When immunologists study infections,
we often assume that the host’s defence
strategy involves mechanisms that directly
attack the pathogen to block invasion or
eliminate the invading microorganism.
However, the host can also defend itself
by limiting the damage that is caused by
the infection. Resistance is defined as the
ability to limit pathogen burden, whereas
tolerance is defined as the ability to limit the
health impact of a given pathogen burden.
Tolerance includes all of the mechanisms
that regulate the self-harm that can be
caused by an immune response (known as
bystander damage or immunopathology)
and other mechanisms that are not directly
related to immune resistance. The sum of
resistance and tolerance defines a host’s
defensive capacity. Although a great deal
is known about the molecular mechanisms
that are used to kill pathogens and prevent
infection, a systematic understanding of how
a host regulates the production, repair and
avoidance of the damage that accumulates
during an infection is limited. By broadening
the scope of our studies, we should be able to
identify more of these tolerance mechanisms,
which could aid the diagnosis and treatment
of patients. In this Opinion article, we pro-
pose that we can provide a structure for this
emerging field by borrowing some concepts
from evolutionary biology.
Resistance and tolerance in plants
The concept of a two-component defence
response — involving resistance and tolerance
— is well described by plant ecologists to
assess plant health in pathogen–plant inter-
actions1–5. Reaction norms are a measurement
of the phenotypes for a given genotype across
a range of environments and they are used in
the fields of ecology and evolutionary biology
to measure how an individual responds to
a range of environmental conditions (FIG. 1).
Plant ecologists have adapted this method
to assess the fitness of a plant (for example,
in terms of seed production) in response to
a measurement of pathogen load, be it the
damage that is induced by the pathogen or
the host response to it, or the actual number
of pathogens in the host6. In this context,
resistance is defined as the inverse of the
pathogen burden; when resistance increases,
the pathogen load will decrease. Tolerance
is defined by the slope of the reaction norm;
that is, the more tolerant the host, the flatter
the slope7–8. In other words, plants that are
more tolerant to infection will have a smaller
decrease in their overall health as pathogen
burden increases compared with less tolerant
plants. By using the slope of the relationship
between health and pathogen load, it is easy
to compare populations that differ in their
health before they were infected (a property
known as vigour).
This model has much to offer for our
understanding of defence mechanisms
against pathogens in animals. In vertebrate
models of infectious diseases, we rarely
carry out such analyses and it is practically
impossible to do this for actual patients.
However, the logic behind this type of
analysis could be useful because resistance
and tolerance, as defined in this manner,
have exciting ecological and biomedical
This definition of tolerance is not new
to studies of vertebrate immunity but it is
certainly under-represented. By discussing
known examples of tolerance in animals
in this article, we hope to reignite interest
and encourage a broader application of the
concept of tolerance to vertebrate models
of infectious disease. First, we speculate
on the types of physiology that could be
involved in mechanisms of tolerance in
animals and discuss evidence indicating
that these defensive measures are important
in defining the overall health of a host with
various types of infection. We then discuss
how the concept of tolerance can be studied
systematically and how it can be integrated
into medical practices.
What are the mechanisms of tolerance?
