Environment International 129 (2019) 488–496
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Environment International
journal homepage: www.elsevier.com/locate/envint
Review article
A review of bacteriophage therapy for pathogenic bacteria inactivation in
the soil environment
T
Mao Yea, Mingming Sunb, Dan Huanga, Zhongyun Zhanga, Hui Zhangc, Shengtian Zhangd,
⁎
⁎⁎
Feng Hub, Xin Jianga, , Wentao Jiaoa,e,
a
Key Laboratory of Soil Environment and Pollution Remediation, Institute of Soil Science, Chinese Academy of Sciences, Nanjing 210008, China
Soil Ecology Lab, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China
c
Jiangsu Key Laboratory of Food Quality and Safety-State Key Laboratory Cultivation Base of MOST, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
d
Nanjing Institute of Environmental Sciences, Ministry of Environmental Protection of China, Nanjing 210042, China
e
State Key Laboratory of Urban and Regional Ecology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
b
A R T I C LE I N FO
A B S T R A C T
Handling Editor: Jong Seong Khim
The emerging contamination of pathogenic bacteria in the soil has caused a serious threat to public health and
environmental security. Therefore, effective methods to inactivate pathogenic bacteria and decrease the environmental risks are urgently required. As a century-old technique, bacteriophage (phage) therapy has a high
efficiency in targeting and inactivating pathogenic bacteria in different environmental systems. This review
provides an update on the status of bacteriophage therapy for the inactivation of pathogenic bacteria in the soil
environment. Specifically, the applications of phage therapy in soil-plant and soil-groundwater systems are
summarized. In addition, the impact of phage therapy on soil functioning is described, including soil function
gene transmission, soil microbial community stability, and soil nutrient cycling. Soil factors, such as soil temperature, pH, clay mineral, water content, and nutrient components, influence the survival and activity of phages
in the soil. Finally, the future research prospects of phage therapy in soil environments are described.
Keywords:
Bacteriophage therapy
Pathogenic bacteria
Targeted inactivation
Soil
Review
1. Introduction
With the development of the global economy in the last few decades, an increasing amount of antibiotics has been released into the
environment along with the waste from domestic, industrial, agricultural, and medical activities (Chen et al., 2016; Fang et al., 2018;
Garner et al., 2019; Jiao et al., 2018). This has resulted in the selection
and transmission of antibiotic-resistance bacteria/genes (ARB/ARGs) in
the environment, which threatens the antibiotic efficiency in combating
bacterial infections (Burch et al., 2017; Chen et al., 2018; Couch et al.,
2019; Liu et al., 2019; Qiao et al., 2017). Consequently, a century-old
antibiotic alternative method — the bacteriophage (phage) therapy was
re-applied by scientists to induce lysis of antibiotic-resistant pathogenic
bacteria (ARPB) in various environments, including soil, air, and water
(Gutiérrez et al., 2018; Sun et al., 2018; Watts, 2017; Yu et al., 2018;
Zhao et al., 2019). Phage therapy was initially applied to cure human
bacteria infections, including pneumonia, urinary tract, sepsis, and
surgical site infections in 1940s; which was then overlooked by the
public due to the subsequent discovery of antibiotics (Dewangan et al.,
2017). However, the phage therapy came back into the scientists' visions because of the ever-increasing antibiotic resistance crisis in the
last decade, which not only revitalized the use of phage therapy for the
clinical purpose, but also facilitated its application to control pathogenic bacterial infection in natural environments, namely soil, air, and
water systems (Dou et al., 2018). Consequently, this review mainly
focuses on the recent application of phage therapy in inactivating pathogenic bacteria in soil and its potential influence on microbial stability, diversity and soil function (Sun et al., 2019). Meanwhile, the
impact of soil properties, including soil temperature, pH, clay mineral,
etc. on the phage therapy efficacy is also discussed. At the end of the
article, the future prospect of phage therapy research in soil environment is concluded.
⁎
Corresponding author.
Correspondence to: W. Jiao, State Key Laboratory of Urban and Regional Ecology, Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing 100085, China.
