Review series on helminths, immune modulation and the ... · helminths are large in comparison to...

Review series on helminths, immune modulation and the hygienehypothesis: Immunity against helminths and immunological phe-

nomena in modern human populations: coevolutionary legacies?

Overview

A general consensus has emerged that effector T-helper

cell type 2 (Th2) mechanisms evolved to counter infec-

tions with helminths (and perhaps other large metazoan

parasites) and that these defences are generally deployed

against such pathogens within the context of a significant

regulatory T (Treg) cell response.1 There is also a growing

appreciation that immune responses against helminths

share some of the same signals and mediators as the

body’s damage repair systems.2 As the interaction between

the vertebrate immune system and at least some of the

major helminth groups extends back hundreds of millions

of years,3–5 near to a time when the adaptive immunity

first evolved6,7 (see Fig. 1), reciprocal co-adaptation may

have fundamentally shaped the characteristics of both.

Below we consider the mechanism of anti-helminth

immune responses and how ancient adaptations to deal

with helminth infection may have left their mark on the

way the immune system is structured and controlled. We

discuss how this relates to adverse immunological pheno-

mena seen in modern helminth-free human populations,

such as allergy, autoimmunity and responses to immuno-

pathological infectious agents.

Helminths

‘Helminth’ is a term used to group ecologically similar

worm-like parasites actually derived from three unrelated

phyla: the platyhelminths (tapeworms and flukes), the

nematodes (roundworms) and the acanthocephalans

(thorny-headed worms). A breathtaking diversity of

Joseph A. Jackson,1,2 Ida M.

Friberg,1 Susan Little1 and Janette

E. Bradley1

1School of Biology, The University of Notting-

ham, University Park, Nottingham, and2School of Biological Sciences, The University

of Liverpool, Liverpool, UK

doi:10.1111/j.1365-2567.2008.03010.x

Received 8 October 2008; revised 8 October

2008; accepted 8 October 2008.

Correspondence: J. E. Bradley, School of

Biology, The University of Nottingham,

University Park, Nottingham NG7 2QG, UK.

Email: [email protected]

Senior author: Janette E. Bradley

Summary

Although the molecules and cells involved in triggering immune responses

against parasitic worms (helminths) remain enigmatic, research has con-

tinued to implicate expansions of T-helper type 2 (Th2) cells and regula-

tory T-helper (Treg) cells as a characteristic response to these organisms.

An intimate association has also emerged between Th2 responses and

wound-healing functions. As helminth infections in humans are associated

with a strong Th2/Treg immunoregulatory footprint (often termed a ‘mod-

ified Th2’ response), plausible links have been made to increased suscepti-

bility to microbial pathogens in helminth-infected populations in the

tropics and to the breakdowns in immunological control (allergy and auto-

immunity) that are increasing in frequency in helminth-free developed

countries. Removal of helminths and their anti-inflammatory influence

may also have hazards for populations exposed to infectious agents, such

as malaria and influenza, whose worst effects are mediated by excessive

inflammatory reactions. The patterns seen in the control of helminth

immunity are discussed from an evolutionary perspective. Whilst an

inability to correctly regulate the immune system in the absence of hel-

minth infection might seem highly counter-adaptive, the very ancient and

pervasive relationship between vertebrates and helminths supports a view

that immunological control networks have been selected to function

within the context of a modified Th2 environment. The absence of immu-

noregulatory stimuli from helminths may therefore uncover maladapta-

tions that were not previously exposed to selection.

Keywords: coevolution; coinfection; hygiene hypothesis; regulation; Th2

18 � 2008 The Authors Journal compilation � 2008 Blackwell Publishing Ltd, Immunology, 126, 18–27

I M M U N O L O G Y R E V I E W A R T I C L E

species occur in vertebrates, the global fauna in an indi-

vidual vertebrate host species typically numbering tens or

even hundreds of different taxa. Life cycles may be direct,

with transmission from one definitive host to another, or

complex, involving distinct life-history stages cycling

through different host species. Invading stages often

undertake complex migrations through different organ

systems and tissues once inside the definitive host. Adult

helminths are large in comparison to microbial patho-

gens, individuals varying in size from hundreds of

microns to tens of metres long. Generally, they produce

propagules that are dispersed away from the existing host,

sometimes by an arthropod vector. The relatively slow

maturation time of individuals (a consequence of their

size) and the requirement for host–host dispersal to com-

plete the life cycle mean that the potential for the expo-

nential population growth seen in microbes that

reproduce in situ is very limited. Herein lies a fundamen-

tal difference. Whilst microbes represent an imminent

threat and are usually countered by rapid, relatively vio-

lent inflammatory responses, helminths seem to be han-

dled with gentler immune responses, with a strong

regulatory component, that may take weeks, months or

even years to reach their peak effectiveness.

