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Shifting the paradigm from pathogens to pathobiome: new concepts in the

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 REVIEW ARTICLE
published: 05 March 2014
CELLULAR AND INFECTION MICROBIOLOGY doi: 10.3389/fcimb.2014.00029

Shifting the paradigm from pathogens to pathobiome: new

concepts in the light of meta-omics
Muriel Vayssier-Taussat 1*, Emmanuel Albina 2,3,4 , Christine Citti 5 , Jean-François Cosson 6 ,
Marie-Agnès Jacques 7 , Marc-Henri Lebrun 8 , Yves Le Loir 9,10 , Mylène Ogliastro 11 , Marie-Agnès Petit 12 ,
Philippe Roumagnac 13 and Thierry Candresse 14
1
INRA, UMR BIPAR (Enva/Anses) USC INRA, Maisons-Alfort, France
2
CIRAD, UMR CMAEE, Petit-Bourg, Guadeloupe, France
3
INRA, UMR 1309 CMAEE, Montpellier, France
4
INRA, Université de Toulouse, INP, ENVT, UMR 1225, IHAP, Toulouse, France
5
INRA, UMR CBGP (INRA/IRD/Cirad/Montpellier SupAgro), Montferrier-sur-Lez, France
6
INRA, Institut de Recherche en Horticulture et Semences, UMR 1345, Angers, France
7
INRA, UMR 1290, BIOGER-CPP, INRA AgroParis Tech, Thiverval-Grignon, France
8
INRA, UMR 1253 STLO, Rennes, France
9
Agrocampus Ouest, UMR 1253 STLO, Rennes, France
10
INRA, UMR 1333 DGIMI, Montpellier, France
11
INRA, UMR 1319, Micalis, Jouy-en-Josas, France
12
CIRAD/UMR BGPI TA A54/K, Montpellier Cedex 5, France
13
UMR 1332 Biologie du Fruit et Pathologie, INRA, Villenave d’Ornon Cedex, France
14
UMR 1332 Biologie du Fruit et Pathologie, Université de Bordeaux, Villenave d’Ornon Cedex, France

Edited by: The concept of pathogenesis has evolved considerably over recent years, and the scenario
Patrick Mavingui, Centre National de “a microbe + virulence factors = disease” is probably far from reality in a number of
la Recherche Scientifique, France
cases. Actual pathogens have extremely broad biological diversity and are found in all
Reviewed by:
major groups of microorganisms (viruses, bacteria, fungi, protozoa. . .). Their pathogenicity
Valerio Iebba, ’Sapienza’ University
of Rome, Italy results from strong and often highly specific interactions they have with either their
Catherine Legras-Lachuer, microbial environment, hosts and/or arthropod vectors. In this review, we explore the
Université Lyon1, France contribution of metagenomic approaches toward understanding pathogens within the
*Correspondence: context of microbial communities. With this broader view, we discussed the concept of
Muriel Vayssier-Taussat, Institut
“pathobiome” and the research questions that this raises.
National de la Recherche
Agronomique, Animal Health, USC
Keywords: next generation sequencing, microbial ecosystem, interactions
Bartonella et Tiques, 23 Avenue du
Général de Gaulle,
94 700 Maisons-Alfort, France
e-mail: mvayssier@vet-alfort.fr