Immunologists are used to describing
resistance mechanisms in an organized
manner: an immune recognition event is
followed by the production of effectors,
which results in interactions between
immune cells. By contrast, although immuno-
pathology is a well-known result of an
immune response, its discussion is generally
organized around the resistance mecha-
nisms that generate the pathology, the
organism that is responsible for the disease
or the organs that are affected. Organizing
Two ways to survive infection: what
resistance and tolerance can teach
us about treating infectious diseases
David S. Schneider and Janelle S. Ayres
Abstract | A host can evolve two types of defence mechanism to increase its fitness
when challenged with a pathogen: resistance and tolerance. Immunology is a
well-defined field in which the mechanisms behind resistance to infection are
dissected. By contrast, the mechanisms behind the ability to tolerate infections
are studied in a less methodical manner. In this Opinion, we provide evidence that
animals have specific tolerance mechanisms and discuss their potential clinical
impact. It is important to distinguish between these two defence mechanisms
because they have different pathological and epidemiological effects. An
increased understanding of tolerance to pathogen infection could lead to
more efficient treatments for infectious diseases and a better description of
nATuRe RevIeWs | immunology
vOlume 8 | nOvemBeR 2008 | 889
A host’s health will decrease
as microorganisms reproduce
and drive pathogen load to
Immunocompromised hosts cannot
limit microbial growth, and this leads
to decreased health during infections
The resistance mechanisms of
the host will oppose microbial
growth and thus maintain health
the discussion of tolerance around three
different issues can make it difficult to find
commonalities between the immunopatho-
logical mechanisms that define tolerance. To
overcome this problem, we have organized
our discussion of tolerance mechanisms by
considering the effects that a mechanism
has on tolerance and resistance. We define
three classes of mechanisms that differ in
the strength of the association between
resistance and tolerance (FIG. 2). We consider
that a mechanism affects tolerance if it is
predicted to decrease or increase the slope
of the tolerance curve; it will be important
to understand both how to decrease the
mechanisms that increase the slope of the
tolerance curve and how to augment the
mechanisms that flatten the curve.
Class one. The distinguishing characteristic
of our first class of mechanisms is that it
comprises effector molecules that induce
resistance mechanisms that can cause self-
harm and as a result decrease tolerance, such
that resistance and tolerance are absolutely
linked and their effects are opposite. For
example, reactive oxygen species that are
produced during an immune response
are important for fighting infections,
but their activity can also induce severe
immunopathology and even death in some
cases, thereby decreasing tolerance9,10.
During evolution, we expect that there has
been selection for less toxic effectors and
receptors in the immune system; hosts have
probably evolved effector molecules, such
as antimicrobial peptides (AmPs), that
are less toxic to self than to pathogens11.
A similar selection must have occurred for
receptors that trigger immune responses,
for example, Toll-like receptors (TlRs),
thereby resulting in higher affinity of these
receptors for pathogen-associated molecules
than for self molecules12. This also happens
at an individual level over the lifetime of
animals that have an adaptive immune
response. What most immunologists call
tolerance — the elimination of self-reactive
T-cell receptors and antibodies — should
also increase tolerance according to the
ecological definition of this word. In all of
these examples, the factor that is required
to decrease pathogen load (and thereby
increase resistance) is the same factor that
causes immunopathology and increases the
slope of the tolerance curve (in other words,
Class two. In the second class of tolerance
mechanisms, we have placed regulators that
control both resistance and tolerance. We
have separated these from resistance effec-
tors because these signalling molecules do
not cause pathology directly, and so it might
be possible to separate their effects on resist-
ance and tolerance by selectively blocking
specific signalling pathways or signalling
in specific tissues. For example, tumour-
necrosis factor (TnF) is crucial for fighting
some infections because it activates immune
cells and thus has a pro-resistance function13.
At the same time, the damage that is induced
by effectors of the activated immune cells, as
well as additional pathology that is caused
by other targets of TnF, will decrease the
health of the host and therefore increase the
slope of the tolerance curve. These first two
classes provide examples of factors that are
predicted to show a trade-off between resist-
ance and tolerance.
Class three. Tolerance mechanisms that can
be easily separated from resistance mecha-
nisms form a third class. We suggest that this
group of mechanisms will provide the most
useful candidates when searching for new
drugs and treatments that modulate toler-
ance. We describe five examples here. First,
during an immune response to infection,
toxic compounds can be produced by the
host or pathogen that must be dealt with to
prevent damage to the host; for example, the
destruction of red blood cells during malaria
infection causes free haem (which is toxic
to the host) to enter the circulation. Haem
oxygenase 1 acts as a detoxifying enzyme of
haem14, and defects in this pathway would
cause a decrease in tolerance.
second, resistance responses can be
expensive in terms of energy expenditure,
and appropriate energy management is
required to fuel these responses without
causing irreparable damage to other systems
and to leave enough energy for repair. As
we discuss in more detail later, the fruit fly
Drosophila melanogaster exhibits altered
energy use and wasting of the body when
infected with Mycobacterium marinum, and
this seems to be due to decreased tolerance15.