E-mail addresses: jiangxin@issas.ac.cn (X. Jiang), wtjiao@rcees.ac.cn (W. Jiao).
⁎⁎
https://doi.org/10.1016/j.envint.2019.05.062
Received 19 February 2019; Received in revised form 22 May 2019; Accepted 23 May 2019
Available online 31 May 2019
0160-4120/ © 2019 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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M. Ye, et al.
Siphoviridae
Podoviridae
Filamentous phage
Fig. 1. The structural sketch of bacteriophage.
2. Phages and phage therapy
2.2. Phage therapy
2.1. Phages
Phage therapy is the therapeutic use of phages to treat pathogenic
bacterial infections (Pires et al., 2017; Sun et al., 2019; Yu et al.,
2017b). It was developed and widely used between the 1920s and
1940s until the first large-scale production of the antibiotic penicillin in
1944 (Cisek et al., 2017; Ofir and Sorek, 2018; Williamson et al., 2017).
After that, although phage therapy was still used in some parts of the
world, most research on phage therapy came to a standstill until the
emergence of widespread ARB in the environment (Burch et al., 2017;
Chen et al., 2018; Qiao et al., 2017). In the last decade, due to selective
pressure exerted by antibiotics worldwide, soil has become an important source and pool of ARB and ARGs (Couch et al., 2019; Gutiérrez
et al., 2018; Liu et al., 2019; Sun et al., 2018, 2019). In addition, the
large amount of antibiotics and co-resistance contaminants (such as
heavy metals, pesticides, disinfectant, oxidant, and nitrogen and
phosphorus contaminants) released into the soil resulted in the accelerating transmission of ARGs between bacteria, therein increasing the
frequency of ARG acquisition in pathogenic bacteria (Balcazar, 2014a,
2014b; Subirats et al., 2016). Given that the discovery and synthesis of
novel antibiotics are currently far slower than the natural evolution of
ARPB in the environment, some super-pathogenic bacteria with multidrug resistance (MDR) have been discovered in the soil (Burch et al.,
2017; Chen et al., 2016). This has increased the environmental risk of
ARG dissemination along the soil–plants–animals–humans food chain
(Jiao et al., 2018; Ye et al., 2016, 2018). As a consequence, phage
therapy has reemerged as playing a critical role in the targeted inactivation of ARPB (Lyon, 2017; Pires et al., 2017; Sun et al., 2019).
In contrast to antibiotics, rather than attacking the whole bacterial
population, phage therapy specifically lyses the host bacteria and does
not affect non-host bacteria (Kakasis and Panitsa, 2019; Keen, 2015).
This is the prominent advantage of the phage therapy that the phage
predates specifically on its host bacterium in lieu of acting on the entire
bacterial community (Fig. 2). Furthermore, after the inactivation of the
host pathogenic bacteria, the phage abundance is in proportion to that
of the host pathogenic bacteria and thus, when the host bacteria diminish, the phage count also decreases, which maintains the microbial
stability and diversity (Paez-Espino et al., 2016; Salmond and Fineran,
2015; Watts, 2017).
