REVIEWS

Disease tolerance and immunity

in host protection against infection
Miguel P. Soares, Luis Teixeira and Luis F. Moita
Abstract | The immune system probably evolved to limit the negative effects exerted by
pathogens on host homeostasis. This defence strategy relies on the concerted action of innate
and adaptive components of the immune system, which sense and target pathogens for
containment, destruction or expulsion. Resistance to infection refers to these immune functions,
which reduce the pathogen load of an infected host as the means to preserve homeostasis.
Immune-driven resistance to infection is coupled to an additional, and arguably as important,
defence strategy that limits the extent of dysfunction imposed on host parenchymal tissues
during infection, without exerting a direct negative effect on pathogens. This defence strategy,
known as disease tolerance, relies on tissue damage control mechanisms that prevent the
deleterious effects of pathogens and that uncouples immune-driven resistance mechanisms from
immunopathology and disease. In this Review, we provide a unifying view of resistance and
disease tolerance in the framework of immunity to infection.

Homeostasis
Maintenance of a stable
physiological ‘internal’ state in
multicellular organisms via
feedback mechanisms that
allow physiological functions to
proceed despite variations in
the ‘external’ environment.
Instituto Gulbenkian de
Ciência, Rua da Quinta
Grande, 6, 2780–156
Oeiras, Portugal.
Correspondence to M.P.S.
mpsoares@igc.gulbenkian.pt
doi:10.1038/nri.2016.136
Published online 3 Jan 2017
The pathological outcome of infection is mainly deter-
mined by the degree of metabolic dysfunction and dam-
age inflicted on the host’s parenchymal tissues1,2. Clinical
signs and symptoms of infectious diseases emerge as host
homeostasis becomes compromised because of tissue dys-
function and damage1–3. Current understanding of this
pathological process is limited, presumably impairing
the ability to treat some infectious diseases that remain
associated with high human morbidity and mortality 4.
Immunity provides general protection against dis-
ease and particularly against infectious diseases4. This is
achieved by virtue of immune-driven resistance mech­
an­isms that expel, contain or kill pathogens as the means
to preserve host homeostasis. Therapeutic approaches
based on the induction of immune-driven resistance
mechanisms, such as vaccination, have proven highly
protective against a broad range of infectious diseases4.
The same is true for the use of antimicrobial agents,
such as antibiotics, which functionally mimic resistance
mechanisms by containing or killing pathogens4. The
overwhelming therapeutic success of these approaches
has probably contributed to the perception that resist-
ance mechanisms are the only relevant defence strategy
against infectious diseases. This idea has been challenged
over the past years by the (re)discovery of disease tol-
erance5,6. This evolutionarily conserved host defence
strategy was originally revealed in plants through the
recognition that variation in disease severity can occur
at a population level without a direct correlation to
pathogen load7,8. However, it is now clear that disease
tolerance is fully operational in animals, including
flies9,10, rodents11,12 and humans13, in which it preserves
host homeostasis in response to viral14,15, bacterial15–18,
fungal19 and protozoan11,13,20,21 infections.
In contrast to resistance to infection, disease tol-
erance does not exert a direct negative effect on these
pathogens6 (BOX 1). Disease tolerance is now widely
studied in experimental models of infection, in which
the relationship between host health and pathogen load
can be established at an individual level (BOX 2). In this
Review, we discuss the cellular and molecular mech­
anisms establishing disease tolerance to infection, and
we explore the effects exerted by bona fide immunity
on those mechanisms. We also highlight how symbiotic
interactions with microorganisms and their regulation
by specific components of innate and adaptive immunity
affect disease tolerance to infection22. Finally, we sug-
gest that the mechanisms underlying disease tolerance
to infection can be therapeutically targeted.
Tissue damage control
The mechanisms underlying disease tolerance remain
poorly understood but seem to revolve around several
evolutionarily conserved stress and damage responses
that confer tissue damage control in the infected host1–3
(FIG. 1). These stress and damage responses sustain the
functional outputs of host parenchymal cells under
different forms of stress and damage imposed either
directly by pathogens, that is, virulence, or indirectly
by host immune-driven resistance mechanisms, that is

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Immunopathology immunopathology1,3. Stress and damage responses pro-
Refers to a breakdown of vide metabolic adaptation and repair damage to cellular
homeostasis in which immunity metabolites, macromolecules and/or organelles, as the
functions as the main cause of means to preserve core cellular, tissue and organ func-
disease.
tions required to preserve or restore host homeostasis.
Stress However, this often has detrimental effects on accessory
Any variations in the ‘external’ cell functions, and as such stress and damage responses
environment that disrupt the must be tightly regulated1,3. When these responses fail
maintenance of a stable
to sustain the functional outputs of parenchymal cells,
physiological environment in
which biological processes are
tissues or organs, the default programme becomes
allowed to proceed. programmed cell death (FIG. 1). This is coupled to the
induction of cellular and tissue regenerative responses
that have the capacity to restore the functional output of
damaged parenchymal tissues or organs3,23. As discussed
in further detail below, different types of infection impose
distinct forms of stress and damage, which suggests that
tissue damage control mechanisms might function in a
somewhat pathogen class-specific manner that reflects
these differences to effectively establish disease tolerance
against diverse types of infection6. Although there are
obvious parallels between the protective effect exerted
by tissue damage control mechanisms in the context of
infectious and non-infectious diseases1,6,24, we focus our
discussion on infectious diseases.
Box 1 | Tolerance and disease tolerance
There is a growing interest in understanding disease tolerance, both at a mechanistic
level and its potential therapeutic application. However, the concept of disease
tolerance and its associated terminology can easily be misinterpreted, probably
because tolerance is broadly used to define some core properties of the immune system.
Immunological tolerance is an active process through which specific antigens become
non-immunogenic — that is, fail to trigger adaptive immunity in a given individual — on
the basis of immunoregulatory mechanisms that eliminate or suppress the activation
and proliferation of antigen-specific B and T cells123. Immunological tolerance can
explain immune discrimination between self and non-self, which is a concept deeply
rooted in the understanding of immunity. Although some of the mechanisms regulating
immunological tolerance and disease tolerance are functionally related, these two
phenomena are clearly distinct.
Tolerance is also used to describe how innate immune cells, particularly macrophages,
modulate responses to bacterial lipopolysaccharide (LPS). The cellular and molecular
bases for LPS tolerance have been extensively studied and relate primarily to the
induction of epigenetic modifications in enhancers, which modulate gene transcription
in response to Toll-like receptor 4 (TLR4) signalling124. This is not specific to TLR4, as it
can occur downstream of other pattern recognition receptors (PRRs)125 and other
sensors18. In some instances this response — which is referred to as ‘trained immunity’
(REF. 126) — has been functionally linked to the induction of disease tolerance18.
Tolerance also refers to a related phenomenon in which exposure to a sub-lethal dose
of a given agonist renders cells, tissues, organs or organisms tolerant to a subsequent
higher dosage of the same substance that would otherwise be deleterious. This
adaptive response — which is also referred to as hormesis or adaptation — relies on
the activation of several evolutionarily conserved genetic programmes that confer
protection against these agonists. Some of these genetic programmes overlap with
those regulating stress and damage responses conferring tissue damage control and
disease tolerance to infections1,3.
We use the term disease tolerance to refer explicitly to the same concept defined
more than a century ago in the plant literature5,6, in which disease tolerance defines a
defence mechanism that limits ‘damage to functions and structures’ (REF. 8) imposed
upon the host during an infection, without interfering with pathogen load5,6. Of note,
although disease tolerance by definition is not associated with modulation of pathogen
load, it is possible that this response has an effect on pathogen physiology that is not
revealed by corresponding changes in pathogen load.
Stress responses in tissue damage control
Stress responses are triggered through the engagement
of specific sensors that continuously monitor different
physiological parameters under homeostatic regula-
tion such as temperature, O2, pH, osmolarity, glucose
and ATP1–3. When these parameters change beyond a
certain threshold, ‘stress sensors’ set off signal transduc-
tion pathways that alert cells of a possible disruption to
homeostasis1–3. The ensuing stress responses provide
metabolic adaptation in host cells, which confers tissue
damage control and contributes to the establishment
of disease tolerance to infection1–3 (FIGS  1,2). Signal
transduction pathways triggered upon recognition of
pathogen-associated molecular patterns (PAMPs) or
damage-associated molecular patterns (DAMPs) by pat-
tern recognition receptors (PRRs) can also contribute to
tissue damage control and to the establishment of disease
tolerance to infection25, which has been reviewed else-
where24,26 and is not discussed in this Review. Instead,
we focus on several bona fide stress responses as tis-
sue damage control mechanisms that contribute to the
­establishment of disease tolerance to infection1–3.
Oxidative stress. The oxidative stress response controlled
by the transcription factor nuclear factor erythroid 2‑
related factor 2 (NRF2)27,28 (FIG. 2) is important for the
establishment of disease tolerance to systemic infec-
tions such as malaria 20,29. Briefly, the blood stage
of Plasmodium spp. infection, the causative agent of
malaria, is associated with haemolysis and hence with
generation of extracellular haemoglobin20,21,29,30. Upon
oxidation, extracellular haemoglobin releases its pros-
thetic haem groups, which can function as catalysts in
the production of reactive oxygen species (ROS) and
reactive nitrogen species (RNS). This can lead to oxi-
dative stress and cellular damage of host parenchymal
tissues12,13,16,31, which in turn drive the pathogenesis
of severe forms of malaria30. Genetic polymorphisms
selected through human evolution on the basis of their
protective effect against malaria, such as sickle muta-
tions in the β-chain of haemoglobin, function via a
NRF2‑dependent mechanism that counteracts the
pathogenic effects of labile haem and establish disease
tolerance to the blood stage of Plasmodium spp. infec-
tion20,30,32. Activation of NRF2 is also protective against
polymicrobial33 and Staphylococcus aureus 34 infections,
but whether this is due to the establishment of disease
tolerance is unclear. However, the following two obser-
vations suggest that disease tolerance could indeed have
a role: NRF2 polarizes macrophage responses towards
the promotion of tissue damage control35,36, and NRF2
induces mitochondrial biogenesis in parenchymal cells34,
which probably also contributes to tissue damage control
and disease tolerance to infections.
Hypoxia. Infections can be associated with a local or
systemic decrease in O2 supply to host cells, a condition
known as hypoxia. This is sensed and countered by host
cells via a stress response controlled by the hypoxia
inducible factor (HIF) family of transcription factors37
(FIG. 2). Whether HIF activation in parenchymal cells

