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Helminth Infections - Recognition and Modulation of The Immune Response by Innate Immune Cells

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Helminth Infections - Recognition and Modulation of The Immune Response by Innate Immune Cells

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Review

published: 04 April 2018


doi: 10.3389/fimmu.2018.00664

Helminth infections: Recognition and


Modulation of the immune Response
by innate immune Cells
Claudia Cristina Motran1,2*, Leonardo Silvane1,2, Laura Silvina Chiapello1,2,
Martin Gustavo Theumer1,2, Laura Fernanda Ambrosio1,2, Ximena Volpini1,2,
Daiana Pamela Celias1,2 and Laura Cervi1,2*
1
 Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba,
Argentina, 2 Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones
Científicas y Tecnológicas (CONICET), Córdoba, Argentina

The survival of helminths in the host over long periods of time is the result of a process of
adaptation or dynamic co-evolution between the host and the parasite. However, infec-
Edited by:
Geanncarlo Lugo-Villarino, tion with helminth parasites causes damage to the host tissues producing the release of
UMR5089 Institut de Pharmacologie danger signals that induce the recruitment of various cells, including innate immune cells
et de Biologie Structurale (IPBS),
such as macrophages (Mo), dendritic cells (DCs), eosinophils, basophils, and mast cells.
France
In this scenario, these cells are able to secrete soluble factors, which orchestrate immune
Reviewed by:
Marcela Freitas Lopes, effector mechanisms that depend on the different niches these parasites inhabit. Here,
Institute of Biophysics Carlos Chagas we focus on recent advances in the knowledge of excretory-secretory products (ESP),
Filho (IBCCF), Brazil
Keke Celeste Fairfax,
resulting from helminth recognition by DCs and Mo. Phagocytes and other cells types
Purdue University, United States such as innate lymphocyte T  cells 2 (ILC2), when activated by ESP, participate in an
Amélia Ribeiro De Jesus,
intricate cytokine network to generate innate and adaptive Th2 responses. In this review,
Federal University of Sergipe, Brazil
we also discuss the mechanisms of innate immune cell-induced parasite killing and the
*Correspondence:
Claudia Cristina Motran tissue repair necessary to assure helminth survival over long periods of time.
[email protected];
Laura Cervi Keywords: helminths, excretory-secretory products, phagocytes, M2 macrophages, dendritic cells, effector
[email protected] mechanisms, tissue repair

Specialty section: INTRODUCTION


This article was submitted to
Microbial Immunology, Helminths, or worms, are invertebrate animals that comprise a broad spectrum of different patho-
a section of the journal gens able to affect human health. Among these parasites, there are two major phyla: the nematodes
Frontiers in Immunology (or roundworms) and the platyhelminthes (also known as flatworms), with the latter in turn being
Received: 11 January 2018 subdivided into trematodes (flukes) and cestodes (tapeworms). The helminths infect a vast number of
Accepted: 19 March 2018 people all over the world, and it is estimated that soil-transmitted helminths cause infection in more
Published: 04 April 2018 than 1.5 billion people, or 24% of the entire human population. The main species that infect people
Citation: are the nematodes Ascaris lumbricoides, Trichuris trichiura, Necator americanus, and Ancylostoma
Motran CC, Silvane L, Chiapello LS, duodenale, with some of these producing chronic infections that can last up to 20 years (1).
Theumer MG, Ambrosio LF, Volpini X, The course of infection can vary greatly depending on the helminth. For example, certain filarial
Celias DP and Cervi L (2018)
nematodes are transmitted by mosquitoes and can occupy and obstruct lymphatic vessels, which
Helminth Infections: Recognition and
Modulation of the Immune Response
produces a chronic infection that causes lymphatic filariasis or elephantiasis (2), while other para-
by Innate Immune Cells. sitic nematodes such as T. trichiura are strictly enteric and reside in the epithelium. In the case of
Front. Immunol. 9:664. schistosomiasis, an acute and chronic disease produced by different species of the trematodes worm
doi: 10.3389/fimmu.2018.00664 Schistosoma, the pathology is caused by the inflammatory reaction of the host to the eggs deposited

Frontiers in Immunology  |  www.frontiersin.org 1 April 2018 | Volume 9 | Article 664