Any survey of a vertebrate wildlife population will gen-

erally yield an array of different helminths (see e.g. ref.

8), with many hosts infected by tens, hundreds or even

thousands of individual worms. It also seems reasonable

to assume the same for pre-industrial human populations,

given the rates of helminth parasitism seen in the mod-

ern-day tropics. Almost every organ system and tissue in

the human body (Fig. 2) is a potential target for infec-

tion, and well over 100 species have been recovered from

humans.9 However, in terms of current global signifi-

cance, a smaller number of species might be highlighted,

all of which are primarily distributed in the tropics. In

blood flukes of the genus Schistosoma, water-borne larvae

penetrate the host’s skin before establishing in the blood

vascular system, producing eggs that migrate through tis-

sues before release to the exterior. Larvae of the filarial

nematode Onchocerca volvulus are transmitted by blood-

feeding blackflies and establish in subcutaneous nodules,

from which adult females release millions of microfilaria

larvae into the dermis of the host. The ‘geohelminth’ soil-

transmitted nematodes Ancylostoma duodenale, Necator

americanus, Ascaris lumbricoides and Trichuris trichiura

infect the host’s gut, and from there eggs are passed

to the exterior in faeces. Ancylostoma duodenale and

N. americanus (hookworms) invade the host by larval

penetration of the skin, migrating through the lungs

before arriving in the intestine. Ascaris lumbricoides

(roundworm) and T. trichiura (whipworm) are transmitted

Figure 1. The immune system evolved in the presence of helminths. The earliest dates of colonization by helminth lineages are mapped onto a

phylogenetic history of vertebrates. Also mapped are major putative events in immune system evolution and the appearance of mediators of

importance in anti-helminth responses. Divergence times of the major vertebrate groups from the mammalian lineage are indicated (Mya, million

years ago).96 Macrophage-,97 eosinophil-98 and mast-99 like cells occur in Agnathans (lampreys) predating the appearance of classical adaptive

immunity. The evolution of classical adaptive immunity was possibly preceded100 by two rounds of whole genome, or large-scale partial genome,

duplication (4n and then 8n). Insertion of recombination activating (RAG) genes101 into the genome then allowed the evolution of the recombi-

natorial receptor system underpinning T-cell and B-cell functions. This occurred at some point between the divergences of the Agnatha (lampreys

and hagfishes) and the Chondricthyes (sharks and rays). Colonization by platyhelminths occurred within this period, with all extant parasitic

groups believed to be derived from a single common parasitic ancestor.4 The earliest evidence of Th2 cytokines102–104 and alternatively (aaMF)

versus classically (caMF) activated macrophages105,106 is found in the Actinopterygii (bony fishes). Colonization of land probably allowed the

invasion of primitive tetrapods by parasitic nematodes3,5 (molecular phylogenetic analyses suggest at least four independent invasions).107 The

immunoglobulin E (IgE) isotype, important in anti-helminth responses, is a recent innovation in the mammalian lineage. Ig, immunoglobulin;

M/, macrophage.108

� 2008 The Authors Journal compilation � 2008 Blackwell Publishing Ltd, Immunology, 126, 18–27 19

Helminths: their coevolutionary legacy

by an oral route, the former undergoing a complex

migration through the lungs, and the latter developing

entirely in a mucosal site. Worm infection tends to be

chronic, with maximum individual life-spans of months

or a few years (the gastrointestinal nematodes) to decades

(schistosomes). Pathology mediated by these helminths is

relatively limited: overt symptoms are usually rare in

human populations although adverse outcomes may be

measurable, for example, in reduced growth or cognitive

development. That this limited level of pathogenicity is a

result of adaptation seems likely. For example, outbreaks

in humans in the Philippines of an intestinal capillarid

usually infecting fish-eating birds resulted in severe dis-

ease and a 6% mortality rate from > 1000 confirmed

cases between 1967 and 1990.10

A stereotypical immune response

The development of resistance to gastrointestinal nema-

todes is generally associated with a Th2 response in labo-

ratory models11–13 (Fig. 3a). Findings consistent with this

have been reported in epidemiological studies of hook-

worm,14 roundworm15–17 and whipworm15–17 in humans.