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Box 2 | Experimental identification of mechanisms controlling disease tolerance

By definition, disease tolerance is revealed by variations of host disease severity without a direct correlation with pathogen
load. However, although stress and damage responses regulating tissue damage control and disease tolerance to infection
should not exert direct effects on pathogens, this is often difficult to show because of the inter-relationship between tissue
damage control and immune-driven host resistance mechanisms. For example, tissue damage control should enable
immune-driven resistance mechanisms to operate in a more robust and effective manner without the onset of
immunopathology. As such, tissue damage control can function indirectly to exert a negative effect on pathogens. Hence,
to dissociate disease tolerance from resistance to infection often requires that resistance is stably maintained, for example,
through the use of antimicrobial agents. Under such conditions, experimental modulation of host disease severity is likely
to involve the modulation of tissue damage control mechanisms that contribute to the establishment of disease tolerance.
As most studies investigating mechanisms of host protection against infection are not designed to detect the effect of
disease tolerance, it is often difficult to disentangle disease tolerance from resistance to infection.
When designing experimental approaches to identify mechanisms that regulate disease tolerance, one should consider
quantifying physiological parameters that assess host homeostasis, such as temperature, oxygen, pH, osmolarity or
glucose concentrations. However, these physiological parameters only reveal indirect disruptions of host homeostasis,
a limitation resolved by direct quantification of parameters that estimate the function of tissues and organs such as brain,
cardiovascular system, lungs, kidney and liver. When these parameters are plotted against host pathogen load, they can
reveal variations in disease tolerance. Of note, these parameters should also be quantified at steady state — that is,
before infection — so that host vigour — that is, health status before infection — can be defined. When these parameters
cannot be quantified, incidence of mortality can be used to reveal irreversible homeostasis breakdown13,16,17,20.
The pathogen load of the infected host should ideally be quantified throughout the course of infection, for example,
by sampling tissues in which pathogens accumulate, such as blood in malaria, lungs in pneumonia, liver in hepatitis, and
so on. However, a potential bias of this approach is that it does not account for changes in pathogen behaviour, which can
be reflected by variations in tissue tropism and accumulation at alternative sites. An alternative approach is to quantify
pathogen load in the whole body, as routinely done when infecting flies5,9,10,127. This is more challenging in other species
such as rodents, but it can be achieved using transgenic pathogens expressing reporter genes that can be quantified
throughout the course of an infection by whole-body imaging29.
Disease tolerance is mostly inferred from how a host reacts to infection, which is inferred from the phenotype, that is,
disease severity, produced by a given genotype under a certain pathogen load5,11,128,129. In this analysis of host response
to infection — also known as reaction norm analysis — each individual (genotype) is represented by a single health
parameter and a pathogen load value, which corresponds to the ratio of minimum health parameter to maximum
pathogen load5,11,128,129. However, these reaction norms do not provide information on how the relationship between
phenotype and pathogen load varies over time129. An alternative approach is to plot disease parameters versus pathogen
load over time130. This approach enables mapping of disease trajectories, which are revealed by the concomitant changes
in disease and pathogen load over time130,131. The data from these fitness curves can potentially be used to estimate
individual variations in disease tolerance130,131.

contributes to the establishment of disease tolerance to
infection has not been established, but HIF activation
in macrophages provides metabolic adaptation towards
ATP production via anaerobic glycolytic metabolism
and modulates macrophage polarization38,39 towards an
effector response that promotes tissue damage control
and disease tolerance to infection39,40, for example, in the
context of Helicobacter pylori infection in mice40.
Metabolic stress. Some stress sensors directly or indi-
rectly monitor variations in the relative concentration
of essential metabolites such as ATP or glucose, respec-
tively 1,3. These activate stress responses that adjust
host cellular metabolism to the relative availability of
the metabolites sensed (FIG. 2). In strong support of the
idea that metabolic stress responses can substantially
contribute to the establishment of disease tolerance to
infection is the finding that regulation of host glucose
metabolism is essential to establish disease tolerance to
viral and bacterial infections in mice41.
Osmotic stress. Systemic infections can be associated
with osmotic stress42, which is sensed and counteracted
by osmotic stress responses, such as the one regulated
via the activation of nuclear factor of activated T cells 5
(NFAT5)43 (FIG. 2). This osmotic stress response acts in a
cytoprotective manner in parenchymal cells44, confer-
ring tissue damage control in the kidney during systemic
polymicrobial infections45 and probably in the heart
­during infection with coxsackievirus46 in mice (FIG. 2).
Damage responses and tissue damage control
When cellular stress associated with a given infection
persists in strength and/or time, metabolic adaptation
is no longer sufficient to preserve core cellular func-
tions in the parenchymal tissues and organs that sustain
homeostasis. The ensuing damage inflicted to cellular
metabolites or macromolecules such as DNA, proteins
and lipids, and eventually to organelles, activates spe-
cific damage responses that contribute to tissue damage
control and to the establishment of disease tolerance to
infection1–3 (FIGS 1,2).
Metabolite damage and extracellular release. Metabolite
damage refers to modifications of metabo­lites that com-
promise their original function47. Such modified metabo­
lites can have pathological effects via the impairment of
host cellular functions and the generation of toxic prod-
ucts that promote inflammation, cellular stress and dam-
age47. For example, sustained modifications of soluble

