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Phage Therapy in Aquaculture Management
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Therapeutic bacteriophages, commonly called as phages, are a promising potential alternative to antibiotics in the management of bacterial infections of a wide range of organisms including cultured fish. Their natural immunogenicity often induces the modulation of a variated collection of immune responses within several types of immunocytes while promoting specific mechanisms of bacterial clearance. 

  • aquaculture
  • bacteriophages
  • disease management
  • fish
  • immunology
  • lytic enzymes
  • pathogens
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Update Time: 26 Oct 2021

1. Phage Biology and Spatial Distribution

Bacteriophages or phages, in short, are an alternative to antimicrobials to fight against bacteria due to their unique host range that provides them with an excellent specificity. In addition, contrary to the antibiotic’s negative physiological effects on the host and the generation of bacterial resistance, the use of phages is eco-friendly and without major drawbacks [1][2]. Besides, phages produce lytic enzymes with the ability to act directly on the bacterial cell wall. An important associated advantage is that phages are ubiquitous to all fresh and saltwater environments representing a virtually unlimited source of virions and lytic enzymes. In seawater, the number and variety of phages have a direct and crucial impact on the variability of microbial communities which directly modulate the global biogeochemical cycles in the oceans [3][4]. Quantitative analyses of marine waters using transmission electron microscopy demonstrated that non-tailed viruses are the most abundant, followed by tailed viruses of the families Myoviridae and Podoviridae [5]. This example represents a huge gene reservoir across Earth’s ecosystems. Despite the great awakening interest in phage therapy and the discovery of a vast reservoir of new genes available in the phages of aquatic ecosystems, the composition the phage populations in the different fish species in aquaculture, either from freshwater or saltwater environments are not yet fully understood.

2. Phage’s Life Cycle

The phages like any other viruses depend on the metabolism of their bacterial host for reproduction. During the reproductive process, most phage types completely consume the resources of their host and kill them when releasing their progeny [6]. Initially, phages must infect their host bacteria through the binding of specific receptors that selectively sense specific components of the target bacterial cell wall such as the lipopolysaccharide in Gram-negative, or peptidoglycan in Gram-positive, capsular polysaccharides, and superficial appendages such as pili and flagella [7][8][9]. Following the classical viral reproductive strategies, once the phage inserts their nucleic acid into the bacterium’s cytoplasm, the host cellular machinery is highjacked to induce extensive replication through the lytic cycle (Figure 1). Alternatively, a phage also has the capacity to insert its genetic information into the genome of the host bacterium, thus becoming a prophage. The process of prophage incorporation into the host chromosome is called lysogenization, and the resulting bacterium with the prophage is called a lysogen. Therefore, the genetic material of the prophage is transferred to each daughter cell through cell division following the lysogenic cycle (Figure 1). A huge advantage associated with the lysogenic cycle is that daughter cells will not produce new virus particles until conditions are favorable for the virus or some external stimuli stress the cell and activate the highjacked genes. An additional less known phage reproductive cycle is the so-called pseudo-lysogenic. In the pseudo-lysogenic type, the information encoded by the genome of the phage is not translated immediately, perhaps due to the lack of nutrients and energy for the bacterium. However, it remains inactive inside the host, waiting until the optimal conditions recover for the bacterium to restart its metabolic processes. Then, the phage has the capacity to start again performing the lytic or lysogenic life cycles [10].
Ijms 22 10436 g001 550
Figure 1. The lytic and lysogenic cycle of bacteriophages. The lytic cycle comprises a series of events from attachment of the bacteriophage to the bacterial cell membrane, to the release of daughter phages by the destruction of its bacterial host. In the lysogenic cycle, phage DNA integrates into the bacterial genome without major consequences for the bacterial cell, and where the nucleic acid of the virus replicates along with that of its host.

