Inflammation and oxidative stress in
vertebrate host–parasite systems
Gabriele Sorci*and Bruno Faivre
BioGe ´oSciences, CNRS UMR 5561, Universite ´ de Bourgogne, 6 Boulevard Gabriel, 21000 Dijon, France
Innate, inflammation-based immunity is the first line of vertebrate defence against micro-organisms.
Inflammation relies on a number of cellular and molecular effectors that can strike invading
pathogens very shortly after the encounter between inflammatory cells and the intruder, but in a non-
specific way. Owing to this non-specific response, inflammation can generate substantial costs for the
host if the inflammatory response, and the associated oxygen-based damage, get out of control. This
imposes strong selection pressure that acts to optimize twokey features of the inflammatory response:
the timing of activation and resolution (the process of downregulation of the response). In this paper,
we review the benefits and costs of inflammation-driven immunity. Our aim is to emphasize the
importance of resolution of inflammation as awayof maintaining homeostasis against oxidativestress
and to prevent the ‘horror autotoxicus’ of chronic inflammation. Nevertheless, host immune
regulation also opens the way to pathogens to subvert host defences. Therefore, quantifying
inflammatory costs requires assessing (i) short-term negative effects, (ii) delayed inflammation-
driven diseases, and (iii) parasitic strategies to subvert inflammation.
Keywords: ageing; delayed costs; immune evasion; innate immunity; nitric oxide;
reactive oxygen and nitrogen species
Immune defences may be seen as one of the most
sophisticated products of interspecific interactions.
They are the result of frequent and long ‘arms races’
between hosts and parasites. As a result, hosts have
evolved complex strategies to avoid the negative effects
of parasites, and parasites have evolved many adaptive
responses to counteract and evade the hosts’ defences.
Recognizing pathogenic organisms and clearing infec-
tion is the primary function of immunity (Medzhitov &
Janeway 1997). This self-defence ability exists in
unicellular organisms (that can produce microbicidal
molecules), and reaches a high complexity in
vertebrates (that possess a wide array of effectors that
operate to cope with pathogenic invaders; Armstrong &
Quikley 1999; Bulet et al. 2004).
Vertebrate immunity basically depends on two arms:
innate and acquired immunity. The protective proper-
ties of innate immunity rely on constitutively produced
receptors (pattern recognition receptors) that recognize
distinct and conserved microbial molecular structures
(pathogen-associated molecular patterns, PAMPs),
which are absent from the host: once bound, these
receptors directly activate the host’s immune cells. The
outcome of this activation is the initiation of the innate
inflammatory response (Janeway & Medzhitov 2002;
Akira et al. 2006). By contrast, acquired immunity is
characterized by a vast repertoire of lymphocytes,
bearing antigen-specific surface receptors that recognize
specific antigenic configurations of pathogens and
respond by triggering cellular (cytotoxic T-cells) and
humoral (antibodies) effectors. In addition to specificity,
acquired immunity differs from innate immunity in its
ability to establish an immunological memory, which
allows a more rapid and effective response upon
re-exposure to the antigen (Cooper & Alder 2006).
The dichotomy between innate and acquired immunity,
while useful for a classification purpose, does not mean
that these two branches work independent of one
another. Acquired immunity largely depends upon the
cells of the innate immune response to drive their
functional maturation (Bayne 2003). In spite of the
intimate connection between the innate and acquired
immune responses and the major role played by the
innate effectors in the process of parasite resistance, we
still tend to focus on acquired immunity as the most
important weapon against pathogens. This is evidenced
by the biased representation of the acquired immune
effector systems that have been studied in ecological
immunity studies on vertebrates.
Inflammation is a non-specific process, elicited by
trauma or infection, characterized by the delivery of
fluids, molecules and cells from the blood into
damaged or infected tissues, whose function is to
fend off infectious agents. Although inflammation is
commonly considered a vertebrate phenomenon, an
inflammatory-like status has also been reported in
invertebrates (Libert et al. 2006) where cells releasing
toxic products and chemical signals are involved. The
systemic effects of the vertebrate inflammatory
Phil. Trans. R. Soc. B (2009) 364, 71–83
Published online 17 October 2008
One contribution of 11 to a Theme Issue ‘Ecological immunology’.
*Author for correspondence (firstname.lastname@example.org).
This journal is q 2008 The Royal Society
response include fever and an increased number of
leucocytes recruited for defence (Sell 2001). Several
leucocyte families, e.g. granulocytes, monocytes (the
precursors of macrophages) and lymphocytes, migrate
to the focal area of the infected tissue and secrete
metabolites, which have potent microbicidal properties
that act through phagocytosis and exocytosis (Sell
2001). Upon encounter with an intruder, inflammatory
cells produce peptides that play a key role in cellular
communication. These peptides, called cytokines, can
further activate and recruit other phagocytic cells, as
well as drive their microbicidal activity. Phagocytes can
kill engulfed pathogens mostly through the action of
endogenously produced compounds with cytotoxic
effects, such as enzymes, lytic peptides, as well as highly
reactive oxygen and nitrogen species (ROS and RNS;
Fang 2004; Swindle & Metcalfe 2007). In addition, and
besides their cytotoxicity, at a low dose, ROS and
especially nitric oxide (NO) also play a regulatory role as
modulators of cellular communication and apoptosis
(Matsuzawa et al. 2005; Swindle & Metcalfe 2007).
