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Molecular Microbiology (2007) 65(3), 583–589
doi:10.1111/j.1365-2958.2007.05826.x
First published online 3 July 2007
MicroOpinion
Bacteria between protists and phages:
from antipredation strategies to the evolution
of pathogenicity
Harald Brüssow*
Chemin de la Chaumény 13, CH-1814 La Tour de Peilz,
Switzerland.
Summary
Bacteriophages and protists are major causes of
bacterial mortality. Genomics suggests that phages
evolved well before eukaryotic protists. Bacteria were
thus initially only confronted with phage predators.
When protists evolved, bacteria were caught between
two types of predators. One successful antigrazing
strategy of bacteria was the elaboration of toxins that
would kill the grazer. The released cell content would
feed bystander bacteria. I suggest here that, to fight
grazing protists, bacteria teamed up with those phage
predators that concluded at least a temporary truce
with them in the form of lysogeny. Lysogeny was
perhaps initially a resource management strategy of
phages that could not maintain infection chains.
Subsequently, lysogeny might have evolved into
a bacterium–prophage coalition attacking protists,
which became a food source for them. When protists
evolved into multicellular animals, the lysogenic bacteria tracked their evolving food source. This hypothesis could explain why a frequent scheme of bacterial
pathogenicity is the survival in phagocytes, why a
significant fraction of bacterial pathogens have
prophage-encoded virulence genes, and why some
virulence factors of animal pathogens are active
against unicellular eukaryotes. Bacterial pathogenicity might thus be one playing option of the
stone–scissor–paper game played between phages–
bacteria–protists, with humans getting into the
crossfire.
predation (Brüssow, 2007). Eating is in a way the first
commandment of the laws of thermodynamics imposed
on organisms. If you do not eat, you will starve to death
(with the loss of your somatic cells), and if you do not find
a mate, your germ cells are lost. The interest in food is
perhaps the most vital force in biology because sexual
organisms evolved relatively late in evolution, coincident
with the appearance of eukarya.
Eating
When investigated at a biochemical level, microbes
collectively demonstrate metabolic capacities that dwarf
that of animals (Lengeler et al., 1999). Animals are in the
terminology of feeding modes chemoorganoheterotrophs,
which is but one of the four major nutritional types of
microorganisms. Even when each bacterial species
masters only a small part of this biochemical versatility,
they have learned to complement their biochemical shortcomings in many nutritional interactions with their physical
and biological environment. Bacteria are the inventors of
photosynthesis, they discovered N2 and CO2 fixation, and
methanogenesis evolved in Archaea. These processes go
well beyond feats of nutritional biochemistry and represent key chemical reactions of geochemical importance.
Bacteria have also found creative solutions to starvation.
When leaving exponential growth in a rich medium,
bacteria go into a stationary growth phase, which, in the
laboratory, leads relatively quickly to cell death. However,
many bacteria in nature are chronically on a small diet
(Rappe et al., 2002); they do not divide very frequently
(from once in a month to a year in the ocean or the
sediment, respectively, Schippers et al., 2005), and are
thus exquisitely adapted to long-term survival in the relative absence of food. Only few animals have comparable
starvation solutions (e.g. tardigrade’s anabiosis state).
Three driving forces explain the behaviour of many organisms: the quest for food and for sex, and the avoidance of
Predation
Accepted 8 June, 2007. *For correspondence.
[email protected]; Tel. 0049 21 944 34 24.
In nature, starvation is therefore a less likely cause of
death for bacteria than predation. One predator is smaller
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd
E-mail
584 H. Brüssow
Fig. 1. Phage–bacterium interaction. The
attack of a bacteriophage on a Gram-positive
bacterium is documented in a time series of
electron microscopy ultrathin sections of
Lactobacillus plantatum infected with a large
Myovirus of the SPO1 phage family.
A and B. Phages with empty and full head
adsorbed to the target cell.
C. Demonstrating how the phage crosses with
its tail structure the large cell wall to inject its
DNA into the cytoplasm.
D and E. Cytopathic effects with convoluted
membrane systems developing in the infected
cell.