Motran et al. Innate Cells Shaping Immunity Against Helminths

in the tissues. This triggers the development of granulomas T cells. A predominant Th2 response during helminth infections
constituted by an inflammatory infiltrate and fibrosis around has been widely reported, although the precise mechanism initi-
the eggs. During the evolution of the granulomas, the excessive ating this response has not been fully elucidated (8). Nevertheless,
fibrosis can cause periportal hypertension and even occasionally it is clear that DCs are involved in the recognition of helminths
strokes when its location is cerebral or spinal (3). or their products and the subsequent promotion of Th2 develop-
The survival of helminths in the host for long periods of time ment. In fact, DCs are able to detect multiple ES by expressing the
is the result of a process of adaptation or dynamic co-evolution different innate immune receptors involved in the recognition
between the host and the parasite. In the case of these pathogens, of molecular patterns highly conserved in pathogens or PAMPs.
it is necessary for them to locate a niche suitable for maturation Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and
and propagation without killing or damaging the host. Otherwise, nucleotide binding domain leucine-rich repeat (LRR)-containing
the host would be able to generate an effective immune response (or NOD-like) receptors (NLRs) are the most studied of those
to expel the parasite or at least limit the negative fitness effects of involved in the interaction with helminth-derived molecules.
a given parasite load by inducing tolerance without sacrificing its DCs have been shown to recognize the Schistosoma mansoni
ability to respond effectively to other pathogens. lipid antigen containing phosphatidyl serine through TLR2,
This review is focused on the mechanisms by which phago- while lacto-N-fucopentaose III (LNFPIII) from S. mansoni and
cytes, in particular macrophages (Mo) and dendritic cells (DCs), glycoprotein ES-62 of filaria are recognized through TLR4 (9, 10).
recognize helminth parasites, become activated and induce In all cases, signaling through TLR2 or TLR4 reduces the ability
effector immune responses. We also discuss recent advances in of DCs to produce IL-12 and promotes a polarization toward
the knowledge about how Mo, DCs, and other phagocytes, such a Th2-type response. This association between TLR signaling
as mast cells, Eos, and basophils, are involved in the shaping of and polarization toward Th2-type response is surprising, as this
the innate and adaptive immune responses. We analyze the pro- signaling has been mostly associated with the development of a
tective immune mechanisms generated against helminths, with Th1-type response. However, it is important to highlight that the
a particular emphasis being placed on the trematodes Fasciola signaling cascade initiated in DCs downstream from TLRs, after
hepatica. their ligation by molecules derived from helminths, differs from
that exerted by Th1 stimuli (such as LPS). Thus, the ligation of DC
TLR4 by bacterial LPS strongly activates the mitogen-activated
HELMINTH RECOGNITION BY MAP kinases (MAPK) p38, JNK, and ERK, whereas the recogni-
PHAGOCYTES: MODULATION OF THE tion of LNFPIII of Schistosoma by TLR4 present in DCs only
IMMUNE RESPONSE BY SECRETED induces phosphorylation of ERK (9). Similarly, the ES-62 protein
PRODUCTS of filaria and LNFPIII activate TLR4, but unlike LPS, they drive
the response toward a Th2-type profile, suppressing the activa-
Unlike other parasites, helminths are macropathogens, a condi- tion of p38 and JNK and inhibiting the production of IL-12 in
tion that prevents them from being ingested by phagocytic cells. an ERK-dependent manner. In the same way, the recognition of
Thus, during infection by helminths, the products secreted by ES from eggs of S. mansoni through TLR2 is associated with the
these parasites play a fundamental role as modulators of phago- stabilization of the MAPK ERK, which promotes polarization to
cyte activation by modifying the microenvironment in which Th2 through the stabilization of the transcription factor c-Fos
these cells participate in the induction and instruction of the (which in turn suppresses the production of IL-12) (11). One
innate and adaptive immune responses. possible explanation for these differences could be the association
The term “excretory/secretory antigens” (ES) refers to the of the TLRs with different co-receptors, which may interfere with
parasite molecules that are released at the interface between the the downstream signaling cascade under TLRs. An example of
parasite and the cells of the immune system by various mecha- this situation is the case of zymosan (an insoluble carbohydrate
nisms, such as active secretion and diffusion from parasitic soma. obtained from a yeast cell walls), which induces the production of
These molecules are originated from adult worms intestinal the anti-inflammatory cytokine IL-10 by simultaneously signal-
content as well as female worms uterine content released during ing through the carbohydrate receptors dectin-1 and TLR2 (12).
egg or larval deposition (4, 5). The development of systematic In fact, this mechanism of pattern-recognition receptors crosstalk
proteomic analysis has allowed many of the main ES helminth could be occurring in the identification of carbohydrate hel-
products to be characterized (6). These studies have revealed a minths by the CLR. Consequently, it has recently been shown that
common set of proteins that are secreted by helminths, including the omega-1 molecule, a glycoprotein with ribonuclease activity
protease enzymes, glycolytic enzymes, protease enzyme inhibi- secreted by S. mansoni eggs, signals via the mannose receptor
tors, antigens homologous to allergens, and lectins. However, as (MR) through its carbohydrate domain. This recognition allows
ES composition varies in different parasites and is affected by the the internalization of omega-1 in DCs, with its RNAse activity
stage of their life cycles, the reported different effects of ES on being essential for inducing the Th2-type response (13). Other
phagocytic cells may just be reflecting the complexity of their glycans derived from helminths, such as a LewisX-containing
composition (5, 7). glycan secreted by both the eggs and the schistosomula of
Dendritic cells are mediators between innate and adaptive S. mansoni, are recognized by DC-SIGN and MR receptors on
immunity, consequently, they play the principal role in the rec- DCs, while carbohydrates rich in N-acetyl galactosamine are
ognition, capture, processing, and presentation of helminth ES to recognized by the macrophage galactose-type lectin (4).