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Immunity Pathogen Immunity activity. Haem catabo­lism by the NRF2-regulated haem

oxygenase 1 (HO1) also contributes to prevent lipid
Stress
Stress ­peroxidation31 (FIG. 2).
responses
Proteotoxic damage. Proteotoxic damage responses aim
Damage to repair or eventually to degrade unfolded nascent or
Damage
responses
mature proteins as a means to preserve essential cellu-
lar functions53,54. These can function as tissue damage
Cellular control mechanisms and promote the establishment of
Cytotoxicity
regeneration
disease tolerance to bacterial infection53,55–58 (FIG. 2). Of
note, proteotoxic damage responses are also involved in
Tissue Tissue the regulation of immune-driven resistance mechanisms
damage control dysfunction against intracellular bacteria and viruses, some of which
in turn evolved to modulate these responses as a strategy
Disease Infectious to repress host resistance53,59.
tolerance disease

Figure 1 | Tissue damage control and disease tolerance. Immunity exerts a negative
effect on pathogens and triggers stress and damage in hostNature Reviewstissues,
parenchymal | Immunology
which
can lead to cytotoxicity, tissue dysfunction and disease. Tissue damage control
mechanisms involve several stress and damage responses that function in a concerted
manner to protect parenchymal cells and tissues from dysfunction or damage caused by
pathogens or by immune-driven host resistance mechanisms. Tissue damage control
initially relies on stress responses that rewire metabolic pathways as the means to
preserve the core functional outputs of parenchymal cells1,3,151. If stress persists over time,
damage to intracellular metabolites, macromolecules and cellular organelles develops1.
This activates damage responses that repair these different types of damage to preserve
core functional outputs of parenchymal cells. Programmed cell death is triggered if this
second layer of tissue damage control fails to preserve the functional outputs of
parenchymal cells. When this occurs, the last layer of tissue damage control becomes
cellular regeneration and tissue repair. If this still fails to preserve or to restore the
functional outputs of parenchymal cells, the outcome is tissue dysfunction and damage,
which is revealed by the appearance of the clinical signs and symptoms of infectious
diseases. Immune responses regulate stress, damage and regenerative responses that
underlie tissue damage control mechanisms and that contribute to the establishment of
disease tolerance to infection.
metabolites that promote their phase transition into crys-
tals are sensed by PRRs, which can trigger inflammatory
Ataxia-telangiectasia responses that are deleterious to the host 48. Thus, lim-
mutated kinase iting the pathological effects of metabolite d ­ amage can
(ATM kinase). A serine and ­promote disease tolerance to infection (FIG. 2).
threonine protein kinase that is
recruited and activated by
DNA double-strand breaks and Lipid damage. Lipid peroxidation can impair cellu-
that has an important role in lar membrane function, which eventually leads to the
the activation of DNA damage release of intracellular content 49,50 (FIG. 2). Moreover,
responses.
sensing of lipid peroxidation products by PRRs50, such
Necroptosis as Toll-like receptor 4 (TLR4), can exacerbate tissue
A specific form of programmed damage, as shown during pathogenesis of influenza
cell death mediated via a virus infection51. Expression of phospholipid hydro­
genetically encoded mechanism peroxide glutathione peroxidase 4 (GPX4) has a central
involving receptor-interacting
serine/threonine-protein
role in inhibiting lipid peroxidation28,52. This salutary
kinase 1 (RIPK1) and RIPK3 effect occurs via a mechanism that relies on glutathione
and the mixed lineage kinase supply from an NRF2‑regulated pathway involving
domain-like (MLKL) solute carrier family 7 member 11 (SLC7A11; which
pseudokinase.
together with SLC3A2 encodes the cystine/glutamate
Ferroptosis antiporter), glutamate–cysteine ligase catalytic sub­
Genetically encoded form of unit  (GCLC),  ­g lutamate-­c ysteine ligase modifier
programmed cell death driven ­subunit (GCLM, which encodes the γ‑glutamylcysteine
by loss of activity of the lipid synthetase γGCS) and GSS (encoding the glutathione
repair enzyme glutathione
peroxidase 4 (GPX4) and by
synthetase)28,52. This suggests that activation of the
the accumulation of lipid transcription factor NRF2 contributes to counter lipid
hydroperoxides. peroxidation via a mechanism that supports GPX4
DNA damage. Infections are associated with host
DNA damage and consequently with the activation
of DNA damage responses60 (FIG. 2). This probably occurs
via a mechanism involving the MRE11–RAD50–NBS1
complex, which activates ataxia-telangiectasia mutated
kinase (ATM) — a master regulator of the double-­
stranded DNA damage response61. Activation of ATM
confers tissue damage control and disease tolerance
to polymicrobial infections in mice17, which suggests
that DNA damage responses contribute to maintain
both the genetic integrity and the functional outputs of
­parenchymal cells during infection.
Damage to cellular organelles. Autophagy is an evolu-
tionarily conserved damage response that supports cell
function under stress conditions that elicit damage to
cellular organelles62 (FIG. 2). Autophagy regulates inflam-
matory responses and modulates disease tolerance to
infections caused by pathogens such as Sindbis virus63
and S. aureus 64 as well as to polymicrobial17 infections in
mice. Of note, autophagy can also function as a resist-
ance mechanism against intracellular pathogens, so
called xenophagy 62.
Cell death in tissue damage control
When stress and damage responses fail to preserve cel-
lular functional outputs, the default response is, in most
cases, programmed cell death (FIG. 1). Different forms of
stress and damage are associated with distinctive forms of
programmed cell death and ensuing pathophysio­logi­cal
consequences65. For example, failure to resolve oxidative
stress can lead to necroptosis66 and failure to repair lipid
peroxidation induces ferroptosis67. Irreparable DNA dam-
age results in the induction of different programmed cell
death pathways, including apoptosis68, which is ­regulated
by the caspase family of cysteine proteases.
Although programmed cell death can damage host
parenchymal tissues and lead to organ dysfunction, this
relationship is not always straightforward because pro-
grammed cell death is also part of a resistance mechanism
against intracellular pathogens69. However, the trade-off
of this resistance mechanism can be particularly high,
depending on the relative capacity of different tissues to
withstand cell loss without compromising tissue function
and homeostasis6. The pathophysiological relevance of

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Figure 2 | Relative contribution of stress and damage responses to the Toxins