The triggering of the Th2 response programme by intesti-

nal nematodes, orchestrated by cytokines including inter-

leukin (IL)-4,12 IL-5,18 IL-9,19 IL-13,20 IL-2121 and IL-2522

and IL-33,23 leads to a stereotyped cascade of effector

mechanisms, potentially including immunoglobulin E

(IgE) isotype-switched B-cell responses, mast cells, eosino-

phils, basophils and increased permeability, smooth

muscle contractility and mucus production in the gut.

Increases in IL-13-driven intestinal epithelial cell (IEC)

turnover24 and production of the protein resistin-like

molecule beta (RELMb),25 which interferes with nematode

chemotaxis, may also be involved in protection. However,

only a subset of the recruited mediators26 may be impor-

tant effectors in resistance against any individual gastroin-

testinal nematode species. For example, in mouse model

systems, mucosal mast cell responses are critical for worm

expulsion in Trichuris muris and Trichinella spiralis infec-

tion19,27,28 but not in Heligmosomoides bakeri29,30 or Nip-

postrongylus brasiliensis infection.31 Th2 responses are also

triggered by tissue-dwelling (histozoic) species such as the

schistosomes32 and filarial nematodes,33 although it is not

clear-cut how important Th2-driven effector mechanisms

are in protecting the host.34–38 In these cases Th1 mecha-

nisms can be implicated in resistance and are perhaps

especially important in killing incoming larval stages38,39

migrating through tissues, but once the definitive site is

reached the adult parasite may survive for many years.

Fibrotic responses can be a prominent feature of the host

reaction against histozoic species: Th2-driven granulomas

are focussed upon eggs in Schistosoma spp.38 and fibrosis

in Onchocerca infection can be associated with microfilar-

ial migrations and occur around the onchocercoma

nodules enclosing adults.40

Figure 2. The wide range of organ systems targeted by a selection of the helminth parasites occurring in humans.


J. A. Jackson et al.

increased permeability

Goblet cells –

Epithelial cells –

increased mucus production

DCTH0

IL-10 TGF-β

aaMΦ

MΦ

I L-4

, I L

- 13

& I

L-2

1Arginase-1

IL-10 TGF-β

IL-5

IL-9

IL-4 & IL-13

IL-4

Smooth muscle –increase in contractility

IgE

B-cell

IL-4(a)

(b)

Treg

Eosinophil

Mast cell

Goblet cell

Epithelial cell

Smooth muscle

Plasma cell

DC

IL-10 TGF-β IL-10

TGF-β

Worm PAMP

IgG4

DC

?

TSLP

EDN

?

Treg

TH2

TH1TH17

TH0

TH2

Figure 3. Cells and molecules involved in the generation of immune responses in helminth infections. Solid arrows indicate signalling influences

on cells (with important signalling molecules indicated alongside), and dashed arrows indicate the developmental trajectory of an individual cell

type. (a) A widely accepted hypothesis for the function of mediators and effectors involved in the modified Th2 response against helminths. Path-

ogen-associated molecular patterns (PAMPs) from helminths may stimulate the differentiation of dendritic cells (DCs) that bias T-helper (Th)

cell polarization towards Th2 or regulatory T (Treg) cell subsets. Th2 cells produce a range of cytokines driving effector responses, including:

eosinophil responses, mast cell responses, isotype-switched B-cell responses, increases in intestinal permeability, smooth muscle contractility and

mucus production, and the differentiation of alternatively activated macrophages (aaMF). Treg cells induced in the periphery and producing sup-

pressive cytokines [interleukin (IL)-10 and transforming growth factor (TGF)-b] dampen levels of innate and adaptive immune activation. (b) A

model incorporating alternative hypotheses for early events in the initiation of anti-helminth responses. Helminth PAMPs might stimulate signal-

ling activity in other ‘front-line’ cell types (eosinophils, basophils, mast cells or intestinal epithelial cells) which, in turn, influences DCs or even

naı̈ve Th (Th0) cells. Damage-associated molecular patterns (DAMPs) released by dying cells, or signals resulting from apoptosis, might also

influence either DCs or Th0 cells. EDN, eosinophil-derived neurotoxin; TSLP, thymic stromal lymphopoetin.