3. Phage Lytic Enzymes and Depolymerases

Lysins derived from phages degrade bacterial peptidoglycans and are classified into five groups, depending on the bonds these enzymatic proteins cleave in the bacterial peptidoglycan [11]. Although their function is exclusively to degrade the cell wall of bacteria, the lytic enzymes of phages present a tremendous structural diversity and a significant number of different mechanisms of action [12][13][14][15].

In general, lysins are more likely to lyse Gram-positive bacteria because their cell wall peptidoglycan is directly exposed on the cell surface unlike Gram-negative bacteria. However, the study of phages or their lysins has been limited to a few fish pathogens such as Streptococcus agalactiae, Lactococcus garvieae, Renibacterium salmoninarum, Streptococcus iniae, and S. dysgalactiae, which are highly associated with disease outbreaks in fish farms.

4. Interactions between Phage and the Fish Immune System

4.1. Phage-Mediated Activation of Inflammation

Bacteriophage treatment was associated with opposite shifts in the inflammatory response in several test models, both in vivo and in vitro [16][17][18][19]. However, the results seem to depend not only on the cellular or animal model used but also on the type of phage applied and the panel of cytokines analyzed. Phage therapy in humans can also modify the levels of some cytokines produced by blood cells in treated patients [20]. In fish, some researchers have analyzed the cytokines’ response to the presence of bacteriophages alone or the coinfection of phages with their target bacteria. For example, phage therapy reduced the expression of the proinflammatory cytokines tnfa and il1b in the inflammatory response generated by Pseudomonas aeruginosa infection in zebrafish embryos [21][22]. Besides, using the adult zebrafish (Danio rerio) and the E. tarda model of infection, other authors also showed that although a phage treatment induced the expression of cytokine genes at specific time points, a robust proinflammatory response was undetected in the host [23]. Furthermore, a recent study has shown that a phage lysate of A. hydrophila induced a more robust immune response in Cyprinus carpio when compared to a formalin killed vaccine [24]. As a proof-of-concept, a novel commercial preparation containing three bacterial phages (BAFADOR®) applied on European eel (Anguilla anguilla) caused the stimulation of cellular and humoral immune parameters in response to an experimental challenge with A. hydrophila and P. fluorecense [25].

4.2. Phage-Specific Adaptive Responses

Due to the protein structure of the phage envelope, these proteins are the target of the adaptive immune system, which response with the production of neutralizing antibodies against them. Early studies with mice and even amphibians showed that phage exposure of the animals induced primary and secondary antibody responses [26][27][28]. It is expected that some phage epitopes stimulate an antibody response in experimental models. However, antibody production depends on the route of phage administration, the application schedule and dose, and individual features of a phage. Consequently, the results of studies where an antibody response to phages has been verified are very heterogeneous. Phagocytosis by immune patrolling cells seems to be a significant process of bacteriophage neutralization within animal bodies [29]. Moreover, although blood in humans and animals, including fish, is deemed sterile, genomic analysis has shown a rich phage community, which inevitably comes into continuous contact with immune cells in this rich fluid [30]. Despite these mechanisms of phagocytosis, antigen presentation, and antibody production by the immune cells against phages, the number of antibodies produced does not affect phage therapy outcomes.
On the other hand, due to the numerous and constant presence of large numbers of phages in our microbiota, it is not surprising that a low but stable background of antibodies against them is produced. Therefore, in some human or animal tests, high antibody levels have not been found against the phages used. Phage-derived RNA and ssDNA could directly contribute to B cell activation and the synthesis of anti-bacteriophage antibodies [31][32]. Despite the production of antibodies by animals against phage core or tail proteins, the induction of antibodies seems irrelevant for treating infections because the antibacterial effects of phages are faster than antibody formation in acute infections [33]. Conversely, the production of antibodies against phages could interfere with the outcome of the infection in chronic infections [34]. However, no robust studies have demonstrated an antibody-mediated immune response after inoculation or experimental infection with phages in fish.