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Motran et al. Innate Cells Shaping Immunity Against Helminths

It is well known that for Th2 differentiation, the early production Mast cells originated from bone marrow, enter the peripheral
of IL-4 is essential. However, DC activation by helminth products blood, and complete their differentiation in tissues such as the
fails to induce IL-4 secretion. Therefore, it can be assumed that skin or gut. A relevant study from Hepworth et al. demonstrated
the modulation of DCs to promote Th2 polarization is dependent the involvement of mast cells in the development of the innate
not only on a direct effect of helminths or their products on these and adaptive Th2 responses during helminth infection (22). This
cells but also on cell interaction with tissue-derived factors, such study showed that in the absence of mast cells, mice infected with
as the “alarmins,” thymic stromal lymphopoietin (TSLP), matrix Heligmosomoides polygyrus bakeri or Trichuris muris revealed a
metalloproteinase 2 (MMP-2), IL-33, IL-25, and Eos-derived deficiency in the production of the alarmins IL-25, IL-33, and
neurotoxin (EDN), among others, which also have an impact on TSLP derived from tissues. This led to an impaired innate and
DC activation [reviewed in Ref. (14)]. adaptive Th2-type responses; thus, showing the relevance of mast
In contrast, to what was observed on DCs, the basophils cell-induced responses during the early stages of gastrointestinal
and Eos have been reported to be involved in the development helminth infection.
and amplification of the Th2 response, because of their ability Interestingly, Eos, basophils, and mast cells can also modulate
to produce and secrete IL-4. Moreover, in addition to being key and instruct the adaptive immune response after their stimulation
cells in the link between innate immunity and the development through the release of the granules’ content, as will be described
of the Th2 response, basophils, and Eos are phagocytes that are below.
able to sense PAMPS as well as to process and present helminth
antigens to naive T  cells (15). Eos from healthy humans either
treated with extracts from Brugia malayi or isolated from mice MODULATION OF PHAGOCYTE
infected with this parasite have shown maturation signals with ACTIVATION BY F. hepatica
increasing MHC class II and some co-stimulatory molecule
expression (16). In a similar way, Strongyloides stercoralis antigen- Fasciola hepatica is a causative agent of fasciolosis, which is a
pulsed Eos induce Th2-type responses when injected into mice neglected disease that affects a vast number of cattle and sheep
(17). Accordingly, Eos from MHC II-deficient mice fail to induce throughout the world and now is becoming an emerging disease
this type response, thereby highlighting the crucial role of these in humans (23). During its migration through the host tissues,
cells as antigen-presenting cells (APCs) in the induction of the the parasite excretes and/or secretes many products capable of
Th2 adaptive immune response. modulating the immune response. Soon after infection, the larval
Basophils are granulocytes which represent about 1% of the stage of F. hepatica crosses the intestinal wall and reaches the
circulating white blood cells. They are phagocytic cells able to peritoneum. At the same time, the recruitment of alternatively
induce inflammatory responses and share many characteristics activated Mo occurs, with upregulation in the expression of Fizz,
with mast cells, such as the expression of the high-affinity Ym1, and arginase-1.
Fc receptor for IgE (FcεRI) and the TLRs, TLR2 and TLR4. Many investigations have shown the ability of F. hepatica ES
Basophils can also release mediators (including leukotrienes, (24), F. hepatica tegumental antigens (FhTeg) (25), and ES-derived
prostaglandins, and histamine) that promote luminal fluid flow, enzymes [such as thioredoxin peroxidase (26), 2-Cys peroxire-