INTRODUCTION AND RESEARCH CHALLENGES the transmission of plant viruses vectored by these insects (van
Recent studies of infectious agents have clearly demonstrated that den Heuvel et al., 1994; Morin et al., 1999) and that symbiotic
Koch and Hill’s fundamental postulates of “one microbe—one Wolbachia spp. disrupt, by unknown mechanisms, the coloniza-
disease” has shown its limits. Indeed, it is now established that tion of mosquito salivary glands by the dengue and Chickungunya
many pathogens live and interact with other micro-organisms viruses, thus limiting their transmission (Tortosa et al., 2008;
(not only bacteria, but also protists, fungi, viruses, or phages) Mousson et al., 2010, 2012; Blagrove et al., 2013). Similarly, an
in vast communities, all generating and participating in complex Enterobacter bacterium from the Anopheles gut microbial flora
interactions that may influence or drive disease processes (Chow renders mosquitoes resistant to infection with the human malaria
et al., 2011; Rogers, 2012). As exemplified by several studies on gut parasite, by interfering with parasite development through the
microbial communities, some commensal bacteria of the intesti- production of reactive oxygen species (Cirimotich et al., 2011).
nal flora can become virulent under the influence of diverse Such interactions may also exist in other ecosystems (soil, seeds,
factors, such as the actions of other micro-organisms (follow- vertebrate hosts. . .) and may impact pathogenic processes.
ing horizontal gene transfer between commensal and pathogenic It is within this context of microbial community interac-
bacteria) (Stecher et al., 2012) or of antibiotics which cause tions, that we define the “pathobiome” concept, which represents
shifts in microbiome composition. Likewise, arthropod vectors the pathogenic agent integrated within its biotic environment.
carrying human, animal or plant pathogens can be colonized Understanding the pathobiome thus requires (1) an accurate
by commensal and mutualistic microbes, which are then able knowledge of the microorganism community defining it, (2) clear
to influence pathogen transmission (Weiss and Aksoy, 2011; Su evidence of any effect(s) this microorganism community has on
et al., 2013). For example, it has been shown that the GroEL pro- pathogenesis, (3) an understanding of the impact of the microor-
tein produced by aphid or whitefly endosymbionts is involved in ganism community on persistence, transmission and evolution of

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Vayssier-Taussat et al. The new pathobiome concept

pathogenic agents, and (4) knowledge of biotic and abiotic factors every pathogen- and/or pathobiome-specific microbial commu-
that may disrupt the pathobiome and lead to onset of patho- nity from diverse biological and/or environmental samples will
genesis. These various aspects represent new scientific issues of need to be described and compared. In addition to serving as
remarkable complexity and will constitute major research chal- a starting point to address questions in other research areas,
lenges in the coming years. The development of meta-omics, and these approaches will have direct impact on the broad fields of
in particular metagenomic approaches, will provide invaluable diagnosis and etiology (Barzon et al., 2011; Chiu, 2013; Sherry
tools in the pursuit of an understanding of pathobiomes.(See et al., 2013). For the first time, these methods will permit reli-
Figure 1). able and sensitive identification of pathogens associated with
each ecosystem (such as within a plant compartment, an animal
RESEARCH AIMS organ or an arthropod vector) without any a priori knowledge. As
INVENTORIES TO DEFINE “PATHOBIOMES” DIVERSITY with other metagenomic studies, it is clear that these approaches
The first scientific objective is to accurately describe the biodiver- will reveal hitherto unsuspected microorganisms, including novel
sity of relevant microbial communities. Toward this goal, major pathogens, as has already been demonstrated in several studies
methodological advances are required including the development (Chiu, 2013; Beer et al., 2013; Drexler et al., 2013).
of new strategies, techniques and tools to achieve an effective For some methodological aspects, it will be possible to rely on
and comprehensive inventory and description of pathobiome developments from more advanced fields of metagenomics, such
diversity (Zaura, 2012; Frisli et al., 2013). Recent advances in as environmental microbiology (Rajendhran and Gunasekaran,
high throughput sequencing technologies (e.g., 454 and Illumina) 2008; Buee et al., 2009; Lombard et al., 2011). This is indeed the
enable the exploration of microbial diversity at an unprece- case for the bioinformatic analysis of bacterial 16S data, fungal
dented scale. However, novel methodologies are now required to ITS data or metatranscriptomic approaches developed for other
analyze this wealth of data. Indeed, metagenomic studies have microbial ecosystem studies (Cole et al., 2009; Schoch et al., 2012;
revealed the extraordinary richness and diversity of viral, bacte- Sherry et al., 2013). The increasingly widespread multiplexing
rial and parasitic communities in multiple different ecosystems approaches are also an interesting and affordable way to generate
(Willner et al., 2009; Santos and Anton, 2011; Fancello et al., the large amounts of data necessary for the application of com-
2012; Lecuit and Eloit, 2013). However, the tools required to parative statistical approaches to microbial communities from
accurately measure and compare pathobiome diversity, such as numerous samples (See Cosson et al., in this issue).
bioinformatic pipelines and databases, are still largely rudimen- Certain specific aspects of the pathobiome will require tai-
tary. In order to measure the impact of the community on the lored and original developments, such as the ability to identify
occurrence, transmission, and evolution of a given pathogen, pathotypes and genotypes to an infra-specific level, and will need