establishment of disease tolerance to infection. Pathogen-derived toxins, such as Oxidative KEAP1 and NRF2
pore-forming toxins, can function as a major driving force in the pathogenesis of Hypoxic PHD2 and HIF
Stress
infectious disease by inducing stress and damage to host cells, which eventually leads Stress Metabolic AMPK, PI3K, responses
to programmed cell death152. Production of reactive oxygen species (ROS) and reactive AKT and FOXO
nitrogen species (RNS) by macrophages or polymorphonuclear cells is a common host Osmotic NLRP3, NLRC4,
immune resistance mechanism against various pathogens153,154, which can lead to AKAP13 and NFAT5
oxidative stress153,154. This is sensed by Kelch-like ECH-associated protein 1 (KEAP1)27,28 Metabolites NLRP3, P2X,
— which under homeostatic conditions constitutively promotes the ubiquitylation and CD39 and CD73
proteolytic degradation of the transcription factor nuclear factor erythroid 2‑related Lipids HO1 and GPX4 Damage
Damage
factor 2 (NRF2)27,28. Both ROS and RNS repress KEAP1 activity and enable NRF2 Proteins AMPK, HSF1 responses
activation, which triggers the expression of effector genes regulating oxidative stress and UPR
responses27,28. Hypoxia is counteracted by a stress response triggered by the O2 sensor DNA ATM and p53
prolyl hydroxylase domain protein 2 (PHD2)37, which constitutively represses the Organelles Autophagy
activity of the hypoxia inducible factor (HIF) family of transcription factors, under Tissue Tissue damage
normoxic conditions37. HIF activation can also occur under normoxic conditions37, dysfunction control
in response to pattern recognition receptor signalling, reduced intracellular iron
availability or ROS. Hence, HIF activation might confer metabolic adaptation to
different types of stress associated with infection37. Metabolic stress resulting from Infectious Disease
reduced intracellular ATP content is sensed and countered by a metabolic stress disease tolerance
response controlled by AMP-activated protein kinase (AMPK)155. Metabolic
stress resulting from a systemic reduction in glucose concentration is sensed indirectly Nature Reviews | Immunology
by insulin receptor156. When insulin levels drop, phosphoinositide 3‑kinase (PI3K) and this defence strategy is supported by the realisation that
AKT activation are reduced, promoting the activation of the forkhead box O (FOXO) intracellular pathogens evolved a range of mechanisms
family of transcription factors156. Activation of FOXO family members functions in a that can modulate host genetic programmes controlling
tissue-specific manner to promote or to repress disease tolerance to infection. programmed cell death, presumably as a strategy to
For example, FOXO activation in epithelial cells regulates the expression of genes
escape resistance to infection70.
encoding antimicrobial peptides157 and antioxidant enzymes158, which contribute to
maintain epithelial barrier integrity and as such are protective against infection in
Programmed cell death of infected cells is coupled
flies157,158 and mice159. Conversely, activation of FOXO1 and FOXO3α in muscle cells to phagocytosis by bystander macrophages or dendritic
promotes myofibre atrophy and muscle wasting associated with sepsis in mice160 and cells (DCs), which present pathogen-associated antigens
Mycobacterium marinum infection in flies127. Osmotic stress can be sensed by to CD4+ T helper (TH) cells or CD8+ cytotoxic T lym-
inflammasomes161,162, containing NLRP3 (NOD-, LRR- and pyrin domain-containing 3) phocytes (CTLs) and thereby elicit an antigen-­specific
or NLRC4 (NOD-, LRR- and CARD-containing 4)162 as well as by the A‑kinase anchor adaptive immune response that targets and kills the
protein 13 (AKAP13), which activates nuclear factor of activated T cells 5 (NFAT5)43, remaining reservoir of infected cells. Clearance of dam-
a transcription factor that provides metabolic adaptation to osmotic stress and confers aged and dying cells is associated with macrophage
tissue damage control during infection45. Metabolite damage, such as imposed by polarization towards the production of cytokines and
phase transition into crystals, functions in a pro-inflammatory manner as shown, for
lipid mediators that limit the extent of inflammatory
example, for uric acid-driven monosodium urate crystals163 or cholesterol crystals164.
This is sensed by NLRP3 inflammasomes, triggering a downstream signal transduction
reactions71. These include interleukin‑10 (IL‑10) and
pathway, which involves the apoptosis-associated speck-like protein containing a 15‑deoxy‑Δ‑­prostaglandin J2 (15d‑PGJ2), which induce
CARD (ASC), caspase 1 and interleukin‑18 (IL‑18)48. Extracellular release of the expression of HO1 (REFS 72,73). Haem catabolism by
metabolites, such as ATP, is sensed by the P2X purinergic receptor165, which signals via HO1 modulates macrophage responses towards inhibi-
inflammasomes161 to promote inflammation and tissue damage165. This is countered by tion of pro-­inflammatory gene expression74 and probably
the catabolism of extracellular ATP and ADP into AMP and adenosine by CD39 and exerts cytoprotective effects in bystander cells75. This pro-­
CD73, respectively165, which exert immunoregulatory effects, promoting the resolving response is also associated with the production
establishment of disease tolerance to Toxoplasma gondii166 or Helicobacter spp.167 of growth factors, such as platelet-derived growth factor
infections in mice. Presumably these effects are mediated via adenosine-driven (PDGF), and cytokines, including transforming growth
signalling through transmembrane adenosine G protein-coupled cell surface
factor‑β1 (TGFβ1), which can directly affect paren­
receptors110,168. Lipid peroxidation is counteracted by several damage responses49
including the induction of haem oxygenese 1 (HO1)31, which promotes the
chymal cells to promote tissue regeneration, regulating
establishment of disease tolerance to bloodstream infections16,20,21,29–31. Whether yet another layer of tissue damage control23.
inhibition of lipid peroxidation by the glutathione–glutathione peroxidase 4 (GPX4) Although some tissue damage control mechanisms
pathway also promotes disease tolerance to infection has not been established. function in a cell-autonomous manner, other mech-
Damage to proteins or proteotoxic damage is sensed by heat shock proteins, which anisms seem to rely on bystander innate and adap-
activate heat shock factor 1 (HSF1)54, and is sensed in the endoplasmic reticulum by the tive immune cells. As discussed in the section below,
78 kDa glucose-regulated protein (GRP78) chaperone and inositol-requiring protein 1 tissue-resident leukocytes probably have a predom-
(IRE1)53, which activate the unfolded protein response (UPR). HSF1 activation confers inant role in this non-cell autonomous mechanism of
a survival advantage against Enterococcus faecalis and Pseudomonas aeruginosa ­establishment of disease tolerance to infection.
infections in Caenorhabditis elegans55,56 and against Listeria monocytogenes infection in
mice57. The UPR prevents immunopathology associated with P. aeruginosa infection in
C. elegans58 and preserves homeostatic control of microbiota interactions with the host
Immune regulation of tissue damage control
gut epithelium53. The DNA damage responses controlled by Ataxia-telangiectasia In this section we discuss how tissue-resident macro­
mutated kinase (ATM)17 and by p53 (REF. 169) confer tissue damage control and phages, innate lymphoid cells (ILCs) and regulatory T
disease tolerance to pulmonary bacterial infections in mice. Damage to cellular (Treg) cells affect tissue damage control mechanisms and
organelles is counteracted by autophagy, which modulates disease tolerance to a thereby contribute in a non cell-autonomous manner to
variety of infections17,62–64. the establishment of disease tolerance to infection (FIG. 3).

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Alarmins
Endogenous molecules
released from damaged cells
and sensed by receptors of the
immune system that alert for
tissue dysfunction or damage,
associated with disruption of
homeostasis.
Macrophages. Tissue-resident macrophages express high IL‑18 and IL‑33, which polarize macrophages towards
levels of PRRs and various other receptors that sense tissue-healing regenerative responses and, as discussed
PAMPs, DAMPs or alarmins released from damaged cells, in the previous section, can contribute to the establish-
including cytokines that alert cells to the disruption of ment of disease tolerance to infection (FIG. 3a). Signalling
homeostasis76,77 (FIG. 3a). These cytokines include IL‑1α, via other sensors, such as the aryl hydrocarbon receptor
(AHR) — a ligand-dependent transcription factor that
senses exo­genous environmental toxins and endogenous
a Parenchymal cells ligands — can also polarize macrophages towards the
establishment of disease tolerance to bacterial infections18.
Macrophage antimicrobial responses are associated
NO with the expression of genes that can promote tissue
CO
H2S damage control in parenchymal cells. These include
IL-1, inducible nitric oxide synthase (iNOS), which generates
PDGFR ILR IL-18
and nitric oxide (NO), HO1, which generates carbon mon-
IL-33 oxide (CO), and cystathionine β‑synthase (CBS), which
PDGF, TGFβ, generates hydrogen sulphide (H2S) (FIG. 3a). These gaso­
TNF, IL-6 and ILR
IL-10 transmitters78 diffuse across cellular membranes to sense
DAMP
the metabolic status of microorganisms79 while driving
Macrophage PRR metabolic adaptation in host parenchymal cells78,80, sup-
Stress L-Kynurenine porting tissue damage control and contributing to the
AHR
Sensor establishment of disease tolerance to infection13,29 (FIG. 3a).
PRR Sensor Cytokines produced during these responses have a dual
Dying infected cells role, for example, tumour necrosis factor (TNF) can trig-
Pathogen undergoing PCD ger programmed cell death and also activate pro-survival
(PAMP)
responses via activation of the nuclear factor‑κB (NF‑κB)
family of transcription factors81 (FIG. 3a).
b Parenchymal cells Phagocytosis is also associated with the produc-
tion of ROS by macrophages, which supports stem cell
division and differentiation towards tissue healing and

