B. Bacteriophage (phage)
B.2. Phages infecting Aeromonadaceae
The first phages infecting Aeromonadaceae (Hereinafter referred as Aeromonas phages) was studied in the electron microscope in 1965 (16). Its host, which was identified as an Acelobacter sp., was later reclassified as Aeromonas sp. (124).
Subsequently, Paterson isolated nine Aeromonas phages infecting A. salmonicida from trout ponds and fish hatcheries, and described the characteristics of 4 selected isolates (110). A halophilic and psychrophilic phage, specific for a marine Aeromonas spp., was isolated from sea water collected at a depth of 825 m (147).
In 1971, 35 Aeromonas phages infecting A. salmonicida, which isolated from sewage, surface water, fish hatcheries and lysogenic bacteria, were characterized by serology and various biological criteria. Sixteen of these phages were studied by electron microscopy and were divided into three morphological groups (115). At least 8 additional phages infecting A. salmonicida were described since 1980 (73, 74, 119), and two phages infecting A. hydrophila were recently isolated from sewage (28). However, those isolated Aeromonas phages have not been classified in that time. Among the phages of known morphology, all but one had contractile tails and isometric or elongated heads. The exception is Bradley's phage, which had a short tail and resembles Salmonella phage P22 (16). Moreover, since physico-
21
chemical properties of Aeromonas phages were almost completely unknown, their classification depended largely on morphology and serological data (2). In addition, many Aeromonas phages were described without accurate morphological micrographs, until the first morphological characteristics of about 35 Aeromonas phages, mostly infecting A. salmonicida, were thoroughly investigated by Ackermann in 1985 (2).
In a recent review of Ackermann in 2007 (1), a total of 43 phages infecting Aeromonadaceae (especially in A. hydrophila and A. salmonicida) have been reported, and all of those were morphologically classified as tailed phages belonging to Caudovirales (33 of Myoviridae, 7 of Siphoviridae and 3 of Podoviridae). And among the Aeromonas phages belong to family Myoviridae, most of them were classified into P1-, P2- and T4-like viruses in the VIIIth ICTV Report (http://www.ictvdb.org/Ictv/index.htm) (42). With the technological advances in phage research, the morphology and genetic functions of T4 phage and T4-like phages infecting Escherichia coli or other bacteria were thoroughly investigated (31, 112), and provided an attractive model for the study of comparative genomics and evolution of phages. In this respect, recent studies of Aeromonas phages have also focused on virulent (or lytic) T4-like phages and have included extensive genomic investigations (31, 83, 101, 110, 113, 134); the complete genome sequences of 4 T4-like phages (Aeromonas phage 25, 31, 44RR2.8t and Aeh1), and only one exception of the complete genome of P2-like temperate Aeromonas phage (designated as φO18P) infecting A. media have already been published in GenBank. And in 2012, we fully sequenced the two T4- like Aeromonas phages (phiAS4 and phiAS5) infecting A. salmonicida subsp.
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salmonicida, and one T7-like Aeromonas phage (phiAS7) which belongs to Podoviridae and infects A. salmonicida subsp. salmonicida. The characteristics of those previously sequenced 8 Aeromonas phages were summarized in Table III.
Table III. Sources and properties of the sequenced Aeromonas phages up to 2012
Phage Family Host Isolation
source/contry
Genome
size (bp) Reference 25 Myoviridae
(T4-like)
A. salmonicida
subsp. salmonicida Fish farm/France 161,475 (112)
31 Myoviridae (T4-like)
A. salmonicida
subsp. salmonicida Fish farm/France 172,963 (112)
44RR2.8t Myoviridae (T4-like)
A. salmonicida
subsp. salmonicida Fish farm/Canada 173,591 (87)
Aeh1 Myoviridae
(T4-like) A. hydrophila Sewage/USA 233,234 (28)
φO18P Myoviridae
(P2-like) A. media A. media O18
strain/Germany 33,985 (11)
phiAS4 Myoviridae (T4-like)
A. salmonicida
subsp. salmonicida River/Korea 163,875 (79)
phiAS5 Myoviridae (T4-like)
A. salmonicida
subsp. salmonicida River/Korea 225,268 (80)
phiAS7 Podoviridae (T7-like)
A. salmonicida
subsp. salmonicida Fish farm/Korea 41,572 (81)
B.3. Therapeutic application of phages
Even though phages were discovered in the early of 20th century, the research of the past half-century is almost rare on the possible therapeutic applications against infectious bacterial diseases (6). The poor understanding of bacterial pathogenesis and phage-host interactions led to a succession of badly designed and executed
23
experiments. Furthermore, with the advent of antibiotic therapy, the use of phages became underestimated after the World War II. The discovery of antibiotics diverted research attention from phage therapy, mainly in the USA and Western Europe in 1940s. However, the use of the phage therapy has persisted without interruption in Eastern Europe and Soviet Union, and phages were commercialized by a number of companies (65). With regards to human health, in the past, phage was commercialized and administered in Poland and the Soviet Union orally, tropically or systemically to treat a wide variety of human infections (suppurative wound, gastro-enteritis, sepsis, osteomyelitis, dermatitis, emphysemas and pneumonia) in both adults and children with showing promising results (5). And in the 1970s, previous enthusiasm on the application of phages to prevent and treat bacterial infections in human was recovered (5, 10); studies of Smith et al. using E.