FIGURE 1 | Overview of the pathobiome concept and scientific challenges for the coming years.

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Vayssier-Taussat et al. The new pathobiome concept

to address the additional specific problems generated by phages, approaches fail to reflect the actual activity or dynamics of
viruses, and parasites. microbial communities. The need to develop broader “meta-
Finally, it should be emphasized that we still only have a omic” approaches such as in situ metatranscriptomics and
very limited understanding of how pathogenic agents themselves, metaproteomics is thus clear as any technical limitations of these
including bacteriophages (as pathogens of bacteria), contribute methods are being progressively circumvented (i.e., by direct
to the functioning of many ecosystems (Santos and Anton, 2011), next-generation cDNA sequencing for transcriptomics) (Simon
so that this aspect will undoubtedly be an important issue to be and Daniel, 2011). A metatranscriptomic study conducted on a
addressed in the coming years. multispecies biofilm model composed of species found in healthy
oral biofilms has, for example, recently unraveled the importance
PATHOBIOME MODULATION OF PATHOGENESIS, FUNCTIONAL IMPACT of pathogens in controlling gene expression of a healthy oral
OF THE COMMUNITY community, thus demonstrating the usefulness these approaches
A second major challenge is to shift from descriptive to functional (Frias-Lopez and Duran-Pinedo, 2012).
metagenomics, in order to understand exactly how the patho- Short term priorities remain the acquisition of metagenomic
biome modulates pathogenesis, and to which extent it impacts data with improved quality from ecosystems of interest (sampling
on its environment, regardless of the ecological niche considered. of relevant pathobiomes). To address and resolve the complexity
A large number of studies have been dedicated to understanding of these systems, innovative strategies are needed that will require
how a single pathogen interacts with its host, without taking into in-depth mathematical and statistical analyses.
account the role of the overall microbial environment. The tran- Functional metagenomic approaches will also aim to deter-
sition to a broader pathobiome perspective involves revisiting the mine the common denominator as well as the specificities of
Koch and Hill’s postulates at the level of microbial communities, particular ecosystems. Indirectly, these methods raise the ques-
and raises the question of the nature and diversity of the micro- tion of the nature of the “functional biological model” studied
biota present in a healthy individual, and of factors promoting for a given pathobiome, and of its integrative scale, from single
the emergence of potentially disease-causing pathobiomes. For cell to complex populations, including their intricate intermedi-
instance, as recently reviewed (Lecuit and Eloit, 2013), the role ate levels (tissues, organs, individuals. . .). Experimental designs
of the gut microflora community is becoming increasingly rec- must be carefully prepared and implemented such as to mimic
ognized as a key factor in the onset of inflammatory diseases. these complex interactions, continually taking into account co-
Similarly, the microbiota contribution toward promoting infec- infection and synergies between different microorganisms. Here,
tion and spread of enteric viruses is receiving more attention the challenge will be to identify those pathobiome agents which
(Kuss et al., 2011). In the future, understanding the interac- are beneficial to the host (probiotics, bacteriophages, competi-
tion of the microbiota with pathogens (=pathobiome) and the tors, activators of host defences), the conditions that may hinder
host might provide new insights into the pathogenesis, as well as the development of pathogenesis, or the emergence of damaging
novel avenues for preventing and treating intestinal and systemic variants or sub-populations from healthy communities (Santos
disorders. and Anton, 2011; Zarco et al., 2012).
The spreading of antibiotic resistance genes is another exam-
ple of the vital importance of the microbial context, as pathogens MICROBIAL ECOLOGY AT THE LEVEL OF THE PATHOBIOME
may be able to acquire resistance phenotypes from environmen- The third goal is to understand the impact of microbial communi-
tal reservoirs (Dantas and Sommer, 2012; Perry and Wright, ties on the persistence, transmission, and evolution of pathogens.
2013). The most recent evidence for the transfer of antibiotic In particular, to elucidate the spatio-temporal dynamics of these
resistance genes between the environment and the clinic is pro- communities, the ecological interactions between microorgan-
vided by Forsberg et al. (2012). Using an innovating metagenomic isms within communities, as well as the evolutionary forces at
approach, the authors identified DNA sequences in cultured play (mutation, selection and gene flow)—especially when it
multi-drug-resistant soil Proteobacteria which had 100% iden- comes to pathogen survival, extinction or dispersal. Many macro-
tity to resistance genes found in clinical pathogens, including ecological concepts could be applied to micro-ecology, although
resistance against β-lactams, tetracyclines, aminoglycosides, sul- some may require reformulation to fit the microbial lifestyle
fonamides, and chloramphenicol. Although the authors could not (Little et al., 2008; Rogers et al., 2013).
definitively show that these genes originated from soil organ- The ecosystems within which pathogens evolve are defined
isms due to the nature of their metagenomic approach, these by their abiotic and biotic dimensions, including both host and
results emphasize the importance of the soil resistome, regardless vector populations. Pathogens must adapt to selective pressures
of the direction of gene flow (from soil to clinic, or vice versa). associated with these complex ecosystems, in particular to both
Functional metagenomic approaches offer an opportunity to host and vector defense mechanisms (Little et al., 2008; Rogers
unravel the role of the host in shaping and modulating the equi- et al., 2013), as well as to any environmental fluctuations impact-
librium of these microbial communities. The host’s response(s) ing on their survival and/or dispersal outside of hosts or vectors
and their “history” (etiological, epidemiological, immunologi- (see next section). In addition, microorganisms interact with each
cal) will also need to be taken into account (Conrath et al., other. Antagonistic and mutualistic behaviors have evolved as
2002). adaptations to living in microbial communities. Microorganisms
Because metagenomic DNA-based analyses cannot differ- cooperate, compete with, or even prey upon each other to
entiate between expressed and non-expressed genes, these better exploit resources. As with macroorganisms, competition