5. Potential of Phage Therapy in Aquaculture Settings

During the fish and shellfish production cycle, these animals are already in daily contact with billions of bacteriophages, which assures us that they are safe. However, in their use against bacterial infections where massive phage production is required, we must consider several factors.
As phage treatments constantly require isolating the bacterium causing the disease, once a helpful phage is characterized against this bacterial strain, a stable batch of technically challenging preparations must be produced for field use. Consequently, one of the most critical challenge for microbiologists working directly or indirectly with aquaculture is the standardization of stocks used to treat infections or combat biofilms in aquaculture facilities. These stocks require strict quality control for purity, viability, and stability, implying that the correct conservation of the stocks is necessary for preparations containing single or mixed phages (phage cocktail). Titer, dosage, and quality of phage preparations are crucial parameters in standardizing experiments in the laboratory and experimental infections in field trials. Since we know that while some phages can grow exponentially inside a bacterial population from a low initial concentration, other phages need to maintain a relationship between the number of bacteria and the number of phage particles to achieve an adequate performance. Therefore, we must empirically verify this critical parameter. Very recently, a phage cocktail containing seven bacteriophages (three against A. hydrophila and four against P. fluorescens) has been tested in the European eel (Anguilla anguilla) and rainbow trout (Oncorhynchus mykiss), reducing the mortality of fish challenged with strains of these two species of bacteria [25][35]. Cocktails have also been used successfully in laboratory tests or small field trials in food protection or veterinary and human medicine [36][37][38][39]. In these and other studies, many phages (cocktail) are used to carry out the experiments, but in most cases, only the phage that has presented better results in vitro is subsequently characterized [40][41][42][43]. Second, it would be desirable to know phage genetics with sufficient precision. After all, we must consider that when we intend to use bacteriophages in aquaculture, they may contain genes for resistance to antibiotics or bacterial virulence genes that can produce noticeable side effects because they replicate exponentially in contact with their target bacteria. We must also remember that many antibiotic residues end up in continental or oceanic waters due to anthropogenic activities. Therefore, we must be aware that even phages isolated from aquatic environments can carry antibiotic resistance genes or virulence factors [44][45]. At present, although each time their number increases, not all phages used in in vitro or in vivo assays against fish or shellfish bacterial pathogens have been entirely genetically analyzed or characterized (Table 1 and Table 2).