The other recurring immunological characteristic of

helminth infections is that despite significant responses,

for example vigorous antibody responses and eosino-

philia, which may or may not be effective in resistance,

there is often a marked systemic suppression of innate

and adaptive immunity41 in the host. This may be linked

to expansions of regulatory CD4+ CD25+ T cells produc-

ing the suppressive cytokines transforming growth factor

(TGF)-b and/or IL-1042–44 and perhaps other suppressor

T-cell subsets,45 including CD8+ T cells with cytokine-

independent suppressive activity.46 Immunoepidemiologi-

cal studies in humans have strongly associated regulatory

cytokine activity and/or immunological hyporespon-

siveness with increasing infection intensity in filarial

nematodes,37,47 Schistosoma flukes48,49 and intestinal nema-

todes.50 A further important dimension in helminth infec-

tions is the differentiation of alternatively activated

macrophages (aaMFs)2,51 under the influence of IL-4,

IL-13 and IL-21. Whilst aaMFs recruit to the site of

infection52 and have been implicated as functional effec-

tors,53 they also have strong anti-inflammatory properties,

secreting IL-10 and TGF-b, and strongly expressing genes

such as Arginase-1, Ym1 (chitinase-3-like protein 3) and

FIZZ1 (resistin-like molecule alpha)54 whose functions

relate to the repair of extracellular matrices, wound

healing and fibrosis.

The overall outcome of a helminth infection may there-

fore be an environment with down-regulated proinflam-

matory responsiveness, activated damage repair

mechanisms and a tightly controlled development of Th2

anti-parasite effector responses. Although exposure to

helminths in exposed human populations typically begins

in early childhood, delayed age-intensity peaks55 and sub-

stantial reinfection rates56 are a testament to the slow

development of immunity.

Evolution of the Th2 arm: home win or scoredraw?

From a ‘worm’s view’ the nature of the host response is

such that primary worm infections are often successful,

but secondary waves of invasion are likely to encounter

progressively increasing levels of resistance. The appar-

ently evolutionarily fixed nature of the stereotypical anti-

helminth Th2/Treg response57 may stem from the fact

that, within the constraints acting on both protagonists, it

maximizes fitness in both the host and some individual

parasites.58 For the host, the highly regulated Th2 anti-

worm response and initial toleration of infection may

lead to greater fitness than the generation of violent, ener-

getically costly and potentially immunopathological

responses to a low or intermediate threat. For the para-

sites in primary infections, relative fitness may be very

high because they can survive and reproduce whilst later

invaders succumb to the developing immune responses.

There might therefore be strong host-mediated selection

for parasite genotypes that co-operate with, rather than

subvert, the Th2/Treg phenotype, perhaps even to the

extent that there could have been synergistic coevolution

of complementary pathogen-associated molecular pattern

(PAMP)–host innate receptor recognition systems. Stabi-

lizing features of such an interaction might be that the

parasite cannot easily evolve mechanisms for incoming

stages to evade or subvert a fully developed memory

response in a well-adapted host and that primary infec-

tions that fail to stimulate a Th2 response might benefit

late-arriving competitors, penalizing the fitness of early

colonizers.

As mentioned above, Th2 mediators are important in

defence against metazoan parasites, but also for damage

repair,57 and it is intuitive that the two roles might be

evolutionarily linked. Worm infections are likely to pro-

duce high levels of local tissue damage associated with the

feeding and migratory activities of individual parasites.

There may also sometimes be a requirement for the host

to physically contain (‘wall off’) dangerous motile stages

by fibrotic reactions within tissues. It thus seems plausible

that, during evolution, anti-worm mediators may have

been ‘grafted’ onto the control networks that regulate

wound repair and tissue remodelling. Mechanisms

involved in wound healing and responses to helminths

are not totally overlapping, of course, as the latter also

involve genuine effector mechanisms (IgE, mast cells and

esoinophils) not usually implicated in wound repair,

and themselves capable of generating immunopathology.

However, the intimacy of damage repair and anti-

helminth responses may give clues as to the enigmatic

signals that initiate dominant immune responses in worm

infections.