Figure 1 | Definitions and implications of resistance and tolerance. A | resistance, which is a
measure of the ability of a host to limit pathogen growth and thereby maintain health, can be inter-
polated from these graphs as the inverse of the mean of the pathogen load. tolerance, which is a
measure of the ability of a host to survive an infection at a given pathogen load, is the slope of the
curve that relates host health to pathogen load. B | the slope that describes tolerance is not a fixed
property and can vary between strains and possibly even during an infection in one individual. shown
are three examples of how strains can differ in terms of tolerance and resistance to pathogen infec-
tion. Ba | these two strains have similar resistance profiles (mean pathogen load is the same) but the
strain shown in blue has stronger tolerance. Bb | In this hypothetical example, the two strains have
similar tolerance properties, but the strain shown in blue has weaker resistance. Bc | these two strains
have different tolerance and resistance properties. examples of different reaction norms have been
adapted from REF. 42.
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Nature Reviews | Immunology
Resistance and tolerance
are tightly linked
Resistance and tolerance have an
Resistance and tolerance
Third, we propose that processes that
prevent physiological damage will also affect
tolerance. some immune responses can
induce physiological changes that are delete-
rious for some organs. For example, sepsis
can induce fatal changes in cardiovascular
physiology, including hypercontraction of
the heart and altered vascular tone, which
must be inhibited to prevent damage and
to increase tolerance16.
The fourth group of repair mechanisms
is related to the third group; if pathology can
not be entirely prevented, then repair of tissue
damage is necessary. For example, infection
with the helminth Nippostrongylus brasiliensis
in mice causes severe damage to the pulmo-
nary environment during larval migration
through the lungs and triggers the production
of several factors that are important for lung
repair. These factors include elastin, procol-
lagen and matrix metalloproteinases, the
production of which results in rapid resolution
of the helminth-induced damage17,18.
We propose a fifth group of mechanisms,
which comprise evolutionary solutions
to infection that affect tolerance in a
pathogen-specific manner. examples of
these evolutionary solutions include the
genetic traits that offer increased defences
against malaria19–23. We discuss these
examples in more detail later. Of course,
we expect more examples to be revealed as
tolerance mechanisms in animal defences
are explored further.
If we consider only pathogenic interactions
between bacteria and hosts when defining
tolerance mechanisms, we risk missing the
large number of non-pathogenic inter actions
that occur with bacteria. Interactions with
mutualistic and commensal bacteria might
reveal more tolerance mechanisms. For
example, humans do not normally raise
pathological immune responses to lipopoly-
saccharide (lPs) in the intestinal lumen.
Therefore, the human body plan, which
sequesters microorganisms to certain regions
of the body, could also be considered to be a
tolerance mechanism. In addition, the native
microbiota forms an integral part of resistance
and tolerance mechanisms in humans; if
there is a normal intestinal flora, humans
can tolerate a certain number of pathogens in
the intestines, but this tolerance is decreased
if the flora is altered with antibiotics.
In all of these examples, resistance and
tolerance are considered to be host proper-
ties. However, we know of many virulence
factors in bacterial pathogens that affect
resistance; so, do pathogens also encode
tolerance factors? A good place to look for
these might be in mutualistic bacteria or
in pathogens that cause chronic infections.
Tolerance mechanisms in invertebrates
studies that examine immune-defence
systems in invertebrates commonly estimate
the genetic contribution to immunity by
measuring a single parameter of immuno-
competence; for example, pathogen load or
antimicrobial activity are used to represent
the effects of infection on host fitness24–26.
This has been a successful approach, and
studies like these led to the dissection of the
Toll and immune deficiency (Imd) signalling
pathways in D. melanogaster27–36. such
studies also led to the observation that flies
that lack these two pathways cannot produce
AmPs and therefore have high bacterial
loads and die rapidly after infection. These
studies were based heavily on dissecting the
mechanism of immunocompetence (in this
case, nuclear-factor-κB-mediated regulation
of AmPs) and measured phenotype (survival)
only as a secondary characteristic36–40.