nerve stimulation, and intestine contractility upon activation and doxin (27), fatty acid binding protein (28) and more recently
IL-4 secretion (18). Although basophils are an important source heme-oxygenase-1 (29)] to modulate Mo phenotype toward an
of IL-4 and IL-13, they have been shown to be dispensable in alternative activation. This profile promotes three fundamental
the generation of the Th2 response in some helminth infections effects: the secretion of anti-inflammatory factors, the driving
[e.g., during Nippostrongylus brasiliensis infection in basophil- toward a Th2-profile and an increase in the pro-fibrotic factors
deficient mice (Mcpt8-cre)]. Th2 polarization occurs even in the involved in wound healing (Figure  1) (30). These are essential
absence of these cells (19). By contrast, injection of mice with steps to compensate for the damage caused by the migration of
IPSE/alpha-1 protein derived from S. mansoni eggs induces IL-4 the parasite in the host tissues, thereby allowing its establishment
production by basophils, which contributes to initiating a Th2- in the liver during the chronic phase of the disease.
type response, emphasizing the importance of basophils IL-4 Interestingly, a secreted peptide from F. hepatica called hel-
in the linking of innate immunity and Th2 development (20). minth defense molecule 1 (FhHDM-1) has been shown to have
Recent studies have proposed that basophils can act as APCs, and, the ability to destabilize lysosomal acidification, which impairs
in this regard, the ability of basophils as APCs to promote the Mo NLRP3 activation and consequently inflammasome func-
Th2-type response against helminth parasites might be depend- tion, resulting in the downregulation of IL-1 β production. These
ent on MHC II expression. However, two controversial points authors propose that in the absence of a Th1-type inflammatory
arise from different studies proposing basophils as APCs: first, milieu, the Th2-type immune response and parasite survival is
the low expression levels of the H-2M invariant chain, crucial favored (Figure 1) (31).
in the regulation of the MHC-II peptide loading and, second, In addition, a mechanism of inhibition of TLR-dependent
the low levels of MHC II expression in these cells compared to Mo activation was described by Donnelly et al. In this study, the
professional APCs. These issues have been clarified recently, since cysteine protease activity of F. hepatica Cathepsin L1 (FheCL1),
basophils can obtain peptide–MHC-II complexes from DCs by has been involved in the degradation of TLR3 within the endo-
trogocytosis, allowing these cells to function as APCs, promoting some upon TLR3 and TLR4 stimulation. The ability of FheCL1 to
a Th2-type response (21). inhibit TRIF-dependent signaling is a strategy used by F. hepatica

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Motran et al. Innate Cells Shaping Immunity Against Helminths

Figure 1 | Fasciola hepatica modulates macrophage activation. F. hepatica ES, F. hepatica tegumental antigens (FhTeg), and ES-derived enzymes, such as
thioredoxin peroxidase (Tpx), 2-Cys peroxiredoxin (Prx), and heme-oxygenase-1 (AO-1) drive Mo phenotype toward an alternative activation profile. Fatty acid
binding protein (Fh12) binds the co-receptor CD14 and inhibits LPS-induced TLR4 activation, suppressing the expression of IL-12, TNF, IL-6, and IL-1β. F. hepatica
Cathepsin L1 (FheCL1) induces TLR3 degradation, which impairs LPS-induced TLR4–TRIF-dependent pathway with the consequent inhibition of inflammatory
cytokine production. The decrease of an inflammatory cytokine milieu might promote the inhibition of a Th1 type response favoring a Th2 profile. F. hepatica defense
molecule 1 (FhHDM-1) has been shown to have the ability to destabilize lysosomal acidification, which impairs Mo NLRP3 activation and consequently
inflammasome function, resulting in the downregulation of IL-1 β production.