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Vayssier-Taussat et al. The new pathobiome concept

for nutrients and space plays an important role in shaping species as has been recently shown for Bartonella spp. (Guy et al.,
microbial interactions. In the human gut for instance, compe- 2013).
tition for resources is thought to impede pathogen infection, a A major challenge in pathobiome research will thus be to
phenomenon called the “barrier effect” (Casadevall and Pirofski, develop and apply concepts and approaches of microbial ecology
1999; Akira et al., 2006; Jones and Dangl, 2006). Such a barrier and evolutionary biology to pathogens and the microbial com-
effect has also been implicated in counteracting pathogen infec- munities in which they exist. A peculiarity of pathobiomes is that
tion at the epidermal surface of both plants and animals (Beattie they involve multiple complex interactions within microbial com-
and Lindow, 1999; Chen and Tsao, 2013; Findley et al., 2013). munities, the host and the environment, and are subject to strong
Antagonistic effects have also been evidenced in the mosquito selection pressures that sometimes lead to extreme adaptations
midgut between the bacteria Enterobacter sp. and the human (e.g., species which have recently become intracellular parasites,
malaria parasite, Plasmodium falciparum, leading to reduced (Casadevall, 2008). Metagenomic approaches will facilitate the
malaria transmission by mosquitoes (Cirimotich et al., 2011). The complete description of microbial communities associated with
killing of bacteria by microbial eukaryotes and bacteriophages the different phases of a pathogen’s life cycle, and thus will
also has a global effect on bacterial communities (Pernthaler, aid in the identification of species that may act as partners or
2005). In the field of environmental science, for example, phages antagonists. Particular attention should be paid to the impact
have been shown to play a crucial role in structuring microbial of the pathobiome on the molecular interactions involved in
communities involved in biogeochemical cycling (Suttle, 2007). A infection and transmission (vertical or horizontal). To effectively
better understanding of phage–host interaction has already ben- combat plant and animal diseases, a major challenge will be to
efited those secondary applications which rely on phage-resistant identify those levers which control or manipulate those micro-
bacteria to produce foods and biotechnological products (Samson bial communities associated with pathobiomes. Understanding
and Moineau, 2013). Although similar studies in the field of the internal processes of microbial communities is necessary to
therapeutics are lacking, it is also hoped that knowledge of phage– enable predictive modeling of ecological dynamics of microbial
bacterium dynamics will eventually contribute to our ability to communities. Such predictive models can provide guidance for
manipulate our own microbiota by using adapted phages as bio- strategies aiming to manipulate communities in plants or animals
control agents. Within this context, the use of phage therapy has and modulate their pathogenicity.
recently received renewed interest in an effort to solve those prob-
lems in human therapy linked to antibacterial resistance (Samson SELECTIVE FORCES, SUCH AS ENVIRONMENTAL AND
et al., 2013). HUMAN-MEDIATED DISTURBANCES, SHAPE VIRAL, AND BACTERIAL
Individual microorganisms evolve in the context of a com- PATHOBIOMES