The list of species of fish bacterial pathogens in which lytic phages have been studied is not complete. It may be essential to conduct these studies in species of greater interest in aquaculture, such as Photobacterium damselae subsp. piscicida, bacterial anaerobes, mycobacteria, Nocardia, several Aeromonas species, Enterobacterales, pseudomonads, vibrios, and the Gram-positive bacteria mentioned above. Few studies with fish bacterial pathogens have characterized or evaluated the presence or evolution of phage-resistant strains. Some works have investigated this phenomenon in various fish pathogens such as Flavobacterium [46][47][48], Yersinia ruckeri [49], Aeromonas salmonicida [40][50], and Vibrio anguillarum [51]. The mechanisms by which bacteria become resistant to phages is also an area of intensive research, especially since the discovery and application of the clustered regularly interspaced short palindromic repeats (CRISPR) system.
Most of the studies with fish pathogens have used controlled laboratory conditions to verify the control exerted by these lytic phages to their pathogenic bacterial host. However, more studies on these interactions under natural conditions would be desirable. One of the critical parameters is the multiplicity of infection (MOI). The use of high or low multiplicities of infection seems to be a key parameter for achieving effective lysis of the bacterial population and the appearance of resistance to the phages used. Therefore, comparative studies are needed to relate MOIs used in vitro and in aquatic environments, where phages are exposed to environmental conditions and factors such as dilution or variability of the target bacteria in their natural environment. A better understanding of the biology of viruses and a greater capacity to standardize the settings related to preclinical or laboratory research can also help in the advancement of regulatory affairs. As bacteriophage research continues to grow, we believe that microbiologists and immunologists working in areas related to aquaculture can use phages or their lytic enzymes to offer many promising advances in the fight against pathogenic bacterial species affecting cultured fish and shellfish.
Table 1. Phages used against Gram-negative bacterial fish and shellfish pathogens.
Source Enrichment ɸ Characterization Method Phage Strains Name Family * Genome Length References
Aeromonas hydrophila River water No TEM ɸ2 and ɸ5 Myoviridae ~20 kb [52]
Fishponds; Polluted rivers Single TEM N21, W3, G65, Y71 and Y81 Myoviridae; Podoviridae n.d. [53]
Stream water Single TEM, dsDNA pAh-1 Myoviridae ~64 kb [54]
Sea water Single TEM, DNA sequencing Akh-2 Siphoviridae 114,901 bp [55]
Carp tissues Single TEM AHP-1 Myoviridae n.d. [56]
Lake water Single TEM, dsDNA, DNA sequencing AhyVDH1 Myxoviridae 39,175 bp [57]
River water No TEM, dsDNA, DNA sequencing MJG Podoviridae 45,057 bp [58]
Sewage water Single TEM AH1 n.d. n.d. [59]
Striped catfish pond water Single TEM, dsDNA, DNA sequencing PVN02 Myoviridae 51,668 bp [60][61]
River water   TEM, dsDNA pAh1-C
Myoviridae 55 kb
58 kb
Wastewater No TEM, dsDNA, DNA sequencing Ahp1 Podoviridae ~42 kb [63]
Aeromonas punctata Stream water Single TEM, dsDNA IHQ1 Myoviridae 25–28 kb [64]
Aeromonas salmonicida River waters, two passing through fish farms Single TEM, DNA sequencing SW69-9
Myoviridae 173,097 bp, 173,578 bp and 174,311 bp [65]
River water Single TEM, DNA sequencing phiAS5 Myoviridae 225,268 bp [66]
Sediment of a Rainbow trout culture farm Single TEM, dsDNA, DNA sequencing PAS-1 Myoviridae ~48 kb [67]
Wastewater from a seafood market No TEM, DNA sequencing AsXd-1 Siphoviridae 39,014 bp [68]
Sewage network water from a lift station Single TEM AS-A
Myoviridae n.d. [40][41]
River water No TEM HER 110 Myoviridae n.d. [69][70]
Aeromonas spp. Gastrointestinal content of variated fish species No TEM, DNA sequencing phiA8-29 Myoviridae 144,974 bp [71][72]
Citrobacter freundii Sewage water No TEM, DNA sequencing IME-JL8 Siphoviridae 49,838 bp [73]