The initiation and control of immune responsesin worm infections

Whilst the exact signalling pathways by which Th2

responses are initiated remain obscure, helminth products

seem able to stimulate the development of partially acti-

vated DCs,59 with suppressed expression of Toll-like

receptors (TLRs) and activation markers,60,61 that pro-

mote Th2 and/or Treg phenotypes.59,62,63 From an analogy

with the very well-known pathways by which Th1 cells

are induced, the simplest model for the initiation of Th2

responses in helminth infections would be an interaction

between a PAMP derived from a worm and a pattern rec-

ognition receptor (PRR) expressed by a DC. Worm

PAMPs might act via one or more of the TLR family, or

perhaps other classes of innate receptor64,65 such as

C-type lectins, nucleotide-binding oligomerization

domain-containing protein (NOD)-like receptors or

protease-activated receptors. Prospecting of helminth

excretory-secretory (ES) products for molecules with



TLR-mediated immunomodulatory effects, mainly focus-

sing on DCs, has yielded a number of examples that

might be consistent with such a model. Synthetic lacto-

N-fucopentanose III, equivalent to a molecule occurring

naturally in soluble egg antigen (SEA), has been reported

to interact with TLR4 to produce Th2 polarizing DCs66

and schistosome lyso-phosphatidylserine may interact

with TLR2 to produce Treg polarizing DCs.67 ES-62 from

the filarial nematode Acanthocheilonema viteae is reported

to exert immunomodulatory effects on macrophages68

and DCs69 by a TLR4-dependent mechanism.70 However,

the interaction of ES-62 with TLR4 on mast cells, which

results in the inhibition of Th1 but not Th2 cytokine pro-

duction, does not involve classical TLR signalling.71 Also,

the Th2-inducing effects of SEA on DCs have recently

been shown to be independent of MyD88, TLR2 and

TLR4.72 A further consideration is that PRRs on cell types

other than DCs may be important (Fig. 3b), as responses

that favour a Th2 environment have been reported in ba-

sophils,73,74 mast cells,71 eosinophils75 and IECs.76 In the

case of IECs, Trichuris muris infection stimulates inhibitor

of kappa-B kinase beta (IKKb)-dependent expression of

the cytokine thymic stromal lymphopoetin (TSLP), which

can stimulate the differentiation of Th2-inducing DCs.

Innate responses by eosinophils include secretion of

eosinophil-derived neurotoxin (EDN), which mediates

TLR2/Myd88-dependent activation of DCs that drive

in vivo antigen-specific adaptive responses towards a Th2

phenotype. A wide range of other alarmin-type signalling

molecules can be released during infection (e.g. defensins,

cathelicidins and high-mobility group 1 box proteins),

including some with known pro-inflammatory influ-

ences,77 but perhaps others with undiscovered Th2-induc-

ing activities. Even if DCs are pivotal in initiating

expansions of Th2 cells, pattern recognition by these cells

themselves might not therefore be necessary, as cytokines

or alarmins released following pattern recognition by

more ‘frontline’ cells, such as IEEs (Fig. 3b), could be suf-

ficient for maturation of Th2-inducing DC phenotypes. It

is even possible that some Th2-inducing signals might

bypass DCs altogether and act directly on T lymphocytes

prior to acquisition of a terminally differentiated pheno-

type.59

Apart from an exploration of cell types other than DCs,

the overlap between effector and tissue repair functions in

anti-helminth immune responses suggests that the search

for innate ‘pattern recognition’ signals initiating anti-

worm responses might need to consider endogenous host

molecules that convey information about cellular damage

(Fig. 3b) and that trigger anti-inflammatory programmes

appropriate for wound healing. During helminth infection

such damage-associated molecular patterns (DAMPs; here

used to denote endogenous signals only) might be sensed

by elements of the innate immune system, perhaps as

combinatorial signals with PAMPs.57 A range of endo-

genous molecules have been shown to interact with recep-

tors of the TLR2, TLR3, TLR4, TLR7, TLR8 and TLR9

families, including some that are released on cell damage

and that can exert either stimulatory or anti-inflamma-

tory effects.78 For example, suppressive IL-10-inducing

ligands for TLR9 have been characterized,79 some of the

most potent of which contain TTAGGG multimers char-

acteristic of mammalian telomeres.80 Regulatory T cells

may also be induced by other endogenous mechanisms:

interactions with apoptotic cells, or phosphatidylserine

from apoptotic cells, causes differentiation of immature

DCs with tolerogenic properties favouring anti-inflamma-

tory Th phenotypes.81–84 It even seems a possibility that

much of the Treg activity in a worm infection could be

initiated by signalling from endogenous molecules. In the

case of anti-helminth Th2 responses, however, cross-talk

between worm PAMPs and the innate immune system

would be expected to be important, as many anti-

helminth effectors (e.g. IgE and mast cells) are recruited

that are apparently unconnected to wound healing.