coli models with mice and farm animals, showed that phages could be used for both treatment and prophylaxis against bacterial infections (129). From then, several other Polish and Soviet Union study groups presented successful clinical applications of phages against drug-resistant bacterial infections in humans as well as animal models (5). The therapeutic efficacy of phage against infectious diseases caused by Pseudomonas aeruginosa (56, 144), Staphylococcus aureus (including MRSA) (149), E. coli (10), Enterococcus faecium (including VRE) (13), Streptococcus pneumoniae (75), Helicobacter pylori (26), Klebsiella pneumoniae (6) and Salmonella enteritidis (44, 135) has been shown in experimental animal models. However in recent decades, the emergence of antibiotic-resistant bacteria has substancially enhanced the interesting phage therapy even by USA and Western Europe. And nowadays, more than a dozen of companies and universities are
24
working on phage therapy for human, using current standards of clinical and microbiological research (15).
Recent studies evaluated phages as biocontrol agents in food (50, 67, 85, 135), in plants (45), to control cyanobacterial blooms and for wastewater treatment (150).
Additionally, bacterial diseases are a major problem in the expanding aquaculture (6, 126, 141). The increasing problems related to worldwide emergence of antibiotic resistance in common pathogenic bacteria, and the concerns about its spreadings in the aquaculture environments demanded alternative methods to control bacterial pathogens in fish and shellfish. Phage therapy has been showed a potentially viable alternative to antibiotics used in aquaculture to control indigenous and non-indigenous bacterial disease in farmed fish (6). In addition, some studies of phages were concerned with identifying those phages for use in bacterial typing schemes or for the characterization of its properties, including their potential role in virulence. Remarkably, there have been several attempts of phages to prevent bacterial infections in aquaculture (Table IV), and these previous experimental applications proved that phage could be useful for controlling bacterial infections of fish or shellfish. In the same manner, the experimental applications of phages to control A. salmonicida subsp. salmonicida have been attempted (68, 138), but those studies faced several difficulties with failures regarding fish protection. Therefore, our goal of this study was to find novel Aeromonas phages infecting A. salmonicida subsp. salmonicida, and to verify its therapeutic efficacy in Korean salmonids against furunculosis.
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Table IV. The representative use of phages to control bacterial pathogens in aquaculture (6).
Bacteria Phage Treated
fish/shellfish Effects References Aeromonas
salmonicida HER1107
HER 110
Brook trout (Salvelinus fontinalis)
The onset of furunculosis in brook trout was delayed by 7 days
(68)
Vibrio harveyi
Siphoviridae phage isolated from oyster tissue
and from shrimp hatchery water
Shrimp larvae
(Penaeus monodon) Improved larval survival (78)
Lactococcus garvieae
Siphoviridae phage isolated from diseased fish
and sea water in fish culture cages.
Yellow tail (Seliora quinqueradiata) and Ayu (Plecoglossus
altivelis)
Protective/curative effect (increase in the survival
rate)
(96)
Lactococcus garvieae
Siphoviridae phage isolated from diseased fish
and sea water in fish culture cages.
Yellowtail (Seliora quinqueradiata)
Protective/curative effect (increase in the survival
rate)
(97)
Pseudomonas plecoglossicida
PPp-W4 (Podoviridae)
and PPpW-3 (Myoviridae)
Ayu (Plecoglossus
altivelis)
Reduced infection and
increased fish survival (105)
Pseudomonas plecoglossicida
Myoviridae and Podoviridae isolated from diseased ayu and the rearing pond
water
Ayu (Plecoglossus
altivelis)
Protection against
experimental infection (106)
Aeromonas salmonicida subsp.
salmonicida
Aeromonas salmonicida phages O, R and B
Atlantic salmon (Salmo salar L.)
Lower rate mortality but similar absolute mortality. No protection was offered by any of the
phage treatments.
(138)
Vibrio harveyi Siphoviridae phage
Shrimp larvae
(Penaeus monodon) Improved larval survival (139)
26
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