Approaches that look primarily at
phenotypes tell a different story. To better
understand the relationship between disease
resistance and host fitness, 11 different
genotypes of D. melanogaster were infected
with Pseudomonas aeruginosa, and the
correlation between pathogen burden and
host survival was examined41. These geno-
types varied significantly in terms of both
bacterial titres (a measure of resistance)
and survival, but there was no correlation
between these two parameters; the geno-
types that had low bacterial titres were not
necessarily the healthiest. This indicates that
processes other than resistance are used by
D. melanogaster to cope with the stresses of
infection, and that tolerance, not resistance,
is a crucial determinant of host survival
during this type of infection. Furthermore,
these results indicate that genetic variation
for tolerance exists in invertebrates41.
Another study examining the
mechanism by which M. marinum kills
D. melanogaster found that M. marinum
infection leads to body wasting, with a
progressive loss of fat and glycogen15. It
seems that M. marinum infection decreases
the activation of the insulin effector kinase
AkT, resulting in increased forkhead box O
(FOXO) transcriptional activity, which
drives the wasting process in flies and ulti-
mately leads to death. The authors showed
that this wasting could be suppressed by
decreasing FOXO activity in the fly, which
had no effect on bacterial load but increased
the survival of D. melanogaster. Therefore,
protection against M. marinum infection
was not a resistance effect, but a tolerance
effect that was based on altered energy use
by the host. This is one of the few examples
Figure 2 | mechanisms of tolerance. We propose that mechanisms of tolerance can be grouped in
three classes according to the strength of the association with mechanisms of resistance. a | In class
one, resistance and tolerance mechanisms are tightly linked and have opposite effects. For example,
receptors and effectors of the immune response (resistance mechanisms) — such as peptidoglycan-
recognition protein (PGrP) receptors and antimicrobial peptides in Drosophila melanogaster —
undergo selection to restrict immunopathology (a tolerance effect), and changes in these molecules
are anticipated to always affect both the resistance and tolerance properties of a host. b | In class two,
resistance and tolerance mechanisms have an intermediate codependence. For example, for the
tumour-necrosis-factor-like molecule eiger in D. melanogaster, it might be possible to separate the
resistance and tolerance effects that occur through eiger signalling in different tissues. c | In class
three, the tolerance mechanisms do not affect resistance. these mechanisms only affect the ability to
tolerate an infection and have no effect on the ability to limit the growth of the microorganism. For
example, insulin signalling during infection of D. melanogaster with Mycobacterium marinum can result
in altered energy metabolism that protects against body wasting.
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of a D. melanogaster infection for which the
cause of death is known, and it seems to
be due to a problem with tolerance rather
than due to increased susceptibility to
infection or proliferation of the pathogen15.
The detection of tolerance mechanisms
during infections in a genetically tractable
organism, such as D. melanogaster, offers
promising potential to identify pathways
that are involved in regulating these toler-
ance properties, which might ultimately
be translated into biomedical practices.
Tolerance properties in vertebrate models
evidence for genetic variation for resistance
and tolerance traits has been shown in mice
that have been infected with the protozoan
parasite Plasmodium chabaudi. Råberg et al.42
reported the first study that applied the
statistical framework of reaction norms
developed by plant ecologists to a vertebrate
model (FIG. 1). To measure the variation
of tolerance in animals, they infected five
strains of mice with P. chabaudi and tested
three different clones of P. chabaudi that dif-
fered in infection intensity. To measure host
health, they recorded the severity of anaemia
and weight loss in infected mice. These
health indicators were then plotted against
peak parasite density, which is indicative
of parasite burden. As noted previously,
there was significant variation in the degree
of resistance between the mouse strains
(when comparing peak parasite density).
Interestingly, the slopes that were generated
from the reaction norms varied between the
different mouse strains, which indicates that
there is also variation in tolerance between
the mouse strains tested. In addition, they
observed a negative correlation between tol-
erance and resistance, which indicates that
there is a trade-off between these defence
mechanisms. The mechanisms of tolerance
in these mice are unknown42.
The tick-transmitted spirochete Borrelia
burgdorferi is the causative agent of lyme
disease in humans. In the mouse model of
lyme disease, B. burgdorferi causes arthritis
that ranges in severity depending on the
genetic background of the infected mouse.