F. The breakdown of the cell wall and the
release of the cytoplasm (G). The figure is
from Chibani-Chennoufi et al. (2004), with
permission from American Society for
Microbiology.
than bacteria: these are viruses that carry the telling name
bacteriophages (‘bacterium eaters’) (Fig. 1). Phages are a
global player (Fuhrman, 1999): it is currently estimated
that 90% of the ocean biomass is prokaryotic and that
phages lyse about 20% of the bacterial biomass every
day (Suttle, 2006). The other big killer is protozoa, singlecelled eukaryotes that graze on bacteria (Sherr and Sherr,
1987). Over long averages, phages and protozoa each
cause about half of the bacterial mortality, but at any given
time point and specified place, either one or the other
predator might dominate the bacterial killing (Fuhrman
and Noble, 1995, Suttle, 2006). Phages and protozoa
leave few room for predator bacteria such as Bdellovibrio,
individual hunters that drill a hole into their bacterial prey
and multiply intracellularly somewhat like phages (Sockett
and Lambert, 2004), or myxobacteria that show a wolf
pack-foraging strategy by socially secreting digestive
enzymes on their bacterial prey.
origin (Forterre, 2006). For example, the genome of
Escherichia coli phage T4 is certainly not derived from
its bacterial host: the guanosine-cytosine content of the
two genomes differs dramatically, only few T4 and E. coli
proteins share sequence similarity, but on tree analysis,
they are placed on branches that diverged before the
separation of bacteria from eukarya (Miller et al., 2003).
It is thus not farfetched to surmise that some phages are
as old as bacteria. In fact, one might even speculate that
some phages (note that phages are not monophyletic)
might derive from ‘life’ forms that predate LUCA, the last
universal common ancestor, which is postulated at the
root of the universal tree of life. The genomes of phages
are so varied, covering double- and single-stranded
DNA and RNA, that one gets the impression that they
are remnants of genomes at an experimental stage
before LUCA settled for double-stranded DNA as the
universal genetic repository (Forterre, 2005).
Antiquity arguments
Arms race
Bacteria are collectively very old; their origin goes back
3 billion years ago. At that time, prokaryotic Archaea
were around, but not eukaryotic grazers. Archaea are
very special: as far as we know, they never tried out
photosynthesis, they did not develop into pathogens,
and they do not prey on bacteria. Thus, for half of their
evolutionary history, bacteria were apparently without
major predators – but was this really the case? This
picture of a predator-free Arcadia is probably incorrect.
Bacteriophages do not leave fossils, but genome
sequencing of bacteriophages points to their ancient
Long before Darwin, the book of Genesis formulated,
apparently overlooked by creationists, the basic principles
of modern biology: ‘be fruitful and multiply’ and ‘replenish
the earth and subdue it and have dominion over every
living thing that moveth upon the earth’ are poetic formulations of the selfish gene concept. However, Nature has
built-in checks and balances to prevent uniformity in life.
Monoculture has the inherent risk of narrowing genetic
diversity, which could lead to the extinction of entire ecosystems in a changing world. The essence of biology is
genetic variability such that Nature still has promising
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd, Molecular Microbiology, 65, 583–589
Bacteria between protists and phages 585
models up her sleeves to cope with the most dramatic
environmental changes. Predation has important biological functions to maintain variability. Let’s again look to the
T4/E. coli couple. To escape infection, bacteria must
sense the presence of foreign DNA within their cytoplasm
and destroy this alien DNA. Fittingly, one hot spot of
genetic variability between E. coli strains is in restriction/
modification genes (Milkman, 1999), which distinguish
between genetic self and non-self and destroy invading
DNA not carrying the appropriate modification signals. T4
phage has an answer to this onslaught – it contains one of
the most heavily modified DNA genomes known and is
resistant to the action of most restriction endonucleases
(Karam, 1994). The arms race is on. Let’s take another
example: the receptor for many T4 phages on the E. coli
cell is the surface-exposed lipopolysaccharide (LPS)
molecule (Karam, 1994). The bacterium can thus escape
from its phage predator by changing the chemical identity
of LPS. It is probably not a chance event that a second hot
spot of genetic diversity between E. coli strains is in the
LPS genes (Milkman, 1999). In T4-like genomes, the antireceptor genes are likewise a hot spot of genetic diversification (Tétart et al., 1998) – again we see the genetic
footprints of an arms race.
