [97]. Also,
detect S. aureus, including antibiotic resistant (MRSA) and
it has been reported that milk whey prevents phages from
susceptible (MSSA) strains (Microphage, Inc.).
reaching their host cell surface [98] due to the agglutination
of S. aureus cells upon contact with raw whey [98, 99]. Besides the five foodborne pathogens described above,
However, the work by Garca et al. [100] on the use of several other foodborne pathogens are responsible for ill-
phages in curd manufacturing processes provides evidence nesses, hospitalizations, and deaths, such as Clostridium spp.,
that phages are stable and active during enzymatic curd Shigella spp., and Vibrio spp. Nonetheless, these are not
formation suggesting that pH is, in fact, the most crucial discussed further as to date there is a limited number of
inactivation factor. Furthermore, these authors postulated articles on the use of phage against these pathogens.
International Journal of Microbiology 9
5. Concluding Remarks and Future Perspectives it may be reasonable to verify the ecacy of phage after
the process where phages were applied or, at least, at the
Soon after the discovery of phages, several studies produced end of the processing stage. Nevertheless, it is well evident
negative results frequently associated with their inappro- that even after phage treatment, changes in food items still
priate usage, including administration to treat viral and occur during transport and storage. Future studies should
unknown agent diseases. Now, when once more the potential also focus on improving the general understanding of the
of phages is being evaluated mostly due to the increasing mechanisms of phage resistance acquired by the hosts and
emergence of multiresistant strains, it is important not to the rate of elimination from the animal body. In addition,
repeat the same mistakes. Furthermore, the adoption of further evaluation of phage for biosanitation purposes is still
phage administration and delivery routes, control proce- not well documented for the pathogens listed above.
dures, concentrations, and timings of application among Although the results of the above-described studies
other parameters based on results found in the literature appear to be encouraging, they should be interpreted
must be done with caution as the ecacy of each phage or cautiously. For instance, some phage studies have proven that
cocktail of phages is highly dependent on the phage-host phages are inecient in reducing their host, such as phage
systems in study. Furthermore, sampling of experimentally delivery on foods and drinking water for controlling E. coli
contaminated animals and foods and their treatment/control 0157 : H7 in poultry and ruminants, and reduced ecacy of
with phage should mimic as much as possible the conditions some of the phages reported. Also, the emergence of phage-
found at preharvest and postharvest (slaughterhouse, pro- resistant phenotypes is reported by several authors; however
cessing, and at retail) stages. For example, to estimate the this has not significantly aected the results of the phage tri-
input of the slaughterhouse into the process chain, samples als on animals and can be managed with using phages which
should be collected before and after cooling. Ready-to-eat target those resistant phenotypes. Nonetheless, summarizing
food usually undergoes several processing stages, and thus briefly the results described recently: (i) phage therapy is
10 International Journal of Microbiology
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[10] D. L. Croci, D. de Medici, C. Scalfaro et al., Determina-
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Foundation for Science and Technology in the scope of and temperature on phage control of beef spoilage, Journal
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63734/2009 and SFRH/BPD/48803/2008, respectively. and J. A. Heinemann, Phage inactivation of foodborne
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