Worm versus man: coevolutionary legacies?

An ideal organism would be able to perfectly control its

immune system under any combination of infection chal-

lenges and antigenic stimuli. However, organisms are not

perfect and have been selected to perform optimally

within the set of conditions encountered by their ances-

tors. In humans, one of these past conditions is arguably

exposure to a diverse community of helminth parasites.

The relationship between helminths and vertebrates is

ancient and can be traced back to when nematodes

invaded primitive tetrapods3 and the ancestral platyhelm-

inths4 first appeared in fishes prior to the colonization of

land (Fig. 1). In the intervening time, individual helminth

lineages may have diverged, switched between host lin-

eages, or become extinct many times. However, if the pat-

tern of infection seen in present-day wildlife populations

can be extrapolated into the past, then almost every natu-

ral vertebrate population would have been exposed to a

varied assemblage of worm-like pathogens. Because hel-

minth infection is and (probably) has been so ubiquitous,

mammalian immune systems may have been selected to

anticipate that they would suffer chronic exposure to

large-bodied Th2/Treg-inducing pathogens. In other

words, there would have been selection for immunoregu-

latory systems that work well in the context of worm

infection. However, there would rarely have been selec-

tion for immunoregulatory systems that work optimally

when worms are absent (the situation seen in modern

human populations). The absence of parasitic worms and

their strong Th2/Treg-inducing influences may therefore

uncover flaws in immunoregulatory networks that have

previously been hidden from selection.85,86 Such a sce-

nario might explain the dramatic increases in allergy and



autoimmune conditions in Western countries and is sup-

ported by the protective effect of helminth infection, or

helminth-derived products, in laboratory models of

allergy43,87 and automimmunity.85,88

The future

The strong Th2/Treg-inducing influence of worms, and the

possibility that the immune system may malfunction in

the absence of such stimuli, has global public health impli-

cations: both for the parts of the world population that are

helminth-free and for the parts that remain exposed. In

the first case, a search for molecules that mimic the immu-

noregulatory stimuli seen in worm infections may one day

yield pharmaceuticals that can be used routinely to induce

healthier, better regulated immune systems. Given the inti-

mate link between immune responses to worms and tissue

repair, it might be necessary to go beyond a search for

PAMPs that interact with DCs and to extend this to

include other cell types65 and other molecular patterns57

including DAMPs. For helminth-exposed populations it

has been demonstrated that the immunosuppressive activi-

ties of worm infections may make individuals less respon-

sive to microbial pathogens and to vaccination. This is a

major concern because wherever helminth infection is pre-

valent so too are dangerous microbial infectious agents,

such as human immunodeficiency virus (HIV), Mycobacte-

rium tuberculi and malarial parasites. Anthelmintic treat-

ment programmes might result in significant health

benefits from the increased immunological responsiveness

against such pathogens. However, a ‘flip-side’ to this coin

might be foreseen in the context of highly immunopatho-

genic coinfections such as malaria or influenza, whose

worst effects are caused by excessive immune responses.

The potential realism of this scenario is supported by labo-

ratory model studies suggesting that gastrointestinal nema-

tode infections suppress immunopathology during

influenza.89 It is also at least hinted at by the contradictory

body of epidemiological90,91 and laboratory model92–95

data for interactions in malaria–helminth coinfections.

The consequences of de-worming for susceptibility to the

worst symptoms of important immunopathogenic infec-

tions are therefore of urgent interest for further laboratory

model studies and should be carefully monitored in the

field.58

Acknowledgements

JEB is grateful for research funding from The Wellcome

Trust, The Royal Society, The Natural Environment

Research Council, the European Commission and The

University of Nottingham. IMF and SL are respectively

supported by research funding from the European Com-

mission (Marie Curie Early Stage Research Training) and

The University of Nottingham.

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