IL-22R EGFRs IL-33 Figure 3 | Immune regulation of tissue damage control.

a | Tissue-resident macrophages use pattern recognition
IL-1
receptors (PRRs), interleukin receptors (ILRs) and/or aryl
EGFs ST2 hydrocarbon receptors (AHRs) to sense environmental cues,
ILC2
(e.g. AREG)
including pathogens, dying infected cells and alarmins —
Stress
such as damage-associated molecular patterns (DAMPs),
interleukin‑1 (IL‑1), IL‑18, IL‑33 or l‑kynurenine generated
IL-22 by host parenchymal cells via tryptophan 2,3‑dioxygenase18
IL-1R
ILC3 — that alert cells to disruption of homeostasis. Signalling by
Stress these sensors polarizes macrophage responses to resolve
NCR inflammation and to assist parenchymal cells in restoring
c Parenchymal cells homeostasis18,170,171. This non cell-autonomous mechanism
supporting tissue damage control is mediated by the
production of gasotransmitters, including nitric oxide (NO),
carbon monoxide (CO) and probably hydrogen sulphide
(H2S), and by the secretion of cytokines, such as tumour
necrosis factor (TNF), IL‑6 and IL‑10, and growth factors,
EGFRs Stress including transforming growth factor‑β (TGFβ) and members
IL-18 of the platelet-derived growth factor (PDGF) family.
and b | Tissue-resident innate lymphoid cells (ILCs) can sense
IL-33 alarmins, such as IL‑33 and IL‑1, via the corresponding ILRs
EGFs Treg cell ILR
(e.g. AREG) or can sense cellular stress and damage via natural
cytotoxicity receptors (NCRs)85. These trigger the production
MHC TCR of cytokines such as IL‑22 and epidermal growth factors
class II (EGFs), including amphiregulin (AREG), which promote
ILR tissue damage control in parenchymal cells, such as
epithelial cells85,86,88. c | Tissue-resident regulatory T (Treg) cells
Macrophage sense alarmins, such as IL‑18 and IL‑33, which elicit the
Stress production of AREG91–93, affecting parenchymal cells to
promote tissue damage control91–93 and to establish
Sensor
PRR
disease tolerance to infection92. PCD, programmed cell
Pathogen death; PDGFR, PDGR receptor; EGFRs, EGF receptors;
(DAMP) TCR, T cell receptor.

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Nutritional immunity
An evolutionarily conserved
resistance mechanism against
infection based on the host’s
ability to withhold nutrients,
such as iron, from pathogens.
regeneration82. This process involves repression of the
transcriptional programme activated by NRF2 (REF. 83),
revealing a tight integration of stress and damage
responses with subsequent tissue repair and regenera-
tion programmes, which restore host homeostasis23,82,84
(FIGS 1,2). How these apparently conflicting activities
exerted by cytokines such as TNF or ROS are resolved
remains to be understood23. This suggests, nevertheless,
that antimicrobial macrophage responses have built‑in
feedback loops promoting tissue damage control.
Innate lymphoid cells. All three classes of ILCs, that is
ILC1, ILC2 and ILC3, have a crucial role in sensing tissue
dysfunction and damage, regulating tissue damage con-
trol responses85, which contribute to the establishment
of disease tolerance to viral86 and helminth87 infections.
These cells are also operational during intestinal inflam-
mation88. For example, ILC2s can sense alarmins, such
as IL‑33, and promote tissue damage control in epithelia
via a mechanism that involves the production of the epi-
dermal growth factor (EGF)-like molecule amphiregu-
lin85,86,88 (FIG. 3b). Natural cytotoxicity receptors (NCRs)
expressed by ILC3s can sense ligands expressed by path-
ogens as well as self ligands upregulated in response to
cellular stress85, which leads to the production of IL‑22,
an IL‑10 family member that promotes epithelia repair
and regeneration89 (FIG. 3b).
Regulatory T cells. Natural loss of function mutations
in the gene encoding the Treg cell lineage commitment
transcription factor forkhead box protein P3 (FOXP3)
are associated with development of severe immuno­
pathology in both mice and humans90. This suggests
that Treg cells contribute to tissue damage control and
presumably therefore regulate the establishment of dis-
ease tolerance to infection. The physiological functions
of Treg cells have mostly been assigned to their capacity
to restrain adaptive and to a lesser extent innate immune
responses90. More recently, tissue-resident Treg cells were
shown to also promote tissue damage control mechan­
isms91–93, which can contribute to the establishment of
disease tolerance to influenza virus infection92. This pro-
tective effect involves sensing of alarmins, such as IL‑18
or IL‑33, which elicits the production and secretion of
amphiregulin15,91,92 by tissue-resident Treg cells91–93 (FIG. 3c).
Whether this protective effect functions via direct inter-
action of tissue-resident Treg cells with parenchymal cells
or indirectly through immunoregulatory mechanisms
involving tissue-resident macrophages or ILCs has not
been established (FIG. 3c).
Stress and damage responses in immune cells. When
exposed to different forms of infection-associated stress,
tissue-resident macrophages, ILCs and Treg cells should
activate the same stress and damage responses that
operate in parenchymal cells to promote tissue damage
control and disease tolerance to infection. For example,
NRF2 activation in macrophages35 or in T cells94 exerts
immunoregulatory effects that promote tissue damage
control. Furthermore, activation of HIF1α in macro­
phages controls a metabolic response39,95 that shifts
the balance between TH17 and Treg cells96, and thereby
modu­lates immune-driven resistance and possibly dis-
ease tolerance to infection. Activation of other stress and
damage responses in tissue-resident leukocytes probably
exerts similar effects, but this is yet to be determined
experimentally.
Pathogen-specific tissue damage control
Multicellular organisms establish stable symbiotic inter-
actions with a wide range of microorganisms, which
affects different aspects of their physiology 97 and also
modulates resistance and disease tolerance to patho-
gens22 (BOX 3). Infection by viruses, bacteria, fungi, pro-
tozoan parasites or helminths imposes distinct forms
of stress and damage on host parenchymal cells that
are driven by intrinsic differences in virulence mech-
anisms and countervailing host immune-driven resist-
ance mechanisms elicited. Thus, tissue damage control
mechanisms probably function in a pathogen-specific
manner to confer disease tolerance to different types of
infection, as originally shown in flies98 and thereafter
in mice6,99,100. In this section we discuss how immune-
driven resistance to a specific pathogen class regulates
tissue damage control mechanisms that contribute to the
establishment of disease tolerance to pathogens within
the same or other classes.
Intracellular pathogens. Host resistance to intra­cellular
pathogens, such as viruses and certain bacteria, relies to
a large extent on targeting infected cells for programmed
cell death by type 1 immunity-driven cytotoxic mechan­
isms101 (FIG. 4a). Hence, tissue damage control mech­anisms
opposing type 1 immunopathology should not rely on
cytoprotection of infected cells, as this would compro-
mise resistance to intracellular pathogens. Instead, these
tissue damage control mechanisms are more likely to
promote cell regeneration and tissue repair as a means
to compensate for loss of infected and bystander paren-
chymal cells, restoring tissue homeo­stasis15,92 (FIG. 4a). The
mechanisms by which this occurs are not completely
established but are probably tissue specific6 and involve
the production of EGF and PDGF family members as
well as TGFβ, which promote stem cell proliferation
and/or differentiation into parenchymal cells and thereby
restore tissue integrity and f­ unction23 (FIG. 4a).
Extracellular parasites. Host resistance to extracellular
metazoan parasites mainly depends on type 2 immu-
nity 101,102. Some of these parasites are damaging to host
parenchymal tissues, which presumably explains why
type 2 immunity encompasses tissue damage control
mechanisms that contribute to the establishment of dis-
ease tolerance103 (FIG. 4b). Type 2 immunity targets patho­
gens primarily for containment or expulsion, probably
because of the inherent failure of most immune-driven
cytotoxic molecules to kill large metazoan parasites
such as helminths (FIG. 4b). In addition, type 2 cytokines
promote macrophage polarization towards granuloma
formation and thereby contain pathogens and deprive
them of essential nutrients. This resistance mechanism,
known as nutritional immunity, is perhaps best illustrated