Truce
However, Nature has also inbuilt safeguards that allow
some organisms a temporary rest from this genetic arms
race. Low-abundance bacteria can become invisible to
their predator phages when they slip under a critical
threshold of 104 specific cells per millilitre (Wiggins and
Alexander, 1985). Marine ecologists developed the ‘killing
the winning population’ concept (Wommack and Colwell,
2000). Phages amplify only on the successfully outgrowing clone thriving to numerical dominance in a given ecological setting. Phages force down the winner and, as they
cannot attack minority clones, phages thereby enforce
genetic diversity in the environment. The threshold is also
in the interest of phages, as it also prevents an overzealous phage from driving its host, and thereby also itself, to
extinction.
There is a second safeguard to phage overkill: as
phages cannot multiply well in starved cells (Los et al.,
2007), the malnourished cell is spared from death.
Phages that happen to infect a starved cell can go into a
kind of dormancy (pseudolysogeny in T4) until bacteria
resume growth with the arrival of new food. E. coli phage
lambda goes a step further by integrating its genome as a
prophage into the bacterial chromosome. Lysogeny gives
the phage a rest from the ‘divide et impera’ lifestyle of
virulent phages and a long-term chance for survival under
conditions not allowing to maintain an uninterrupted infection chain.
Coexistence
Ironically, phage lysis increases bacterial growth by
feeding non-infected bacteria with the cell content
released by the infected cell (microbial loop) (Wommack
and Colwell, 2000). DNA from decaying bacteria and their
phages can become an important N and P source for
bacteria that have found a good C source (e.g. Vibrio on
copepod exoskeletons). Vibrio might develop competence
primarily for nutrition and only secondarily for genetic
variation (Meibom et al., 2005). In contrast, if bacteria are
grazed by protists, most of their biomass is shifted to
animals further up in the food chain.
Lysogeny is more than a temporary peaceful coexistence between phage predator and bacterial prey. By
becoming part of the bacterial chromosome, the prophage
takes a new genetic identity. If it wants to get a lift by the
bacterial cell as a hitchhiker, it must cooperate (Canchaya
et al., 2003). We should not be surprised to learn that
phages carry useful genetic functions for the bacterial cell.
In Firmicutes, these lysogenic conversion genes are frequently located near the phage attachment site and might
be the result of imprecise excision of the prophage from
the previous bacterial genome. As phages are not tightly
limited by species boundaries (Pajunen et al., 2001), the
bacterial cell can explore a much larger DNA sequence
space with phages than they can with conjugative
plasmids.
There is indeed good circumstantial evidence that
phages had a major impact on the evolution of bacterial
chromosomes (Canchaya et al., 2004). In addition,
phages have spread photosynthesis genes between their
bacterial hosts and have thus influenced the evolution of
photosynthesis (Sullivan et al., 2006). Finally, bacterial
pathogenesis has apparently evolved with the help of
phages (Brüssow et al., 2004). To appreciate the latter
link, we must go back 1.5 billion of years.
Antigrazing strategies
Palaeontologists dated the first ecologically diversified
protist world at about 1.5 billion years ago (Javaux et al.,
2001). Then, a new situation emerged for bacteria: both
viral lysis and protist grazing now threatened them. After
being engaged in a long arms race with phages, bacteria
had to ‘design’ strategies against grazing protists (Fig. 2).
Molecular data support the antiquity of the interaction
between bacteria and amoeba: intracellular chlamydiales
encode an enzyme that steals ATP from amoeba. This
bacterial gene diverged c. 1 billion years ago at the
eukaryotic radiation time (Greub and Raoult, 2003). If you
look into contemporary ecosystems, you see that bacteria
have found a number of solutions to the protist problem
(Matz and Kjelleberg, 2005). Small protozoa prefer prey
in the 1–3 mm size range. Growing to oversize helped
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd, Molecular Microbiology, 65, 583–589
586 H. Brüssow
as an antipredation strategy. These bacteria become
unpalatable, and protists reject the prey a few minutes
after their ingestion. Armour makes you clumsy – so other
bacteria use instead high motility combined with small
size to reduce their grazing mortality. In our context, the
most interesting antipredation strategy is toxin production.