Phages are viruses that infect and replicate within host bacteria and
archaea (Dewangan et al., 2017; Lyon, 2017). Phages have relatively
simple structures composed of proteins (60%) that encapsulate a DNA
or RNA genome (40%) (Fig. 1) (Paez-Espino et al., 2016; Williamson
et al., 2017). Phages are among the most abundant entities in the
biosphere (Yu et al., 2017a). It has been estimated that there are more
than 1031 population on the planet with a total weight of 109 tons (Dou
et al., 2018; Yu et al., 2017b). They are ubiquitously distributed in
environments populated by bacterial hosts, including soil, water, air,
and the intestines of humans and other animals (Simmonds and
Aiewsakun, 2018; Yu et al., 2015). According to morphology and nucleic acid (Sequence or type of DNA/RNA), phages can be classified into
Siphoviridae, Podoviridae, Myoviridae, and Filamentous phages (International Committee on Taxonomy of Viruses, ICTV). As shown in
Fig. 1, the phage generally at the length of 20–200 nm, consists of a
head, filled with DNA, long tails with a collar, a base plate with short
spikes and tail fibers (Adriaenssens and Brister, 2017; Aiewsakun and
Simmonds, 2018; Simmonds et al., 2017; Tolstoy et al., 2018). Most of
the phages have double-stranded DNA (dsDNA) genomes while a small
proportion has single-stranded DNA (ssDNA), double-stranded RNA
(dsRNA), or single-stranded RNA (ssRNA) genomes (Aiewsakun et al.,
2018; Howard-Varona et al., 2017). Phages can also be divided into
lytic phages and temperate phages based on whether or not their DNA
genome is integrated into the bacterial genome (Bao et al., 2018; Hobbs
and Abedon, 2016). For lytic phages (Fig. 2), six stages are involved in
the reproductive cycle, including attachment, penetration, transcription, biosynthesis, maturation, and lysis, which commonly result in the
destruction of the infected host bacteria (Keen, 2015; Ofir and Sorek,
2018; Trudil, 2015). In contrast, temperate phages usually integrate
their genomes into the host bacterial chromosome and stably pass the
phage DNA information to the progeny of bacteria during host bacteria
reproduction (Erez et al., 2017; Howard-Varona et al., 2017; Samson
et al., 2013). Under the pressure of disturbing factors (e.g., ultraviolet,
high temperature, ionizing radiation, antibiotics, or heavy metals) it is
likely that the temperate phages convert into a lytic cycle and lyse the
host bacteria (Kim and Bae, 2018; Salmond and Fineran, 2015; Wang
et al., 2018a).
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Fig. 2. Phage in lytic and lysogenic cycle.
Fig. 3. Phage therapy to control pathogenic bacteria in soil-plant systems.
3. Phage therapy for pathogenic bacteria inactivation in the soil
environment
2017). Plaques form on the plate because of bacterial lysis by phages;
large transparent plaques commonly consist of functional phages that
can be selected and isolated by repetition of the two-layer plate method
(Hayes et al., 2017; Parmar et al., 2018; Pires et al., 2015). The obtained phages are then subjected to phenotype and genotype determination (Samson et al., 2013; Xing et al., 2017). In addition, phage DNA
or RNA can be extracted for genome size estimation and DNA library
construction (Simmonds et al., 2017; Tolstoy et al., 2018). By combining the whole genome sequencing and open reading frame (ORF)
data, the phylogenetic tree can be constructed to precisely determine
the genotypic features of the obtained phages (Agboluaje and
Sauvageau, 2018; Kot, 2018; Wang et al., 2018b).
3.1. Isolation, identification, and morphology of functional phages
For successful phage therapy to inactivate pathogenic bacteria, the
most critical prerequisite is that there are appropriate lytic phages that
can recognize and lyse the pathogenic bacteria (Lyon, 2017; Pires et al.,
2017). Therefore, the large-scale application of phage therapy depends
on the size of the phage source bank (Górski et al., 2015; He et al.,
2018). Currently, the two-layer plate method is extensively used to
isolate functional phages from soil (Kwiatek et al., 2017; Lu et al.,
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host bacteria, resulting in the DNA (including ARG sequence) release
and degradation in the soil environment. In addition to the soil environment, the polyvalent phage also played a significant role in declining the level of the host bacteria and ARGs in the lettuce cultivated,
suggesting the potential migration of the phages from the soil to the
above-ground plant along the soil food chain. Additionally, highthroughput sequencing revealed that phage application to the soil facilitated the diversity and stability of the soil indigenous and lettuce
endophytic bacterial community. Zhao et al. (2019) compared the effect of a single host-specific phage, phage cocktail, and polyvalent
phage inoculation on the inactivation of host bacteria E. coli K12 and P.
aeruginosa PAO1 in the soil-carrot system. The inactivation efficiency of
the host bacteria in the system followed the order of phage cocktail > polyvalent phage > single host-specific phage. In addition, other
than disturbing the indigenous bacterial community, all the phage inoculation treatments resulted in the maintenance of, if not increase in,
the diversity and stability of the microbial community (Zhao et al.,
2019). When considering both the host bacterial inactivation efficiency
and the ecological disturbance, polyvalent phages were the optimal
technique with potentially broad applications.