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by the modulation of host iron metabolism as a strat-
egy to deprive pathogens of this essential nutrient 104.
Macrophage polarization by type  2 cytokines also
deprives pathogens of access to other essential nutrients
such as arginine, which is depleted via the expression of
high levels of arginase in macrophages105. Arginine deple-
tion also prevents sustained T cell activation and thereby
limits immunopathology 105. As a trade-off, nutritional
immunity can impose metabolic stress on host parenchy-
mal cells, thereby activating stress responses that confer
meta­bolic adaption and possibly tissue damage control
and disease tolerance to extracellular parasites (FIG. 4b).
Extracellular bacteria and fungi. Host resistance to
pathogenic extracellular bacteria and fungi relies to a
large extent on TH17 immunity 101. Most of the immune

Box 3 | Microbiota and disease tolerance

There are numerous examples of symbiotic microorganisms that enhance resistance to infection in animals22. The
bacterial endosymbiont Wolbachia, for example, enhances resistance to Drosophila C virus in flies10,132 and to dengue,
chikungunya as well as Zika virus infections in mosquitoes133,134 (see the figure, part a). This protective effect has been
linked to priming of the insect innate immune system and possibly competition for resources supporting pathogen
replication135,136. Symbiotic interactions between bacteria and mice can also promote immune-driven resistance
mechanisms against viral137, bacterial138 or protozoan139,140 infections (see the figure, part a). This suggests that the
establishment of stable symbiotic interactions between microcellular and multicellular organisms is a widespread
recurrent trait that modulates host resistance against a range of pathogens.
Symbiotic bacteria can also modulate tissue damage control and disease tolerance to infection in multicellular
organisms10,22,141,142 (see the figure, part b). For example, Wolbachia enhance disease tolerance to flock house virus
infection in flies10 and against Plasmodium relictum infection in mosquitoes142. In mice, bacteria that colonize the gut
— such as the human symbiont Bacteroides fragilis — confer disease tolerance to Helicobacter hepaticus infection143,
whereas the gut symbiont Escherichia coli O21:H+ confers disease tolerance to Burkholderia thailadensis or Salmonella
enterica subsp. enterica serovar Typhimurium infections141 (see the figure, part b).
Although the mechanisms by which endosymbiotic bacteria promote disease tolerance to viral infections in insects
are not completely understood, some mechanistic insight is emerging in mice22. For example, the gut commensal E. coli
O21:H+ confers disease tolerance to systemic bacterial infections via a mechanism that involves the activation of the
NLRC4 (NOD-, LRR- and CARD-containing 4) inflammasome, which induces the production of interleukin‑18 (IL‑18)141.
This alarmin sustains the production of insulin-like growth factor 1 (IGF1), which activates the phosphoinositide
3‑kinase (PI3K)–AKT signal transduction pathway and represses the expression of the E3 ubiquitin ligases atrogin 1 (also
known as FBXO32) and MURF1 (also known as TRIM63) in muscle cells141. This prevents the development of muscle
atrophy and the loss of body weight, which are common pathological outcomes of infection. Components of the
microbiota can also modulate disease tolerance by altering the glycosylation profile of the gut epithelia lumen — as
shown for regulation of fucose expression under inflammatory conditions — which modulates microbiota composition,
metabolism and gene expression in a manner that promotes disease tolerance to enteric infection by Citrobacter
rodentium144. Modulation of host metabolism by bacterial components of the microbiota145 probably also modulates
tissue damage control mechanisms and disease tolerance to infection22. Whereas bacterial symbionts such as
Clostridium strains146 can promote the development of regulatory T (Treg) cells in mice, it is not clear whether this in turn
modulates disease tolerance to infections.
In the same way that pathogens can modulate host resistance mechanisms, some pathogens can also promote disease
tolerance as the means to support their own survival, proliferation and/or transmission. For example, S. Typhimurium
induces the activation of host RHO GTPases and
mitogen-activated protein kinases (MAPKs), which leads
to the activation of nuclear factor‑κB (NF‑κB) and to the a
expression of downstream pro-inflammatory genes in the Endosymbiotic bacteria Symbiotic bacteria
gut epithelium147. This activation enables S. Typhimurium e.g. Wolbachia i.e. microbiota
to overcome immune-driven host resistance imposed by
the resident gut microbiota147 and promotes invasion of Enhanced resistance to
gut epithelial cells and systemic infection148. During
bacterial invasion of the epithelium, S. Typhimurium Drosophila C virus, Influenza A virus, E. coli
dengue virus and and Plasmodium spp.
secrete proteases that target the NF‑κB family members chikungunya virus infections in mice
RELA and RELB and inhibit the transcription of infections in insects
downstream pro-inflammatory genes149. This
immunoregulatory effect limits tissue damage and
disease severity without interfering with host pathogen b
load149; thus, S. Typhimurium promotes disease tolerance Symbiotic bacteria
to infection. Endosymbiotic bacteria
e.g. B. fragilis and
e.g. Wolbachia
Another example of how bacteria can promote disease E. coli O21:H+
tolerance is the induction of IL‑10 by Staphylococcus
Enhanced disease tolerance to
aureus150. Recognition of staphylococcal peptidoglycan
by Toll-like receptor 2 (TLR2) induces IL‑10, which Flock house virus and H. hepaticus, B. thailadensis,
prevents unfettered T cell activation; hence, the P. relictum infections Salmonella spp. and
response to S. aureus infection promotes tissue damage in insects C. rodentium infections
control and disease tolerance to infection150. in mice