Both resistance and tolerance mechanisms
seem to be important in controlling the
development of arthritis, depending on the
mouse strain. In one study, BAlB/cAnn
mice controlled disease severity by restrict-
ing the number of spirochetes in tissues,
which indicates that this mouse strain uses
resistance mechanisms to control the infec-
tion43. By contrast, C57Bl/6n mice do not
develop severe arthritis regardless of the
number of spirochetes that are found in
the tissues, which indicates that these mice
can better tolerate the pathology of the
infection, through unknown mechanisms43.
The above examples provide phenotypic
evidence of tolerance but are not informative
about the tolerance mechanisms that drive
them. studies of individual mouse mutants
have provided some mechanistic insight into
tolerance. For example, mice that are defi-
cient for an ATP-sensitive potassium (kATP)
channel were found to be more sensitive to
lPs. This channel is expressed in coronary
arteries, and the mutant mice suffered from
heart attacks when challenged with lPs44.
Additional alleles of the kATP gene were iden-
tified in a screen for mice that have altered
susceptibility to murine cytomegalovirus.
viral infection of mice that are deficient
for the kATP channel resulted in decreased
cytokine production and abrupt death, with
no obvious signs of sickness. However, viral
titres were comparable to infected wild-type
mice, which indicates that the kATP channel
is involved in positively regulating toler-
ance during infection. The kATP channel is
thought to work by preventing coronary-
artery vasoconstriction, which is induced
by cytokines that are produced in response
to signalling through TlRs or melanoma
differentiation-associated gene 5 (mDA5)
during some types of infection45. In this
case, the tolerance mechanism seems to
fit in the category of damage prevention.
The phenomenon of lPs tolerance,
which is the transient decreased respon-
siveness to repeated exposure to lPs, is
a well-known example of tolerance46–49.
Traditionally, lPs tolerance was described
as a desensitization of TlRs, which results
in macrophages being hyporesponsive
to subsequent exposure to lPs50–52. One
study examined more closely the effects
of lPs tolerance on the expression of
genes that are under the control of TlR
signalling53. The authors proposed that
because hundreds of genes of many dif-
ferent functions are controlled by TlRs,
it is unlikely that lPs tolerance regulates
all of the signals that are transduced by a
particular TlR, but instead probably acts
in a gene-specific manner. To test this idea
they used an in vitro model system for
lPs tolerance in mouse macrophages and
compared the gene-expression profiles of
naive and tolerant macrophages that had
been stimulated with lPs. They identified
two classes of TlR4-induced genes based
on their functions and regulatory require-
ments. The first class, which included
pro-inflammatory cytokines, was silenced
in the tolerized macrophages, whereas the
second class, which included antimicrobial
genes, was not. Regulation of these classes
occurs at the level of gene transcription
rather than the upstream TlR signal and
involves transient chromatin modifications53.
This study shows that resistance and toler-
ance properties can occur as separate and
distinct mechanisms that are regulated
independently of each other.
Tolerance properties in humans
malaria exerts evolutionary pressure on
humans, and genetic traits that affect resist-
ance or tolerance — such as sickle-cell
anaemia, α-thalassaemia and glucose-6-
phosphate dehydrogenase (G6PDH)
deficiency — have appeared in affected
populations. In the case of α-thalassaemia,
individuals with the mutation have less
severe malarial episodes, and this seems
to be due to increased tolerance properties
because parasite loads are unaffected22. A
possible mechanism for the protective effect
of α-thalassaemia comes from the observation
that there is decreased expression of comple-
ment receptor 1 (CR1) on red blood cells
from individuals with the disease. As CR1
seems to be involved in rosette formation
of red blood cells, which occurs in severe
forms of malaria, α+-thalassaemia red blood
cells have decreased rosetting and therefore
decreased disease severity22.
The phenomenon of natural antimalarial
immunity (known as premunition), in
which infected individuals can withstand
the presence of parasites in their blood
at levels that would elicit sickness in
unprotected individuals54,55, was first
described 70 years ago. We propose that
this might be another example of tolerance
in that the body is somehow tolerating the
Plasmodium spp. rather than inducing a
large immune response that would cause
pathology. A recent model to explain this
phenomenon involves the desensitization
of TlR-mediated signalling, which links
antimalarial immunity to lPs tolerance.