In addition to obtaining functional phages, the biological characteristics of the phages, as well as environmental factors, such as pH,
ionic concentration, temperature, and light conditions, also impact
upon the efficacy of phage therapy (Askora et al., 2014; Saad et al.,
2019; Wang et al., 2016). The optimal infection multiplicity and onestep growth curve also need to be determined to verify the inoculation
ratio and suitable time point (Huang et al., 2018; Jurač et al., 2019;
Tang et al., 2019). Therefore, the phages that were selected for the
phage therapy resource bank were those with strong environmental
resistance, high host inactivation capacity, no toxins, and low host resistance mutation frequency (Hong et al., 2016; Wang et al., 2017a).
3.2. Application of phage therapy in soil-plant systems
At the early stage of phage discovery in 20th century, phage therapy
was primarily used in the field of medicine to treat human pathogenic
bacteria (Domingo-Calap et al., 2016; Torres-Barceló and Hochberg,
2016). Overshadowed by antibiotics since the 1940s, phage therapy
research then mainly focused on controlling bacterial infections in
agriculture and fishery fields and, thus, ‘agricultural phage therapy’ has
been developed to inactivate pathogenic bacteria in soil-plant systems
(Fig. 3). (Bhunchoth et al., 2015; Elhalag et al., 2018; Fujiwara et al.,
2011; Wei et al., 2017). Askora et al. (2014) isolated four phages
(φRSL, φRSA, φRSM, and φRSS) that inactivate the pathogenic Ralstonia solanacearum and the inoculation of the soil with the phage stock
solution significantly decreased the incidence, as well as the extent, of
bacterial wilt in tomato and tobacco plants. Fujiwara et al. (2011) reported that presoaking tomato seeds in phage φRSL1 solution inhibited
R. solanacearum colonization of the tomato root system. The stable
presence of the phage φRSL1 in the tomato shoot further indicated that
the migration of the phage may play a lasting role in controlling pathogenic bacteria in the soil-tomato system. Meanwhile, Frampton et al.
(2014) obtained 275 Caudovirales phages, belonging to Myoviridae,
Podoviridae, and Siphoviridae, from kiwifruit farm soil. Most of the
isolated phages were capable of lysing phytopathogenic bacterium
Pseudomonas syringae pv. Actinidiae. Meczker et al. (2014) isolated
several Siphoviridae phages from phytopethogenic Erwinia amylovoracontaminated apple farm soil and suggested that the phytopathogenscontaminated soils themselves were a ‘weaponry pool’ of corresponding
phages. In addition, Chae et al. (2014) loaded the isolated phages with
skimmed milk powder to protect the phage activity from the negative
impact of ultraviolet light; application of the mixture to rice plants
successfully controlled the rice pathogenic bacterium Xanthomonas oryzae pv. oryzae.