Edwardsiella ictaluri Water from catfish ponds Single TEM, dsDNA, DNA sequencing eiAU
Siphoviridae 42.80 kbp
42.12 kbp
42.69 kbp
River water Multiple DNA Sequencing PEi21 Myoviridae 43,378 bp [76][77]
Striped catfish kidney and liver Single TEM, dsDNA MK7 Myoviridae ~34 kb [78]
Edwardsiella tarda Seawater Single TEM, dsDNA ETP-1 Podoviridae ~40 kb [23]
River water No TEM, DNA sequencing pEt-SU Myoviridae 276,734 bp [79]
Wastewater Single DNA sequencing PETp9 Myoviridae 89,762 bp [80]
Fish tissues and rearing seawater No TEM, DNA sequencing GF-2 Myoviridae 43,129 bp [81]
Flavobacterium columnare River water Single TEM, DNA sequencing FCL-2 Myoviridae 47,142 bp [82][83][84]
Fishpond’s water and bottom sediments No TEM, dsDNA FCP1-FCP9 Podoviridae n.d. [42]
Flavobacterium psychrophilum Rainbow trout farm water Single/double TEM, dsDNA ø (FpV-1 to FpV-22) Podoviridae
(~8 to ~90 kb) [85][86]
Ayu kidneys and pondwater collected from ayu farms Multiple TEM, dsDNA PFpW-3, PFpC-Y PFpW-6, PFpW-7
Myoviridae; Podoviridae; Siphoviridae n.d. [87]
Photobacterium damselae subsp. damselae Raw oysters Single TEM, dsDNA Phda1 Myoviridae 35.2–39.5 kb [88]
Gastrointestinal tract of lollipop catshark Single TEM, DNA sequencing vB_Pd_PDCC-1 Myoviridae 237,509 bp [89]
Pseudomonas plecoglossicida Ayu pond water and diseased fish No TEM, DNA sequencing PPpW-3
Myoviridae Podoviridae 43,564 bp
41,386 bp
Pseudomonas aeruginosa Wastewater No TEM, DNA sequencing MBL n.d. 42,519 bp [92]
Shewanella spp. Wastewater
from a marketplace
Single TEM, DNA sequencing SppYZU01 to SppYZU10 Myoviridae; Siphoviridae. SppYZU01 (43.567 bp) SppYZU5
(54.319 bp)
Tenacibaculum maritimum Seawater Multiple TEM, DNA sequencing PTm1
Myoviridae 224,680 bp
226,876 bp
Vibrio alginolyticus Aquaculture tank water Single TEM, DNA sequencing VEN Podoviridae 44,603 bp [95]
Marine sediment No TEM, DNA sequencing ValKK3 Myoviridae 248,088 bp [96]
Marine water Single TEM, dsDNA St2
Myoviridae 250,485 bp 248,605 bp [97]
Vibrio anguillarum Soft tissues from clams and mussels No TEM, dsDNA 309
Several shapes ~47–48 kb [98]
Sewage water Double dsDNA VP-2
n.d. n.d. [51]
Water samples from fish farms Multiple TEM, DNA sequencing ø H1, H7, S4-7, H4, H5
H8, H20
S4-18, 2E-1, H2
Myoviridae Siphoviridae Podoviridae ~194–195 kb
~50 kb
~45–51 kb
Vibrio campbellii Host strain (V. campbellii) isolated form a dead shrimp No TEM, DNA sequencing HY01 Siphoviridae 41.772 bp [100]
Hepatopancreas of Pacific
white shrimp
Single dsDNA, DNA sequencing vB_Vc_SrVc9 Autographiviridae ~43.15 kb [101]
Vibrio harveyi Shrimp farm, hatcheries and marine water Multiple TEM, dsDNA A Siphoviridae n.d. [102]
Vibrio harveyi No TEM, dsDNA VHML Myovirus-like n.d. [103]
Shrimp pond water Single TEM, dsDNA PW2 Siphoviridae ~46 kb [104]
Water and sediment samples Single TEM, dsDNA VHM1, VHM2
~55 kb,
~66 kb
~69 kb
Hatchery water and oyster tissues Single TEM, dsDNA vB_VhaS-a
Siphoviridae ~82 kb
~59 kb
Commercial clam samples Multiple Genomic analysis, dsDNA ø VhCCS-01
n.d. [107]
Oyster, clam, shrimp, and seawater samples No TEM, DNA sequencing VHP6b Siphoviridae 78,081 bp [108]
shrimp hatchery and farm water, oysters from
estuaries, coastal sea water
Multiple TEM, dsDNA Viha10
Viha1 to Viha7
Myoviridae (Viha4)
~44–94 kb
~85 kb (Viha4)
Seawater sample Single TEM VhKM4 Myoviridae n.d. [111]
Vibrio ordalii Macerated specimens of mussels No TEM, DNA sequencing B_VorS-PVo5 Siphoviridae 80,578 bp [112]
Vibrio parahaemolyticus Sewage sample No TEM, dsDNA VPp1 Tectiviridae ~15 kb [113]
Polluted seawater No TEM, dsDNA KVP40