The bacterium is ingested and releases the toxin after
digestion. Ingestion of a few toxin-producing bacteria can
kill the predator protist, which then releases its cytoplasm
into the medium, which then feeds the bacteria in the
vicinity of the protist (Matz et al., 2004). Such an altruistic
behaviour is theoretically possible in a clonal bacterial
population. In this way, an antipredation strategy even
opens up a new and rich food source. This double advantage would actually represent a strong positive selection
for toxin-carrying bacteria. With respect to toxin production, it seems that bacteria have teamed up with their old
predator phage against the new protist predator.
The origin of bacterial pathogenesis
Fig. 2. Protist–bacterium interaction.
Top: Uninfected Acanthamoeba trophozoite as seen by electron
microscopy. 3500¥ magnification.
Centre: Acanthamoeba trophozoite in the process of phagocytosing
the ‘crescent body’ (arrow), the infectious development stage of
Parachlamydia acanthamoebae (strain Hall).
Bottom: Acanthamoeba trophozoite 36 h after infection with
Parachlamydia acanthamoebae (strain Bn9) (pictures kindly
provided by Gilbert Greub, Institute of Microbiology, University of
Lausanne, Switzerland).
bacteria to get out of the target zone. Another bacterial
solution to the grazing problem is based on masking. In
fact, amoeba need to recognize a surface structure on the
bacterial prey to start the phagocytosis process. Recent
experiments showed selective feeding of gut amoeba
on Salmonella belonging to different LPS serotypes
(Wildschutte et al., 2004). Bacteria could here again play
the same trick they used to escape from phage predation,
namely by varying LPS surface molecules. Armour is
another solution against predation, and the protein
S-layer surrounding many bacteria has been interpreted
As protists gave rise to animals, the phage–bacterium
coalition was carried into animals. In fact, there is some
circumstantial molecular evidence that choanoflagellate
protists are at the root of the metazoa tree (King and
Carroll, 2001) and that choanoflagellates gave rise to
choanocytes in sponges. Interestingly, sponges suffer
remarkably little damage from microbial infections. They
probably owe this resistance to two principles: antimicrobial chemicals that they elaborate, and amoebocytes that
patrol the sponge body for invading microbes apparently
since Precambrian times (Li et al., 1998). Amoebocytes
resemble amoeba protists morphologically, and the
phagocytosis feeding mode is the same in both cell types
(Fig. 3). This antibacterial patrol system of an animal body
was so successful that it was maintained in higher
animals. Amoeba-like phagocytes travel through our body
and screen it for bacterial intruders, and are actively
called to sites of bacterial invasion.
Recall, however, that some bacteria have learned to
defy phagocytic protists and even to use them as food
source (Fig. 2). With the evolution of higher organisms,
bacteria have tracked animals as a suitable food source
(Brüssow, 2007), leading to the evolution of bacterial
pathogenicity. Notably, a major theme of bacterial pathogenicity is the survival of the ingested bacterial pathogen
within phagocytes (Boneca et al., 2007). It is thus not
farfetched to postulate that bacterial pathogenicity
evolved from the antipredation/food quest conflict
between bacteria and protists. In support of this hypothesis is the observation that pathogenic bacteria frequently
target very fundamental cellular processes that have a
complement in protists. Indeed, medical microbiologists
can study pathogenesis using amoeba as model systems,
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd, Molecular Microbiology, 65, 583–589
Bacteria between protists and phages 587
Fig. 3. A mammalian neutrophil white blood cell has engulfed a bacterium in a phagocytic vacuole (panel A white frame). Subsequently,
intracellular granules fuse with the phagosome and discharge their contents (arrows) to form a phagolysosome (B). In addition to this
intracellular killing mechanism, activated neutrophils release fibres called neutrophil extracellular traps that fix and kill bacteria and yeasts (C).