When applying phage therapy in soil-plant systems, it is important
to note that more than one type of ARPB commonly coexists in the
system. The application of one host-specific phage will, therefore, have
limited efficiency considering the complex ARPB contamination status
of the system. As a consequence, phage cocktails (mixtures of multiple
phages) were developed to increase the inactivation efficiency of single
pathogen contamination and mixed ARPB. In addition, Yu et al. (2017a,
2017b) found that by laboratory-directed selection, certain host-specific
phages could evolve into polyvalent phages capable of infecting more
than one host bacteria. However, the impact of phage cocktails and
polyvalent phages on the soil microbial community remained investigated. In our laboratory (Ye et al., 2018), one polyvalent phage
that predated both Escherichia coli K12 and Pseudomonas aeruginosa
PAO1 was isolated from antibiotic-contaminated soil near a livestock
farm in the Yangtze River Delta, China; a soil microcosm trial was
subsequently carried out to explore the inactivation efficacy of the
phage on the host bacteria in the soil. At the end of 63 days of incubation, the phage application not only clearly decreased the abundance of E. coli K12 and P. aeruginosa PAO1, but also stimulated the
dissipation of the corresponding ARG levels (tetM, tetQ, tetW, ampC, and
fosA) in the soil. Considering the multiple reactive locuses of the lyase
in the polyvalent phage, it was able to infect and lyse a wide range of
3.3. Phage therapy to control pathogenic bacteria in soil-groundwater
systems
The soil-groundwater system includes the vadose and phreatic zones
that extend from the surface soil to the aquifer below the water table, in
which most pores and fractures are saturated with water (Cai et al.,
2013; Wang et al., 2011). The system is heterogeneous in both composition and permeation (Fig. 4) (Frey et al., 2015; Szekeres et al.,
2018). The porous vadose zone shows soil properties and connects the
atmosphere and saturation zone, and thus is a suitable zone for pathogenic bacterial colonization and migration in the soil-groundwater
system (Cai et al., 2018). Due to the extensive application of wastewater irrigation and organic fertilizer, vertical migration of ARPB in the
soil-groundwater system has become a threat to ecological safety and
public health under the influence of rain. Forslund et al. (2011a, 2011b)
observed the potential contamination of pathogenic bacteria Salmonella
Senftenberg, Campylobacter jejuni, and E. coli O157:H7 in soil and
groundwater caused by water irrigation. When host-specific lytic
phages were added to the irrigated water, the migration of the pathogenic bacteria from the soil to the groundwater was prevented and the
abundance of the pathogenic bacteria also decreased, thus reducing the
migration risk of pathogenic bacteria in the soil-groundwater system.
Sun et al. (2019) investigated the use of phage therapy to control ARPB
in the undisturbed soil column. The soil column was collected from
clear agricultural soil at the depth of 0–5 m below the surface in the
Yangtze River delta, China. Water with highly abundant ARPB (tetracycline-resistant E. coli K12 and chloramphenicol-resistant Klebsiella
peneumoniae) was applied to simulate wastewater irrigation and its
vertical migration. The application of phages impeded both the ARPB
vertical migration and the ARG dissipation at different soil layers of the
column, with the level of ARPB and ARGs decreased by 2 to 6 folds. In
addition, phage application in this work also maintained the diversity
and functioning of the microbial community, suggesting its potential
application as an environmentally friendly biocontrol method in the
soil-groundwater system (Sun et al., 2019).
It is important to note that the results above were obtained based on
the batch or pot trials, while more evidences are essential to demonstrate the effect of phage therapy on inactivating pathogenic bacteria at
larger scale soil environment. In addition, the arms race between phage
and the host bacteria facilitated the evolution of host bacteria to antagonize the phage infection, which discounts the efficacy of the phage
therapy (Feiner et al., 2015). Therefore, it is of great significance to
work out ways to curtail the bacterial resistance against phage predation by exploring the underlying resistance mechanism, and stimulate
phage therapy application in the soil environment.
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Fig. 4. Phage therapy to control pathogenic bacteria in soil-groundwater systems.
4. Interaction of phage therapy and soil environment
pathways. Comparing with the temperate phages, lytic phages affect
environmental microbial diversity to a greater extent because of their
lysis of the host bacteria. In contrast, though milder, temperate phages
also impact the environmental bacterial functioning by incorporating
into the chromosome of the host bacteria, which commonly change the
secondary metabolism and the fitness of the hosts. Consequently, both
lytic and temperate phages directly influence various environmental
functioning by predating the host bacteria. For instance, when the host
bacteria were involved in the cycling of the nutrient elements (C, N, P,
and S) in the environment, the abundance, composition, functioning
and metabolism of the bacteria would be manipulated by phage predation, which would further influence the nutrient turnover, bioavailability, crop yield, greenhouse gas emission in the environment.