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resistance mechanisms associated with TH17 immunity, Therapeutic modulation of disease tolerance
including pathogen killing, are mediated by neutro- In some cases, effective pathogen elimination by
phils101. This can be associated with the development immune-driven resistance mechanisms fails to over-
of immunopathology, as shown at epithelial barriers come the morbidity or mortality associated with infec-
where ROS and elastase produced by neutrophils can tion. Moreover, current antimicrobial approaches can
cause epithelial cell damage and compromise disease also fail to treat infectious diseases. In these cases, a
tolerance to pathogenic Gram-negative bacteria, for rational pharmacological targeting of stress and dam-
example, in the case of infection with Burkholderia age responses regulating tissue damage control may act
pseudomallei 106 (FIG.  4c). TH17 immunopathology is therapeutically through the establishment of disease
counteracted by tissue damage control mechanisms tolerance to infection. Examples of proof‑of‑concept
that protect epithelial barriers against oxidative stress for this approach are provided by pharmacological
and damage as well as by additional mechanisms that targeting of adenosine receptors110 or labile haem16,
promote tissue repair and regeneration (FIG. 4c). Some which promote the establishment of disease tolerance
of these mechanisms are regulated directly or indirectly to ­sepsis16,110 or malaria20,21,30 in mice.
by IL‑22 produced by TH17 cells or by ILC3s, which When targeting labile haem, several pharmaco­logical
signals via the IL-22 receptor expressed by epithelial strategies can be envisioned. For example, administra-
cells86,88,107 (FIG. 4c). tion of haemopexin — which is a plasma protein that
binds avidly to labile haem and neutralizes its dele-
Disease tolerance to co‑infections terious effects — confers tissue damage control and
Pathogen class-specific tissue damage control mech- disease tolerance to sepsis in mice16. Gasotransmitters
anisms are particularly relevant in the context of co‑­ such as CO21 can also be used pharmacologically to
infections, as shown for bacterial pneumonia following block haem–iron oxidation (Fe2+ to Fe3+) and inhibit
influenza virus infection108. Several mechanisms may haem release from haemoproteins, thereby preventing
contribute to worsen the clinical outcome of these co‑­ its accumulation in plasma during bloodstream infec-
infections. Viral infections can compromise immune- tions20,21. Remarkably, this is sufficient to confer disease
driven resistance99 or tissue damage control15 mechanisms tolerance to malaria in mice20,21,30. When used pharma-
against bacterial co‑infections, as is the case for influenza cologically, the gasotransmitter NO also promotes the
virus and Legionella pneumophila co-­infections15,99. This establishment of disease tolerance to malaria in mice29.
is probably also the case for co‑­infections by rhinovirus, This protective effect of NO occurs via an indirect
adenovirus or parainfluenza and Streptococcus pneumo- mechanism involving the activation of the transcrip-
niae, as well as for Haemophilus influenza and Moraxella tion factor NRF2, the induction of HO1 expression and
catarrhalis co-infections108. The mechanisms by which the downstream generation of CO, which consequently
viruses compromise disease tolerance to secondary bac­ establishes disease tolerance to malaria29–31. In addition
terial infections are probably multi-factorial and have to preventing haem release from extracellular haemo-
been associated with the dysregulated production of globin, the cytoprotective effects of CO75 should also
EGF-like factors, such as a­ mphiregulin15, by ­lung-­resident contribute to promote tissue damage control and dis-
ILCs86 and Treg cells92. ease tolerance to malaria. As labile haem is a potent
Immune-driven resistance mechanisms targeting pro-oxidant, pharmacological use of antioxidants such
viruses can also promote, rather than impair, disease as N‑acetyl cysteine can prevent this pathogenic effect
tolerance to bacterial infections. For example, regula- and thereby confer tissue damage control and dis-
tion of IL‑1β‑induced inflammation by type I interferon ease tolerance to malaria12,13. Moreover, downstream
(IFN) prevents the lethality of systemic Streptococcus events in the signalling transduction pathways driving
pyogenes infection, without affecting bacterial load109. haem cytotoxicity, such as sustained activation of JUN
In this case, signalling via type I IFN receptor in macro­ amino‑­terminal kinases, can also be targeted pharmaco­
phages, DCs and neutrophils represses IL‑1β tran- logically to promote recovery and survival through
scription through signal transducer and activator of ­tissue ­damage control during malaria infection13.
transcription 1 (STAT1), and to a lesser extent through Pharmacological targeting of metabolic stress
STAT2, which ultimately prevents the development of responses, such as the one regulated by 5′ AMP-
lethal IL‑1β‑driven inflammation109. activated protein kinase (AMPK), confers protection
Disease tolerance against one class of pathogens has against the development of organ dysfunction associ­
also been shown to antagonize immune-driven resist- ated with the pathogenesis of sepsis in mice111. This
ance against other pathogen classes. For example, the treatment is not associated with overt modulation of
induction of HO1 expression promotes disease tol- the host pathogen load, which suggests that AMPK
erance to the blood stage of Plasmodium spp. infec- activation contributes to the establishment of disease
tion12,20,21,30 but impairs resistance to Salmonella enterica tolerance to sepsis111. In further support of this idea,
subsp. enterica serovar Typhimurium co-infection100. pharmacological AMPK activation in the brain is
This is thought to involve dysregulated mobilization of sufficient to confer protection against polymicrobial
granulocytes from the bone marrow with concomitant ­infections in mice112.
induction of HO1 during Plasmodium spp. infection, Another possible approach to modulate disease tol-
which reduces their subsequent capacity to generate erance involves targeting the inflammatory response
ROS and to clear S. Typhimurium infection100. to infection without interfering with immune-driven

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resistance mechanisms. This can be achieved, for exam-
ple, by pharmacological inhibition of topoisomerase 1,
which suppresses the recruitment of RNA polymer-
ase II to the promoter of PRR-responsive genes113. This
approach confers a net survival advantage, presum-
ably through the establishment of disease tolerance,
against viral and bacterial infections as well sterile tis-
sue injury in mice113. Pharmacological use of cytokines
that are cytoprotective in parenchymal cells, such as
IL‑10 (REF. 114) and IL‑22 (REF. 115), or that promote
tissue regeneration, such as EGF-like factors, includ-
ing amphiregulin15,92, have also been shown to promote
­disease tolerance to infections in mice.
Furthermore, pharmacological targeting of specific
host resistance mechanisms associated with the devel-
opment of immunopathology is another therapeutic
approach to establish disease tolerance to infection116.
However, as a trade-off, this strategy can be associ-
ated with reduced host resistance and hence increased
pathogen load, as shown for influenza A virus117 and

Intracellular Proliferation and

a pathogen Infected cell PCD differentiation

NK Tissue
Tissue
cell damage
damage
control
IFNγR MHC
TCR class I ROS EGFs,
RNS Macrophage ? PDGFs
or DC and
CTL TGFβ
IL-12 IFNγR
IFNγR MHC
TCR class II
Stem cell
B cell
TH1
cell IFNγ
IFNγR
IFNγ

b TSLP, ILR EGFs? Tissue

Tissue IL-25
and ILC2 damage
damage
IL-33 EGFR control
Eosinophil Parasite ST2
Mast cell VEGF, TGFβ,
Basophil PRR RELMα and
Macrophage ?
RELMβ
IgG1 or DC
and
IgE IL-4Rα
MHC
TCR class II
Granuloma B cell IL-4
TH2
cell
ILR
IL-5 and IL-13

Extracellular
c pathogen
PRR

PRR Tissue
Tissue ROS Macrophage damage
damage Elastase DAMP or DC control

IL-1β IL-22R FGF2R

MHC
TCR class II IL-23 FGF2
IL-1R
TH17
cell
IL-23R
IL-17 Treg cell
Neutrophil
IL-1R IL-22
IL-1β ILC3
IL-17
NCR
Stress