munity. In many ways, the evolution of a microorganism is The emergence of socially/economically relevant diseases is likely
influenced by selection pressures exerted by other microorgan- to be frequently linked with ecological disturbances caused by
isms in the community. Mutation and gene flow are responsible human intrusions into natural ecosystems (Anderson et al., 2004;
for the creation of new genetic variants within populations. In Jones et al., 2008). Displacement of natural plant and ani-
addition, natural selection and genetic drift act by maintain- mal species by intensive agriculture (Malmstrom et al., 2005a)
ing, increasing, or decreasing the frequency of these new genetic or anarchic urban developments, including disturbances associ-
variants within populations. These processes shape the genetic ated with unmanaged sewage (Dinsdale et al., 2008), pollutants
composition of bacterial communities as well as their functional and/or radioactivity, are all important subsets of those intru-
properties. The transfer of genetic information between species sions that represent fundamental disturbances in the diversity
is a central and original mechanism of generating genetic diver- and in the evolutionary dynamics of viral and bacterial commu-
sity in microbial communities (Hacker and Kaper, 2000; Ochman nities inhabiting natural ecosystems. For instance, studies have
et al., 2000). For example, bacterial species can exchange large shown that invasive exotic annual grasses can indirectly increase
regions of DNA potentially linked to pathogenicity (Censini barley and cereal yellow dwarf virus (B/CYDVs) disease inci-
et al., 1996) as exemplified with Edwardsiella tarda, an enter- dence in California native perennial bunchgrasses (Malmstrom
obacterium causing fatal disease in fish. Genomic comparison et al., 2005b). Beyond this example, the numbers of situations
between pathogenic and non-pathogenic strains indicated that in which introduced domesticated plants/animals come into con-
disease-causing strains possessed two pathogenic islands of Type tact for the first time with indigenous viruses or bacteria from
VI and Type III secretion systems, which were absent in harm- native plants/animals, have dramatically increased alongside the
less strains. The Type III secretion system is homologous to the intensification of human activities.
enterocyte effacement locus in enteropathogenic and enterohem- Molecular biology techniques such as molecular typing
orrhagic Escherichia coli. Evolutionary analysis indicated that this and, more recently, metagenomics, have led to considerable
locus was integrated into the E. tarda genome through horizon- progress in understanding adaptive responses of pathogen pop-
tal transfer from E coli (Nakamura et al., 2013). The architecture ulations to human-mediated disturbance. For instance, studies
of communities, which dictates the phylogenetic proximity of of Staphylococcus aureus populations have provided examples of
microbes, affects the probability of gene exchanges. A trait can how human activities can change a population structure, induc-
thus sweep through a microbial community under appropriate ing adaptation of the pathogen to a new host species. Comparative
selection pressure, resulting in strong functional implications, genomics clearly links genomic- and phenotypic-characteristics
such as pathogenicity or the capacity to infect different host with host adaptation, and reveals that major animal-associated