The picture is from Urban et al. (2006), with permission from Blackwell Publishing.
demonstrating the antiquity of these interactions
(Molmeret et al., 2002). Similarly, cell biologists can study
some aspects of cancer in microbial yeast cells.
Phages have played an important role in this process,
as revealed by prophage genomics. I will illustrate this
with two examples. Prophages from Streptococcus pyogenes encode a hyaluronidase that facilitates spread of
the bacterium along the connective tissue of the patient
(‘flesh eating bacterium’), prophage DNase destroys neutrophil extracellular traps (Fig. 3) that should immobilize
invading bacteria (Sumby et al., 2005), and finally a large
number of prophage-encoded superantigens overstimulate the immune system, thereby effectively paralyzing
its action against the invader (Banks et al., 2002).
Prophages from Staphylococcus aureus encode toxins
(e.g. PVL) that induce apoptosis in neutrophil leucocytes
(Genestier et al., 2005). Some S. aureus prophages
include a battery of genes against the body defence
collectively known as an immune evasion cluster (Van
Wamel et al., 2006). This cluster includes an enterotoxin,
which downregulates a chemokine binding site on monocytes; a staphylokinase, which binds defensins; a chemotaxis inhibitor (CHIPS); and a complement inhibitor (SCIN)
(Rooijakkers et al., 2005). Here, prophages direct a coordinated assault on the immune system of the human and
animal host. This is certainly not an isolated case. Prophages from enteropathogenic and enterohaemorrhagic
E. coli, as well as from Salmonella typhimurium, help
orchestrate the takeover of the enterocyte in the mammalian and avian intestine (Tobe et al., 2006). In other cases,
the very toxin that causes the characteristic symptom of
the infectious disease is prophage-encoded: cholera toxin
and diphtheria toxin are famous examples (Waldor and
Mekalanos, 1996). Thus, it seems that bacteria sandwiched between two predators, namely phages and
protist grazers, recruited the predator that concluded at
least a temporary truce with them (prophages) to fight the
protist grazers. Phages had already experience with this
strategy, as they must elaborate antipredation measures
against superinfecting phages (‘immunity functions’) to
avoid sharing their bacterial food source with other
parasites. In association with their host bacterium, phages
opened up new food sources for themselves by feeding
the lysogenic bacterium. Prophages became popular in
some bacterial pathogens; some strains of the E. coli
O157:H7 food-borne pathogen carry so many prophages
(n = 18) that one can nearly speak of a phage in bacterial
disguise (Fig. 4), underlining the intimate coalition
between phages and bacteria.
Outlook
As nature is very playful, evolution is never a one-way
road. Some protists have discovered that, capturing
bacteria as metabolic slaves, instead of digesting them,
might be even more profitable. In this way, cyanobacteria
probably became the chloroplasts of photosynthetic
eukaryotes. Becoming an intracellular bacterium relieved
the phage predation pressure: while cyanobacteria are
the vulnerable prey of many cyanophages (Angly et al.,
2006), viruses that infect chloroplasts are not known.
Bacteria resisting amoeba found in their eukaryotic host
a widespread aquatic reservoir, an evolutionary crib to
evolve genes that allowed them to later resist human
macrophages and a shelter when enclosed inside the
amoeba cyst (Greub and Raoult, 2004). Apparently, just
going from two- to three-player relationships in the evolutionary predator–prey game opens up numerous stone–
scissor–paper playing options. These are not necessarily
theoretical games. Evolutionary thinking in medicine
(‘Darwinian medicine’) might actually also lead to new
practical approaches exploring infection control with
phages (‘phage therapy’) or domesticated bacteria
(‘probiotics’ in bacterial replacement therapy).
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd, Molecular Microbiology, 65, 583–589
588 H. Brüssow
Fig. 4. A phage in bacterial disguise? The
graph shows from the inside to the outside
the genomes from the enterohaemorrhagic
E. coli strains O157 Sakai and EDL933, the
laboratory E. coli strain K-12 and the
uropathogenic E. coli strain CFT073. All
contain multiple prophage sequences
(depicted as red rectangles proportional to
their size). The figure is from Canchaya et al.
(2003), with permission from American
Society for Microbiology.
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