During a Plasmodium spp. infection, the
glycosylphosphatidylinositol (GPI) of
the parasite, which is released during lysis
of red blood cells, induces a pro-inflammatory
response by signalling through TlR2–myD88
(myeloid differentiation primary-response
gene 88). This leads to the production of
pro-inflammatory cytokines, including
TnF, interleukin-1 (Il-1) and Il-6, that
are important for controlling the growth
of the parasite. When parasite levels and
pro-inflammatory-cytokine levels decrease,
anti-inflammatory cytokines, including
Il-10, are produced. This signalling and
892 | nOvemBeR 2008 | vOlume 8
cytokine profile is similar to that mediated
by TlR4 signalling following lPs stimula-
tion. In fact, more than 40 years ago it was
shown that experimentally induced malaria
infections in human volunteers resulted
in cross-tolerance to the febrile response
that is caused by the injection of lPs.
Cross-tolerance between TlR2 (activated
by GPI) and TlR4 (activated by lPs) has
also been shown in vitro56. This might
indicate the existence of a common tolerance
mechanism between antimalarial immunity
and lPs tolerance that involves alterations
in TlR signalling.
Studying tolerance systematically?
We have described how the defence
response in humans and other animals
can be broken down into resistance and
tolerance mechanisms, but we think that
tolerance studies are rare in mammals,
whereas resistance studies make up most
immunological reports. Of the tolerance
mechanisms we do know, many seem to be
tightly linked with resistance mechanisms.
We argue that current immunological
studies that focus on effector mechanisms
and signalling between immune cells can
find only the types of tolerance mechanism
that are tightly integrated in the immune-
signalling network. But what about proteins
such as the kATP channel that seem to lie
outside of traditional immune signalling?
When we limit the scope of our studies
to resistance signalling and effector
molecules, as is often the case in traditional
immunological studies, we miss the outlying
tolerance mechanisms, and these are the
ones that will probably be most useful in
terms of medical intervention because
they are less likely to affect resistance
to microorganisms (BOX 1). We need to
broaden the focus of our studies and take
a holistic approach to understanding the
factors that contribute to disease severity.
We need methods of identifying tolerance
mechanisms that are separable from
Tolerance traits can be determined
genetically, and we suggest that these
properties should be easy to find by
broadening the scope of our assays and
measuring tolerance directly. For the past
decade, D. melanogaster genetic screens
have concentrated on learning how the
AmPs that are downstream of the Toll or
Imd pathways are regulated. These types
of genetic screen are focused on resistance
mechanisms, and therefore mutations that
affect tolerance mechanisms could be easily
missed. We recently published an unbiased
forward genetic screen in D. melanogaster
that coupled the concepts of resistance
and tolerance to identify genes that are
involved in the defence against Listeria
monocytogenes infection57. In this study,
we found that in two-thirds of the mutant
flies, increased susceptibility to death
correlated with increased bacterial burden,
which indicates defects in resistance
mechanisms. By contrast, the remaining
mutant flies died but had comparable levels
of bacteria to the wild-type flies, which
indicates that these mutants were defective
in tolerance mechanisms and could not
endure the pathological consequences of the
infection. similarly, various candidate-gene
knockout studies in mice14,58,59, in addition
to a genetic screen45, have shown that studying
both disease severity and pathogen burden
will reveal the involvement of immune
responses in tolerance mechanisms. We
should carry out future screens that measure
both positive and negative changes in
tolerance that are induced by both gain-of-
function and loss-of-function mutations.
We should also turn to microorganisms for
answers in future studies; because of the
potential benefits that tolerance mechanisms
might have on pathogen infection and
transmission, some pathogens might
have evolved mechanisms to enhance
the tolerance of their hosts.