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Vayssier-Taussat et al. The new pathobiome concept

clones most likely emerged after a human-to-animal host jump, control strategies aiming for better efficacy against the target
followed by subsequent adaptive evolution. S. aureus transmis- pathogen(s).
sion from human to bovine hosts was thought to have occurred
∼5500 years ago, during the Neolithic revolution and the expan- BARRIERS AND CONSTRAINTS TO PATHOBIOME STUDIES
sion of agriculture throughout the Old World (Weinert et al., The barriers to the development of pathobiome studies are
2012). Similarly, the current predominantly poultry-associated both methodological (most likely common to other ecosystems)
clones have most probably emerged after a human-to-poultry and conceptual. Regarding the methodological barriers, they
host jump (Lowder et al., 2009), estimated to have occurred ∼50 pertain to:
years ago (Weinert et al., 2012), and which rapidly disseminated
worldwide thanks to the globalization of the poultry industry • the sampling and sample treatment strategies used to obtain
(Lowder et al., 2009; Fitzgerald, 2012). reliable qualitative and quantitative inventories of microbial
Strong environmental pressures can also shape pathobiomes, diversity in biological samples (plants, animals, arthropods
and turn otherwise pathological interactions into mutualistic or other relevant ecosystems); the unbiased purification and
relationships. In extreme environments, such as in geothermal amplification of nucleic templates (DNA, RNA) (Kim and Bae,
soils in Yellowstone National Park, evolution has selected plants 2011), and the preparation of balanced pools during multiplex-
that harbor fungal endophytes infected with a virus, and all ing. Targets for sequencing will be microorganism-dependent,
three partners are required for thermal tolerance of the system with different and specific problems linked to viruses, bacteria,
(Marquez et al., 2007). and parasites.
Classical molecular biology approaches have shed light on • the scaling up of these methods for deeper sequencing, and/or
the role of environmental and human-mediated constraints on the analysis of larger numbers of biological samples obtained
single microbe species or very limited groups of species, but from contrasting environmental conditions to achieve ade-
cannot fully account for the structure and evolution of entire quate coverage and unbiased microbe identification (Fichot
pathobiomes in response to selective pressures. Pioneering stud- and Norman, 2013; Wendl et al., 2013), to allow comparative
ies have recently generated insights into interactions occurring analyses, and to identify factors that structure microbial com-
within the pathogen-host-microbiome “ménage à trois” (Pedron munities. Thorough comparative analyses require that sample
and Sansonetti, 2008) but in-depth analyses are necessary to are identified through a standard for minimum information
better understand the impact of selective pressures on the interac- (Yilmaz et al., 2011).
tions between the three players, which can result in the pathogen • bioinformatic data analysis: many bioinformatic approaches
acquiring new functions by horizontal gene transfer or convergent and tools are available (software, computing platforms, and
evolution. These interactions may ultimately lead to the occur- pipelines), (Prakash and Taylor, 2012) but so far any real com-
rence of new, more virulent variants, or even to the emergence parative evaluation of these tools or concerted efforts toward
of new diseases due to the combination of synergistic/antagonist their improvement are still largely lacking. In addition, these
phenomena between different pathogens and non-pathogens tools are often also poorly accessible to pathology laboratories,
(fungal, bacterial, or viral) in mixed or reconstructed communi- which are traditionally focused on single agent issues, partic-
ties. In contrast, the acquisition of new functions by the pathogen ularly in project development stages. Finally, long-term data
may reduce pathogenesis or even increase host tolerance, result- storage and communication/collaboration/datasharing issues
ing in a shift toward mutualism. This has been demonstrated for remain of importance.
several acute viruses inducing drought tolerance, an important • tool development for functional pathobiome analysis, in par-
trait in a changing environment, or for the Cucumber mosaic virus ticular the statistical analysis of relationships between the
which confers cold tolerance in red beets (Xu et al., 2008). pathobiome and pathogenesis. Comprehensive metadata anal-
Thus metagenomics might help decipher the mechanisms ysis, mathematics, and statistics are required to extract the
involved in pathobiome evolution in response to multiple factors: relevant information.
• modeling approaches to analyze the interactions between
• host factors (e.g., host diet, immune status, host jumps, microorganisms, and their impact on pathogen transmission
changes in vectors/reservoirs, etc.), are still lacking.
• human activity driven factors, such as implemented control
strategies (e.g., culture or seed treatments, antibiotic prophy- In parallel with these methodological barriers, researchers inter-
laxis, etc..), as well as cropping practices or breeding condi- ested in the “pathobiome” face conceptual hurdles which must
tions, which can all directly impact both pathogens and the be overcome. New sequencing technologies have shifted the study
ecosystem in which they reside, focus from the organism to the community of pathogens and
• environmental factors (e.g., global warming, abiotic stress other microbes within their environment. Such an expanded
imposed on the host(s), vector(s) or reservoir(s), location of point of view results in a paradigm shift, in that the “pathogen”
the host(s) in developed or wild areas etc.). is no longer understood to be a single isolated organism. It is
therefore vitally important to integrate ecological and evolution-
A better understanding of the forces structuring pathogen popu- ary concepts of microbial communities to be able to fully grasp
lations (including pathogen plasticity and their interactions with the roles that ecosystem composition and structure play in the
the host and its microbiota) have the potential to rejuvenate emergence of pathogens and the expression of virulence (Rogers