The effectors of inflammation endoworganismswith
efficient weapons to cope with the pervasiveness of
infectious agents. The most compelling support to this
view is the high sensitivity to infection, and the reduced
survival prospect, of organisms showing deficiencies in
the inflammatory process (Fang 2004). However,
immune systems are not infallible, and the inflam-
matory response should be viewed as a double-edged
sword that protects, but has the potential to harm, the
host. Host tissue may be damaged when immune
defences are misdirected, or overexpressed, leading to
immunopathology. Although the distinction between
immunopathologies and their origin is still debated
(McGonagle & McDermott 2006), there is little doubt
that chronic inflammation produces collateral undesir-
able effects on the host. In addition, it has been
suggested that the cost of infection is more due to an
over-reacting inflammatory response than a direct
effect of the pathogen (Ra ˚berg et al. 1998; Mackintosh
et al. 2004; Graham et al. 2005; Halliwell 2006 for
reviews). To protect their tissues from inflammatory
injury, hosts have evolved a regulatory network based
on a class of cytokines (such as interleukin-10 or
transforming growth factor-b) that control the res-
olution of inflammation once the pathogen has been
cleared (Belkaid 2007).
Although the study of the molecular and cellular
mechanisms of inflammation-based resistance is of
prime importance from a biomedical perspective,
understanding the selective forces and the constraints
shaping the evolution of the diversity of host defences
and parasite strategies to exploit the host requires an
evolutionary approach. The aim of this paper is to
provide a discussion of the evolutionary ecology of
parasite-mediated inflammation. We will first briefly
review the mechanisms, which are at the basis of the
inflammatory response, with a special focus on
the production of ROS and RNS. Then, we will
discuss the selective forces and constraints that are
likely to act on inflammation: the benefits of early and
effective protection against intruders and the inevitable
costs of non-specificity. Because parasite exposure and
host response vary with ontogeny, we will address the
question of age-related costs and benefits of inflam-
mation. Finally, we will see that the pathogens can
modify and manipulate host inflammation for their
own survival and spread. This adds considerable
complexity to the understanding of the evolutionary
ecology of parasite-mediated inflammation.
2. THE ROLE OF ROS AND RNS IN THE
Phagocytic cells, such as macrophages and neutrophils
(heterophils in birds), are at the core of the innate
inflammatory response. Activation of phagocytic cells
induces the production of antimicrobial compounds
that, once transferred into the phagosome, play a
primordial role in killing phagocytized pathogens.
ROS and RNS are probably the most important
micromolecules that intervene during the inflam-
mation-based control of invading pathogens. The
most prominent feature of ROS and RNS is their
generic cytotoxicity. These chemically reactive
molecules cannot discriminate between the structure
of host molecules, cells and tissues and infectious
agents. This is in stark contrast to the fine-tuned
capacity of the cells and molecules of the acquired
immune system, which can recognize specific epitopes
and surgically target the defence response. In §2a, we
will first briefly describe the molecular nature of
ROS and RNS, and their production and will then see
how these reactive molecules achieve the goal of
(a) ROS and RNS
Upon stimulation by a PAMP, neutrophils and
macrophages respond by a marked increase in oxygen
(O2) uptake. This increase in O2 consumption
characterizes the so-called respiratory burst and is the
consequence of the activation of an enzymatic system
(NADPH oxidase or phox) that oxidizes NADPH into
NADPCplus superoxide anion (O$K
Superoxide, in addition to its own cytotoxic effect,
participates in the generation of other, more unstable
and damaging molecules, such as hydroxyl radicals
(OH%), hydrogen peroxide (H2O2) and hypochlorous
acid (HOCl). The half-life capacity to permeate cell
membranes and the cytotoxicity vary greatly across
different ROS. For instance, OH%has a half-life of a few
nanoseconds whereas chloramines are stable for hours
(Swindle & Metcalfe 2007).
RNS are the second class of micromolecules
secreted by phagocytic cells during the inflammatory
response. Nitric oxide (NO%) is the principal RNS
produced by neutrophils and macrophages. NO%is
generated enzymatically in a two-step reaction from
L-arginine substrate (Fang 2004). This reaction is
catalysed by a family of enzymes, the NO synthases
(NOS). The inducible NOS (iNOS) is responsible for
the burst in NO production following an inflammatory
insult. Nitric oxide has a cytotoxic effect but it can also
react with ROS to produce even more powerful
oxidants, such as peroxynitrite (ONOOK) or dinitro-
gen trioxide (N2O3) (Halliwell 2006).
2) (Fang 2004).
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