Of course, genetics is not the entire
story and it is important to remember that
tolerance traits are also affected by the life his-
tory of a host. For example, D. melanogaster
suffer from immune senescence during
ageing and, in one model, this is due to an
age-related loss of tolerance60. D. melanogaster
that have been injected with a lethal dose
of Escherichia coli differ in their death rate
depending on their age, but the growth
rate of the infecting bacteria remains
constant; this indicates a change in tolerance.
We should pay attention to epigenetic
mechanisms for altering tolerance because
these might provide the most rapid route
to developing new treatments.
We stress the importance of testing
various pathogens when studying tolerance
mechanisms, both genetically and epigeneti-
cally. In humans, we anticipate that different
types of disease — for example, bacterial
diarrhoea, pneumonia or sepsis — will have
different sets of mechanisms that control
tolerance. Indeed, the TnF-family member
in D. melanogaster, eiger, has multiple and
opposite roles in immune defence, which
become clear only when various pathogens
are tested61,62. If tolerance is to be modulated
medically, we must ensure that while treating
one infection we do not make a patient
more susceptible to another.
Medicine and tolerance
In current medical practice, doctors can
often recognize when the tolerance of a
patient must be increased, and the tools that
are needed to achieve this are available. For
example, patients with cholera die because
of severe dehydration, and the first line of
treatment for these patients is to administer
electrolytes and to keep them hydrated. This
increases tolerance by limiting pathology
and allows the patients to live long enough
to rely on their resistance mechanisms to
clear the pathogen. Bacterial meningitis
is an example in which we assume that we
Box 1 | Evolutionary implications of resistance and tolerance
Resistance and tolerance are predicted to have different evolutionary effects on the pathogen and
host. In the case of resistance, host–pathogen interactions are expected to drive the co-evolution
of antagonistic traits64,65. Because resistance mechanisms act by directly limiting pathogen burden,
if a host evolves resistance to a particular pathogen, the microorganism will evolve a method to
subvert the resistance. This will drive the selection of more resistant traits in the pathogen
population that can overcome the resistance mechanisms of the host, which will then drive
the natural selection of more effective resistance mechanisms in the host population. This
co-evolutionary relationship prevents a resistant trait from becoming fixed within a host
population66–68 and therefore continues to drive the evolution of host resistance mechanisms.
By contrast, these types of selective pressure are not expected to be placed on pathogens owing
to the evolution of increased tolerance. As tolerance works by alleviating disease severity, it should
have a neutral or possibly positive effect on the pathogen; for example, tolerant hosts might live
longer, thereby increasing the prevalence of the disease and potentially altering its spread. Unlike
resistance, a tolerance trait will eventually become fixed in a host population because it will be
positively selected for. Mechanisms that increase tolerance are not predicted to lead to the
development of highly resistant pathogens. Therefore, understanding tolerance mechanisms
should provide a good foundation for therapies because microorganisms are not anticipated to
develop resistance, and thus the therapy will remain useful for long periods of time. As we discuss
in detail in the main text, several tolerance mechanisms are already targeted in medical practice
to help fight infections66–71.
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Nature Reviews | Immunology
are increasing the tolerance of a patient
by directly manipulating the immune
response. When corticosteroids are admin-
istered in combination with the initial anti-
biotic treatment, they significantly decrease
the risk of mortality and hearing loss63.
The goal of this article is not to highlight
tolerance as a new way of treating patients.
Instead, by using a different description of
our defences against infectious diseases,
we hope to encourage new experiments
to discover more examples of tolerance
mechanisms. such findings could then be
integrated into our current clinical practices
to increase the survival of patients.
The reaction norms that are used by
plant ecologists to measure plant health rely
on a logic that we propose can be applied
to assess patient health. It is impossible to
determine a particular patient’s reaction
norm for tolerance and to use that as a
diagnostic tool, but by systematically
studying tolerance, we will learn more about
the mechanisms that control these properties.
This will allow us to develop diagnostic
tools to monitor relevant mechanisms and
to gain a better sense of tolerance curves for
individual patients. using this information,
doctors could determine whether patients
are sick because their resistance is suboptimal
or because their tolerance is low, and
choose appropriate treatments on the basis
of this knowledge.