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Vayssier-Taussat et al. The new pathobiome concept

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10.1038/nrmicro3096 This article was submitted to the journal Frontiers in Cellular and Infection
Samson, J. E., and Moineau, S. (2013). Bacteriophages in food fermentations: new Microbiology.
frontiers in a continuous arms race. Annu. Rev. Food Sci. Technol. 4, 347–368. Copyright © 2014 Vayssier-Taussat, Albina, Citti, Cosson, Jacques, Lebrun, Le Loir,
doi: 10.1146/annurev-food-030212-182541 Ogliastro, Petit, Roumagnac and Candresse. This is an open-access article distributed
Santos, F., and Anton, J. (2011). “Viral metagenomics and the regulation of under the terms of the Creative Commons Attribution License (CC BY). The use, dis-
prokaryotic communities,” in Metagenomics, ed D. Marco (Norfolk: Caister tribution or reproduction in other forums is permitted, provided the original author(s)
Academic Press), 33–47. or licensor are credited and that the original publication in this journal is cited, in
Schoch, C. L., Seifert, K. A., Huhndorf, S., Robert, V., Spouge, J. L., Levesque, C. accordance with accepted academic practice. No use, distribution or reproduction is
A., et al. (2012). Nuclear ribosomal internal transcribed spacer (ITS) region as permitted which does not comply with these terms.

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