Myoviridae n.d. [114][115]
Seawater or mussels Single dsDNA SPA2
n.d. ~21 kb [116]
Coastal water Single TEM, DNA sequencing pVP-1 Siphoviridae 111,506 bp [117][118]
V. parahaemolyticus isolated from sewage samples collected from an aquatic product market No TEM, DNA sequencing vB_VpS_BA3 vB_VpS_CA8 Siphoviridae 58,648 bp
58,480 bp
Shrimp pond water Single TEM, DNA sequencing VP-1 Myoviridae 150,764 bp [120]
Coastal sand sediment double TEM, DNA sequencing VpKK5 Siphoviridae 56,637 bp [121][122]
Vibrio splendidus Raw sewage obtained from local hatcheries Single TEM PVS-1, PVS-2
Myoviridae; Siphoviridae n.d. [123]
Seawater near a fish farm cage Single TEM, DNA sequencing vB_VspP_pVa5 Podoviridae 78,145 bp [124]
Vibrio coralliilyticus sewage in oyster hatchery Single TEM pVco-14 Siphoviridae n.d. [125]
Vibrio vulnificus Seawater sample Single TEM, DNA sequencing SSP002 Siphoviridae 76,350 bp [126][127]
Abalone samples No TEM, sequencing VVPoo1 Siphoviridae 76,423 bp [128]
Initial host strain (V. vulnificus) No TEM VV1
Tectiviridae n.d. [129]
Vibrio sp. Sewage draining exits Single TEM, DNA sequencing VspDsh-1
Siphoviridae 46,692 bp
60,177 bp
76,310 bp
79,545 bp
113,778 bp
Yersinia ruckeri Wastewater containing suspended trout feces from a settling pond at a trout farm Single TEM NC10 Podoviridae n.d. [49]
Sewage No TEM YerA41 (several phages) icosahedral head, contractile tail n.d. [131]
Sewage No TEM, DNA sequencing, dsDNA R1-37 Myoviridae ~270 kb [132][133]
ɸ Phage enrichment with “single” or “multiple” bacterial hosts; * Classification determined by the authors; TEM (Transmission Electron Microscopy); dsDNA (Double stranded DNA); n.d. (Not determined); ø Several phage strains were isolated but only selected strains were fully characterized.
Table 2. Phages used against Gram-positive bacterial fish and shellfish pathogens.
Gram-Positive Targets Source Enrichment ɸ Characterization Method Phage Strains Name Family * Genome Length References
Lactococcus garvieae L. garvieae isolated from diseased yellowtail No TEM, dsDNA PLgY(16) Siphoviridae n.d. [134]
Yellowtail (Y)
Water (W)
Sediments (S)
Single TEM, dsDNA PLgW1-6
Siphoviridae >20 kbp [135][136][137]
Domestic compost Single TEM, DNA sequencing GE1 Siphoviridae 24,847 bp [138]
L. garvieae host No TEM, DNA sequencing PLgT-1 Siphoviridae 29,284 bp [139][140][141]
Rainbow trout farm water Single TEM, DNA sequencing WP-2 Picovirinae 18,899 bp [142]
Streptococcus agalactiae Tilapia pond No TEM HN48 Caudoviridae n.d. [143]
S. iniae S. iniae host No TEM, dsDNA vB_SinS-44 vB_SinS-45 vB_SinS-46 vB_SinS-48 Siphoviridae ~51.7 kb
~28.4 kb
~66.3 kb
~27.5 kb
Weissella ceti W. ceti host strain No TEM PWc Siphoviridae 38,783 bp [145]
ɸ Phage enrichment with “single” or “multiple” bacterial hosts; * Classification determined by the authors; TEM (Transmission Electron Microscopy); dsDNA (Double stranded DNA); n.d. (Not determined).


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    Galindo-Villegas, J. Phage Therapy in Aquaculture Management. Encyclopedia. Available online: (accessed on 04 July 2022).
    Galindo-Villegas J. Phage Therapy in Aquaculture Management. Encyclopedia. Available at: Accessed July 04, 2022.
    Galindo-Villegas, Jorge. "Phage Therapy in Aquaculture Management," Encyclopedia, (accessed July 04, 2022).
    Galindo-Villegas, J. (2021, October 24). Phage Therapy in Aquaculture Management. In Encyclopedia.
    Galindo-Villegas, Jorge. ''Phage Therapy in Aquaculture Management.'' Encyclopedia. Web. 24 October, 2021.