The term holobiont (Greek, from holos, whole; bios, life; -ont, to be; whole unit
of life) describes a long-term physical association between different living organisms
[1]. Theoretically, this definition encompasses all symbiotic associations (along
the mutualism–parasitism continuum) spanning all taxa. However, in most cases, the
term holobiont is restricted to the host and its associated mutualistic symbionts.
The hologenome theory of evolution considers that the holobiont is the unit under
natural selection in evolution [2], [3]. I argue that this opens new perspectives
on the study of host–parasite interactions. Evidence suggests that all of the diverse
microorganisms associated with the host and parasite play a part in the coevolution.
This new paradigm has the potential to impact our comprehension of the development
and evolution of disease.
It has been established in different model species that immune system maturation requires
the presence of mutualistic bacteria [4]–[6]. The tsetse fly Glossina moritans carries
an obligate mutualist, the bacteria Wigglesworthia glossinidia, which is necessary
for maturation of the immune system during development [6], [7]. In vertebrates, species-specific
gut bacteria are necessary for the maturation and the maintenance of a healthy immune
system [4], [8]–[13]. Organisms are associated with a great variety of microorganisms,
including viruses and unicellular eukaryotes, and we are starting to realize that
they also play an important role in shaping a healthy immune system [14]–[16].
Thus, symbionts indirectly protect the host against various pathogens via immune activation
(Figure 1A, 1B). In some cases, even parasites improve the fitness of their host;
this process is called conditional mutualism [17]. For example, the hepatitis G virus
limits the progression of HIV to AIDS [18], [19], the hepatitis A virus suppresses
infection by the hepatitis C virus [20], and the murine cytomegalovirus protects mice
against infection by Listeria monocytgenes and Yersinia pestis
[21].
10.1371/journal.ppat.1004093.g001
Figure 1
Role of microorganisms associated with the host or the parasite in the host–parasite
interaction.
(A) Host–parasite interaction without associated microorganisms. (B) Host-associated
microorganisms participate indirectly in the immune defense by promoting immune system
maturation. (C) Host-associated microorganisms participate directly in the immune
defense. (D) Parasite interferes with host-associated microorganisms. (E) Parasite-associated
microorganisms participate in the disease.
Host-associated microorganisms also contribute directly to the defense against pathogens
(Figure 1C). The bacteriophage carried by the bacteria Halmitonella defensa, Acyrthosiphon
pisum secondary endosymbiont (APSE) is a conditional mutualist of the pea aphid A.
pisum
[22]–[24]. It encodes toxins targeting the developing larva of the parasitic wasp
Aphidius ervi
[25], [26]. Human gut bacteria directly antagonize bacterial pathogens by producing
antibacterial factors, by competing for elements necessary for pathogen growth (competitive
exclusion), and by limiting their adhesion to host cells [9]. In addition, mucus-associated
bacteriophages participate in the first line of defense against bacteria in various
species, from cnidarians to mammals [27]. Thus, the “holo-immunome” must be studied
for a comprehensive understanding of host resistance to infections.
Host-associated microorganisms are also affected by parasitosis (Figure 1D). In the
coral Oculina patagonica, infection by Vibrio shiloi induces coral bleaching by directly
attacking the photosynthetic microalgal endosymbionts [28], [29]. Symbiotic bacterial
communities associated with the lichen Solorina crocea are also affected by the fungal
parasite Rhagadostoma lichenicola
[30]. HIV and SIV infections are frequently associated with gastrointestinal disorders
that can be explained by an alteration of the gut microbial community [31]–[33]. As
discussed above, such disruptions of host–symbiont interactions favor pathogenesis,
therefore indirectly participating in the disease.
Finally, parasites are also associated with microorganisms that will directly benefit
from an improved fitness of their parasitic host. These symbionts can directly participate
in the disease caused by the parasite (Figure 1E). For instance, parasitoid wasps
of the Ichneumonidae and Braconidae families have independently evolved mutual associations
with DNA or RNA viruses (unpublished work) and play an essential role in the parasite's
success and evolution [34]–[35]. Entomopathogenic nematodes are associated with bacteria
that produce toxins that help degrade tissues for the nematode to feed on [36], [37].
Similarly, the plant-pathogenic fungi Rhizopus sp. has an endosymbiotic bacteria that
produces toxins that have a key role in the disease [38].
Until recently, the role of parasite-associated microorganisms in human diseases had
been underestimated, but examples are now starting to emerge. The Leishmania RNA virus
promotes the persistence of Leishmania vienna parasites by inducing a TLR3-mediated
inflammatory response that renders the host more susceptible to infection [39]. Similarly,
Trichomonasvirus, an endosymbiotic of the protozoan parasite Trichomonas vaginalis
is responsible for the strong proinflammatory response that causes preterm birth [40].
Microorganisms associated with such medically important parasites can now be targeted
to limit the impact or development of the disease.
The theoretical framework provided by considering not only the host but also the parasite
as a holobiont revealed that some interactions have been underestimated and others
have not yet been explored. For example, can microorganisms associated with the host
directly interact with microorganisms associated with the parasite? Can the host defend
itself against infection by recognizing the microorganisms associated with the parasite?
Can parasite-associated microorganisms indirectly promote the disease (by increasing
its fecundity, for example)? Parasitologists, microbiologists, and immunologists have
the monumental task of revealing the myriad interactions occurring between holobiont
hosts and holobiont parasites. This knowledge promises to greatly impact our ability
to develop new treatments and therapies.
These interactions within interactions have major implications for ecologists and
evolutionary biologists, because any host–parasite interaction will be dependent on
all other interactions in the system [41], [42]. The short generation time of microorganisms,
along with the genetic diversity and novelty they provide [43], [44], can play an
important role in the adaptation and evolution of hosts and parasites in their evolutionary
arms race [45]. This coevolution may also be driven by fluctuating selection [46],
in which hosts and parasites interact with different microorganisms over thousands
of years, constantly evolving to favor the most advantageous symbiont at the time.
In addition, associated microorganisms may be pathogenic to non-adapted individuals
and drive speciation [35], [47], [48]. Thus, the study of microorganisms associated
with hosts and parasites is no longer optional; it is, rather, an obligatory path
that must be taken for a comprehensive understanding of the ecology and evolution
of hosts and parasites. It is a necessary step for the prevention and prediction of
disease outbreaks.