Meanwhile, if the host bacteria were ARG-carrying pathogenic bacteria,
the phage's predation on the hosts exerted positive influence on the
environmental health. However, when the host bacteria turned out to
be pollutants'-degrading strains, phage therapy would decrease the
bioremediation effect of the environment. Besides the direct lysis of the
host bacteria, phages also exerted significant influence on the environmental functioning indirectly. Various negatively charged functional groups at the surface of the phage capsid protein, such as sulfydryl-, amino-, hydroxyls interact with positively charged ions in the
4.1. Impact of phage therapy on the soil function
Since phages are strictly bacterial parasites, their reproduction in
the bacterial cell influences the host bacteria abundance, microbial
community interactions, nutrient element cycling, and functional gene
proliferation. Considering that the soil is one of the most important
phage reservoirs, it is important to determine the impact of phage activity on the soil ecosystem (Sun et al., 2019). Phages are active in the
soil and respond rapidly to variations in the host bacteria community
(Dou et al., 2018). As a consequence, it is likely that phages exert a topdown effect on the soil microbial community and, further, affect driven
nutrient cycling in the soil. It was estimated that approximately
10–15% of bacterial death is caused by phage lysis in the aquatic environment and the released cell contents are assimilated by microorganisms for cell growth and reproduction (Feiner et al., 2015; Keen,
2015). Therefore, an increase in the phage abundance commonly stimulates the bacterial growth rate in the environment (Howard-Varona
et al., 2017).
As described in Fig. 5, the impacts of phage therapy on the environmental functioning can be realized through direct and indirect
Fig. 5. The impact of phage therapy on soil function.
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infect as lytic phages, which was likely to convert as lysogenic ones at
the temperature of 15–25 °C (Egilmez et al., 2018). Ma et al. (2016)
obtained one N4-like phage that could infect Achromobacter xylosoxidans, and found that the lysis of the host bacteria was efficient at 4, 25,
and 37 °C, but generally decreased in the lysis effect between 50 and
80 °C. Nagayoshi et al. (2016) isolated the phage φOH3 which predated
Thermus thermophiles HB8 as host bacteria from the sediment in Obama
hot spring in Japan, and detected the optimal growth temperature was
between 70 and 90 °C. Therefore, similar to the host bacteria, the
temperature also played a crucial role in impacting the activity and
infection of the phages in the soil environment.
soil (Yang et al., 2015). For instance, the adsorption between soil particles and the phages could affect the migration of the phages in the soil,
and further the contact frequency between the phages and host bacteria
(Yang et al., 2015), therein impacting the phage therapy on the host
bacterial controlling, and indirectly influencing the environmental
functioning.
4.2. Impact of phage therapy on ARGs transmission in soil
Among the three widely accepted ARG transmission mechanisms—conjugation, transformation, and transduction—the transduction
process is mediated by phages (Calero-Cáceres and Muniesa, 2016;
Lekunberri et al., 2017). Considering the large amount of phages in the
soil, increasing attention has been paid to the role of phages in ARG
proliferation in the soil environment. For both virulent and temperate
phages, after completing the infection, reproduction, and lysis cycles, it
is very likely for the phages to acquire partial gene fragments from their
specific hosts, bacteria, or integrate their own gene fragments into the
plasmids or chromosomes of the host bacteria (Koskella and Brockhurst,
2014; Quirós et al., 2016). In consistence with previous research
(Calero-Cáceres and Muniesa, 2016; Calero-Cáceres and Balcazar, 2019;
Lekunberri et al., 2017), our laboratory isolated phages and bacteria
from soil and sewage sludge, and found the same ARGs between the
phages and the bacteria (Sun et al., 2018). At the same time, the level of
phage-carrying tet genes were positively correlated with the bacteriaharboring tet genes, suggesting that phage DNA was an important reservoir of ARGs, and facilitated ARG proliferation through transduction
in the environment. Therefore, some scientists believed that the frequency of horizontal transfer of ARGs between ARB and antibiotic
sensitive bacteria, and among various bacteria species is much higher
than has been thought previously, and phage-mediated transduction
plays a critical role in stimulating ARG transmission in the environment
(Balcazar, 2014a, 2014b; Larrañaga et al., 2018). Considering the high
abundance of phages in the soil, the role of soil phages as important
ARG vectors to facilitate ARG proliferation in the soil should not be
neglected. It is crucial to consider ways to reduce the ARG dissemination while applying phage therapy in the soil environment.