The intentional manipulation of resist-
ance would increase health by moving the
patient up the reaction-norm curve. This
can be accomplished with current medical
practices, such as vaccination before the
patient encounters the pathogen or admin-
istration of antibiotics once the patient
becomes ill. The manipulation of tolerance
would cause the slope of the curve to change.
If the patient’s tolerance mechanisms are
collapsing, then they will have an extremely
steep tolerance curve. The physician needs
to rotate the reaction norm back up to its
normal position by increasing the tolerance
properties of the patient, and as a result
increase the patient’s health. The manipula-
tion of tolerance is already a common practice
in medicine, for example, as we described for
cholera and meningitis. As the number of
studies that examine tolerance mechanisms
increases, we could develop additional
drugs and therapeutics that can be used to
manipulate a patient’s tolerance and shift their
tolerance curve to a healthy range (FIG. 3).
As discussed in BOX 1, ecologists predict
that resistance and tolerance will have dif-
ferent evolutionary effects on pathogens.
Because host resistance mechanisms place
selective pressures on pathogens, microor-
ganisms will eventually evolve mechanisms
to subvert resistance. We encounter this
problem with many medical treatments that
increase host resistance, including antibiotics.
As tolerance mechanisms are not expected to
have the same selective pressures on patho-
gens as resistance mechanisms, we suggest
that new drugs that target tolerance mecha-
nisms will provide therapies to which patho-
gens will not develop resistance. The types of
tolerance mechanism that could be targeted
for drug manipulation should be chosen
with caution; the tolerance mechanisms
that are tightly linked or inversely related to
resistance mechanisms might not be the best
candidates for drugs, as their manipulation
could affect both resistance and tolerance in
unpredictable ways. Tolerance genes that lie
outside traditional immune-signalling net-
works might be better drug targets, as their
manipulation is not expected to affect central
immune signals and effectors.
Janelle S. Ayres and David S. Schneider are at the
Department of Microbiology and Immunology,
Stanford University, Stanford, California 94305, USA.
Correspondence to D.S.S.
Published online 17 October 2008
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This work was supported by grants AI060164, AI053080
and AI055651 from the National Institutes of Health, USA.
entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
cr1 | eiger | FOXO | IL-1 | IL-6 | MyD88 | tNF | tLr2 | tLr4
α-thalassaemia | glucose-6-phosphate dehydrogenase
(G6PDH) deficiency | sickle-cell anaemia
David s. schneider’s homepage: http://cmgm.stanford.edu/
All links Are Active in the online pDf
Do T cells need endogenous peptides
Nicholas R. J. Gascoigne
Abstract | t cells are sensitive to small numbers of antigenic peptide–MHc ligands
that are distributed among an excess of endogenous peptide–MHc complexes on
the surface of antigen-presenting cells. Although there are accumulating data that
indicate a role for these endogenous peptide–MHc complexes in t-cell receptor
triggering, whether they are necessary, and the nature of their function, is
controversial. In this Opinion article, I argue that endogenous peptide–MHc
complexes are required for t-cell stimulation and that their mechanism of action
differs between cD4+ and cD8+ t cells.
T cells are stimulated by antigenic peptides
that are presented by the mHC class I or
class II molecules expressed on the surface of
antigen-presenting cells (APCs). The classi-
cal, textbook model of T-cell activation (FIG. 1)
states that when the T-cell receptor (TCR)
binds to an antigenic peptide–mHC complex
that is also bound by the co-receptor (that
is, CD4 or CD8), a stable complex is formed.
This results in the phosphorylation of the
CD3-associated immunoreceptor tyrosine-
based activation motifs (ITAms) by the lCk
molecule that is associated with the cytoplas-
mic domain of the co-receptor, leading to
the initiation of the TCR signalling cascade.
However, as only a very small proportion
of the peptide–mHC complexes that are
expressed on the surface of an APC is likely
to be antigenic for a given TCR, and because
most of the peptides that are presented by
mHC molecules are non‑stimulatory peptides
(see Glossary; BOX 1) that are derived from self
proteins, T cells have a ‘needle in a haystack’
predicament. In addition, T cells are sensitive
nATuRe RevIeWs | immunology
vOlume 8 | nOvemBeR 2008 | 895