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Anthracycline Trypanosoma cruzi 118, as well as for human rhinovirus119
A class of red aromatic infections in mice. In some cases, however, pharmaco-
polyketide drugs derived from logical targeting of host resistance mechanisms can con-
Streptomyces spp. bacteria fer tissue damage control without impairing resistance
that intercalate into DNA,
arresting transcription and cell
to infection. This is shown for Mycobacterium tubercu-
division, a property widely losis infection in mice116, in which cyclooxygenase inhi-
used therapeutically against bition using ibuprofen decreases both lung lesions and
cancers. pathogen load. These, among other studies, provide the
proof‑of‑principle that immunoregulatory mech­anisms
can be targeted pharmacologically to confer tissue
damage control and disease tolerance to different types
of infection when antimicrobial therapy alone fails to
­overcome host morbidity or mortality.
An important question to address is how to ration-
ally design therapeutic approaches that would target
tissue damage control mechanisms and confer disease
◀ Figure 4 | Pathogen class-specific tissue damage control mechanisms. a | Type 1
immunity drives resistance to viruses and intracellular bacteria, such as Listeria
monocytogenes, Salmonella spp. and Mycobacteria spp., as well as to intracellular
protozoan parasites such as Leishmania spp.101. The T helper 1 (TH1) signature cytokine
interferon‑γ (IFNγ) has a central role in triggering cytotoxic mechanisms that, although
directed against intracellular pathogens, can lead to tissue damage through various
means, including macrophage polarization towards an antimicrobial response
associated with the production of high levels of reactive oxygen species (ROS) and
reactive nitrogen species (RNS), activation of CD8+ cytotoxic T lymphocytes (CTLs)
and natural killer (NK) cells to kill infected cells via the perforin and/or granzyme
B‑dependent lytic pathway or via the ligation of surface death receptors; and B cell
activation towards the production of cytolytic antibodies that target infected cells for
complement and Fc receptor-mediated cellular cytotoxicity. Tissue damage control
mechanisms counteracting type 1 immunopathology rely on cellular regeneration and
tissue repair to restore homeostasis15,92. The mechanisms by which type 1 immunity
contributes to this tissue damage control response are not clear but probably involve the
production of epidermal growth factors (EGFs), transforming growth factor‑β (TGFβ) and
platelet-derived growth factor (PDGF), which drive the proliferation and differentiation
of stem cells into functional parenchymal cells, restoring tissue integrity and function23.
b | Resistance to extracellular metazoan parasites and other large parasites is mediated
and/or involves type 2 immunity101,102. Pathogen neutralization is achieved via different
mechanisms controlled by TH2 signature cytokines, including interleukin‑4 (IL‑4), IL‑5 and
IL‑13, and by additional type 2 cytokines such as thymic stromal lymphopoietin (TSLP),
IL‑25 or IL‑33, secreted by damaged cells101,102. TH2 signature cytokines drive B cell
activation towards the production of high-affinity pathogen-specific IgG1 and IgE
antibodies that function via Fc‑dependent mechanisms to trigger the activation of
eosinophils, mast cells and basophils, expelling pathogens across epithelia102. Some of
these parasites, for example, helminths, are damaging to parenchymal cells and type 2
immunity encompasses tissue damage control mechanisms that confer disease tolerance
to infection by these parasites103. These mechanisms involve the production of EGFs,
vascular endothelial growth factor (VEGF), TGFβ, resistin-like molecule-α (RELMα) and
RELMβ. c | TH17 immunity confers resistance to extracellular bacteria such as Klebsiella
pneumoniae, Escherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas
gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans,
Coccidioides posadasii, Histoplasma capsulatum and Blastomyces dermatitidis101.
Activation of TH17 cells by cognate T cell receptor (TCR–MHC class II interactions and
activation of group 3 innate lymphoid cells (ILC3s) via engagement of IL‑1 receptor
(IL‑1R) by IL‑1β secreted from damaged cells lead to the recruitment and activation
of neutrophils106. TH17 immunopathology is driven to a large extent by products of
neutrophil activation, such as ROS and elastase. This is countered by tissue damage
control mechanisms regulated directly or indirectly by IL‑22, originating from TH17 cells,
TH22 cells (not shown) or ILC3s, and promoting tissue damage control. Other cytokines
produced by TH17 cells, including IL‑17, can amplify this protective response, working
together with fibroblast growth factor 2 (FGF2) produced by regulatory T (Treg) cells to
promote tissue damage control at epithelial barriers172. DC, dendritic cell; EGFR, EGF
receptor; FGF2R, FGF2 receptor; IFNγR, IFNγ receptor; ILR, interleukin receptor;
PCD, programmed cell death; PRR, pattern recognition receptor.
tolerance to infection. One possible way forward is the
use of functional ‘drug screens’, which have already
been successful in identifying anthracycline as a family of
chemotherapeutic agents inducing disease tolerance to
sepsis in mice17. The therapeutic effect of anthra­cyclines
was associated with the induction of tissue damage con-
trol via a mechanism involving the ATM kinase17. This
and a subsequent study 113 suggest that targeting specific
components of the host DNA damage response machin-
ery has therapeutic potential in the establishment of
­disease tolerance to sepsis.
Finally, a few classes of antibiotics — macrolides,
fluoroquinolones, tetracyclines and polymyxines — are
labelled as immunomodulatory on the basis of their
ability to improve the outcome of chronic disorders via
mechanisms not readily explained by their antimicro-
bial activity 120. Macrolides have the best-documented
immuno­modulatory activity; for example, the therapeu-
tic effects of the macrolide azithromycin in cystic fibrosis
can be dissociated from its antibacterial activity 120. The
immunomodulatory effect of these antibiotics probably
goes beyond inhibition of pro-inflammatory medi­
ators and other immune processes and could involve
the modu­lation of molecular pathways associated with
the regulation of host lifespan. In support of this idea,
tetracyclines increase longevity in Caenorhabditis ele-
gans via a mechanism involving the unfolded protein
response (UPR)121, which is a damage response that
promotes disease tolerance to infections (as discussed
above). Colistin induces the activation of the forkhead
box O (FOXO) pathway, which is another lifespan exten-
sion pathway in C. elegans that confers disease tolerance
to Gram-negative infections122. Of note, these anti­
biotics have not been shown to exert a direct effect on
tissue damage control mechanisms and more definitive
conclusions need to be experimentally confirmed, for
­example, by using germ-free organisms.
Concluding remarks and perspectives
It is now clear that multicellular organisms use two
genetically distinct defence strategies to limit the patho-
genicity of microorganisms. The prevailing view has long
been that immune-driven host resistance mechanisms
that contain, kill or expel invading microorganisms are
the prevailing defence strategy against infectious dis-
eases. However, disease tolerance is an equally impor-
tant host defence strategy against infection, which
does not have a direct negative effect on pathogens and
functionally interacts with immune-driven resistance
mechanisms to limit the severity of infectious diseases.
The cellular and molecular bases of these interactions
are only now starting to be appreciated. A series of
experimental approaches have been used to identify
and characterize the molecular and cellular basis of
tissue damage control mechanisms conferring disease
tolerance to various pathogens. These mechanisms
have so far been restricted to numerous evolutionarily
conserved stress and damage responses, which have in
some cases been associated with immunoregulatory
responses controlling host resistance mechanisms.
How immuno­regulatory mechanisms modulate these

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stress and damage responses to confer disease tolerance
to infection is fairly unexplored. A growing number
of experimental evidence also suggests that symbiotic
microorganisms can regulate disease tolerance to pre-
vent their pathogenicity as well as that of other patho-
gens22. However, whether this regulation occurs via the
induction of immunoregulatory mechanisms and/or
the activation of stress and damage responses remains
to be established. Deciphering the cellular and molecular
nature of these interactions is crucial for understanding,
and perhaps subsequently shaping, therapeutic strat­egies
to manipulate protection against major infectious dis-
eases in which host resistance mechanisms fail to limit
disease severity. Such therapeutic approaches will prob-
ably also be important to overcome the growing global
health threat imposed by the emergence of multidrug-­
resistant pathogens as well as to treat co‑infections
­associated with high levels of morbidity and mortality.

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Acknowledgements
The authors thank J. Thompson and F. Brazza for insightful com-
ments and S. Ramos for careful review and editing of the manu-
script (Instituto Gulbenkian de Ciência). M.P.S. is supported by
Fundação Calouste Gulbenkian, Fundação para a Ciência e
Tecnologia (FCT; PTDC/SAU-TOX/116627/2010 and HMSP-
ICT/0022/2010) and the European Community 7th Framework
program (ERC‑2011‑AdG 294709‑DAMAGECONTROL). L.F.M.
is an Fundação para a Ciência e Tecnologia Investigator and is
supported by the European Community Horizon 2020
(ERC‑2014‑CoG 647888‑­iPROTECTION). L.T. is supported by
Fundação Calouste Gulbenkian and Fundação para a Ciência e
Tecnologia PTDC/BEX-GMG/3128/2014.
Competing interests statement
The authors declare no competing interests.

14 | ADVANCE ONLINE PUBLICATION www.nature.com/nri

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