Given the low transduction frequency in the environment, some
research suggested the limited influence of phage therapy on the ARG
dissemination (Calero-Cáceres and Balcazar, 2019; Lekunberri et al.,
2017). As described in the study of Enault et al. (2017), the whole
genome analysis indicated that ARGs were rarely encoded in the phages
investigated. Meanwhile, the abundance of both ARB and ARGs in the
soil decreased after phage inoculation, indicated that the further degradation of the released ARGs from the lysed host bacteria (CaleroCáceres and Balcazar, 2019; Lekunberri et al., 2017).
Therefore, whether the phage therapy exerts positive or negative
impact on the ARG transmission was determined by environmental
parameters, including the soil physico-chemical properties, the indigenous microbial community and the climate factors, etc. More research thus is needed to qualify and quantify the factors involved.
4.3.2. pH
Variation in the soil pH not only impacted upon the bacteria growth
but also the survival of the phages (Paez-Espino et al., 2016; Pratama
and van Elsas, 2018; Williamson et al., 2017). Ma et al. (2016) reported
that the Achromobacter xylosoxidans phage phiAxp-3 presented the
highest infection activity at neutral pH, which decreased by 90.25%
and 75.76% when the pH was 4.0 and 10, respectively. Similarly, the
Bacillus subtilis phages isolated from soil showed similar resistance to
acid and alkaline pH, and the optimum pH were 7.0 and 8.0. Meanwhile, some phages were stable at alkaline pH, decreased significantly
in the titer at pH 4, and could not survive at pH 2. In contrast to the
direct impact of the pH on the phages' activity, soil pH also exerted an
indirect effect on the phage growth in soil. The absorbance of the
phages to the soil's solid particles commonly results in the increased
survival of the phages in the soil via the absorbance of hydrophobic
colloidal substances on the surface of the soil solid particles (Oh et al.,
2017; Wang et al., 2017b). More specifically, the absorbance of the
hydrophobic colloidal substances on the soil surface is dependent on
the soil surface potential properties and soil pH (Ruppelt et al., 2018;
Wu et al., 2016).
4.3.3. Soil clay
Clay mineral is able to protect phages from losing activity because
of the soil organisms' and relevant factors' disturbance, resulting in the
relatively long survival period of the free-state phage even without the
host bacteria (Bellou et al., 2015; Katz et al., 2018; Tong et al., 2012).
In addition, both the type and the particle size of the clay mineral influence the phage activity, as well as the infection and lysis of the host
bacteria, in the soil. Tong et al. (2012) reported that clay minerals
(kaolinite and bentonite) both decreased the infection efficacy of the
phage MS2 through surface adsorption. Katz et al. (2018) observed that
although goethite, montmorillonite, iolite, and kaolinite all adsorbed
the phage φ6, and the montmorillonite could further lead to the loss of
infection in 35% of the phage. Similarly, Bellou et al. (2015) also reported that the types of the clay mineral were closely associated with
the sustainability of the phages hAdVs，MS2, and ΦΧ174.
4.3.4. Other factors
Some studies have reported that the infection of the host bacteria by
phages varied among soils with different nutrient contents (Williamson
et al., 2017). Since natural soils commonly show a poor nutritional
state, it is likely that the indigenous bacteria in such conditions are not
sensitive to phage infection. Therefore the phages might be present in
an inactivated state when nutrients are limited.
Water content also affects phage activity in the soil (Zhao et al.,
2019). For one reason, water content directly impacted the activity of
the indigenous bacteria in the soil, therein exerting indirect influence
on phages. For another reason, the water content determined the frequency of the contact between the phage and the host bacteria in the
soil by affecting the mobility and migration of phages in the soil.
Moreover, soil water depletion caused by evaporation could lead to the
complete loss of activity of the phages.
Besides the factors described above, other factors, such as contamination, aeration status, and ionic strength, oxygen content affect
4.3. Factors that impact upon the effect of phage therapy in soil
4.3.1. Temperature
According to the optimal growth temperature, soil bacteria can be
commonly classified into three categories, i.e., psychrophilic bacteria,
thermophilic bacteria, and mesophilic bacteria (Sharaby et al., 2017).
Correspondingly, the survival of the soil phages is also temperaturedependent, although not strictly corresponding to their host bacterial
temperature preferences (Kim et al., 2012). Temperature is the most
critical factor that determines whether or not a phage can survive and
grow (Leon-Velarde et al., 2016; Ma et al., 2016). For instance, the
infection capacity of the isolated Burkholderia psedudomomallel phages
in the soil varied with the daily and seasonal temperature variance;
between the range of 30 and 50 °C, the isolated phages were prone to
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the activity and infection capacity of phages in the soil (Wang et al.,
2017b; Williamson et al., 2017). Therefore, to understand the influence
of various environmental factors on the phages activity in the soil, one
needs not only investigate the sole factor's influence, but also explore
the comprehensive impact of multiple factors on the whole phage
community in the soil.
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5. Research prospects
Due to the emergence of antibiotic resistance, the application of
phage therapy has potential because of its capacity to target and inactivate host bacteria. However, the public are still hesitant about its
extensive application because of the concern over its impact on the
ecosystem. Therefore, more effort needs to be taken in the near future
to broaden its development in the soil environment, including:
(1) Phage Resources Development of rapid high-throughput techniques
to obtain abundant phage resources so that the development cost
and time can be reduced to maximize the benefit of the phage
therapy in the soil. Different combinations of phage types should be
tested, such as host-specific phages combined with polyvalent or
cocktail phages to guarantee inactivation of the host bacteria in the
soil.
(2) Phage biodiversity Investigate the biodiversity of the phage community in the soil to clarify the impact of phage therapy on the
structure, composition, and functioning of the soil microbial community and nutrient cycling. More specifically, the competitive
coevolution relationship between the phage and its host bacteria
need to be explored to ensure the security of the soil ecosystem and
the stability/diversity of the soil microbial community.
(3) Phage therapy in the soil-animal system Explore the application of
phage therapy in the soil-animal system, especially the interaction
between the phage and soil animals, such as nematodes, springtails,
and earthworms. Meanwhile, it is important to understand the typical phages in the soil-animal system to obtain the available phage
resources while carrying out phage therapy in soil-animal systems.
(4) Functional genes Clarify the role of phage therapy in the transmission of functional genes in the soil through phage-mediated transduction, including antibiotic-resistance genes, nutrient cycling
genes, and pollutant-degrading genes. By doing so, the potential
impact of phage therapy in the soil carbon sequestration, greenhouse emissions, global climate change, contaminated soil remediation, and crop yield increases will be better understood.
(5) Ecological risk assessment Establish a risk assessment model and
evaluation method to assess the environmental risk of phage
therapy on ecological security and public health and construct an
environmental regulatory system to monitor the safe use of phage
therapy in soil and improve the public awareness of science.
Acknowledgments
This work was financially supported by the National Key Research
and Development Program of China (2018YFC1803100), the Yong Elite
Scientists Sponsors Hip Program by CAST (2018QNRC001), the Jiangsu
Provincial Natural Science Funds for Distinguished Young Scholar
(BK20180110), the National Natural Science Foundation of China
(41771350), the Fundamental Research Funds for the Central
Universities (Y0201700160), the Environmental Protection Research
Project in Jiangsu Provincial Environmental Department (2017005),
the Jiangsu Agricultural Science and Technology Innovation Fund (CX
(17)3047), the Youth Innovation Promotion Association of the Chinese
Academy of Sciences (2018350).
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