to control innate immune responses suppressing consequently A partial inhibition of immunomodulatory factors such as
Th1 development (Figure 1) (32). arginase-1 expression, with TGF-β and IL-10 production has
Similarly, the exposure of DCs to F. hepatica products inhibits been observed when these receptors were blocked (24). In line
the ability of these cells to mature in response to inflammatory with these findings, it was demonstrated that the recognition of
stimuli. Related to this, we have shown that F. hepatica ES inhibits FhTegs by MR-DCs is essential for the induction of Foxp3+ Treg
TLR-activated DCs maturation and their ability to induce alloge- cells and the CD4+ T cells anergy. This study showed that in the
neic responses (33). FhTeg, isolated from the coat of the parasite, absence of MR, the ability of DCs to induce T cell anergy mark-
has also been reported to downregulate inflammatory cytokine ers is downregulated (37). Finally, the participation of the CLR
production and the expression of co-stimulatory molecules in DC-SIGN, which recognizes F. hepatica glycans, has recently
response to TLR and non-TLR stimuli (34). been demonstrated. In fact, DC-SIGN triggering is a critical
The relevance of the modulatory effect of F. hepatica antigens event that induces some DC regulatory functions, such as the
on DCs was demonstrated by the ability of these cells to inhibit ability of these cells to induce anergic/Treg cells (38). Overall, all
inflammatory responses, such as those observed in the collagen- these results highlight the importance of improved knowledge
induced arthritis model (CIA). We evaluated the capacity of DCs about innate immunity receptors such as C-type lectins in the
treated with a total extract (TE) of F. hepatica together with CpG recognition and decoding of helminth molecular patterns, which
to modulate the inflammatory responses in CIA. The immuniza- are relevant to the induction of immunoregulatory responses.
tion of mice with collagen II-pulsed TE/CpG-conditioned DCs
to diminish the severity and incidence of CIA symptoms induced
anti-inflammatory cytokine production and promoted regulatory KILLING OF HELMINTHS MEDIATED BY
T cell (Treg) development (35). In addition, we have identified a PHAGOCYTES AND ANTIBODIES
protein Kunitz-type molecule that is present in TE as being able
to inhibit TLR-induced DCs activation (36). Overall, these find- Among the cells that belong to the innate immune system, in the
ings suggest that the modulation of DC activation might aid the first line of defense against microorganisms, the phagocytic cells
chronic establishment of the parasite in the host. mediate the internalization and destruction of some pathogens,
In recent years, there has been an important advance in the especially those that are opsonized by antibodies. As mentioned
knowledge about the receptors involved in the recognition of above, as helminth parasites are macropathogens, they cannot
F. hepatica products. The role of CLRs, such as MR and dec- be ingested by phagocytic cells. Therefore, the immune system
tin-1 in the interaction with F. hepatica ES has been reported. uses other mechanisms in order to eliminate them, such as

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Motran et al. Innate Cells Shaping Immunity Against Helminths

antibody-dependent cellular cytotoxicity (ADCC), which is also that Eos are an important source of growth factors for plasma
referred to as antibody-dependent cell-mediated cytotoxicity. cell survival, suggesting an important role in the effector func-
The Fc-receptor-bearing effector cells can recognize and kill tion to sustain antibody production (40). Eos produce cytokines
antibody-coated parasite worms by discharging their lysosomal and chemokines, such as IL-4, IL-5, IL-13, TGF-β, IL-10, IL-8,
or granular content (15) (Figure 2). IL-12, IL-18, TNF, CCL11, and CCL5, with these cytokines being
As stated above, helminth infections strongly induce Th2- stored pre-formed in the granules to be rapidly released after Eos
skewed responses associated with cytokines (e.g., IL-4, IL-5, and degranulation (46). Thus, these molecules can rapidly modulate
IL-13), mastocytosis, eosinophilia, and antibody class-switching innate and adaptive immune responses, and emerging data have
producing IgE [reviewed in Ref. (39)]. This antibody isotype is demonstrated that during T. spiralis infection, Eos favors parasitic
greatly elevated in helminth infection and mainly involved in infection by inhibiting the Th1-type response (47). Therefore, it
ADCC. As a result, it is considered almost certain that the con- is questionable whether Eos contribute to anti-helminthic immu-
tribution of Eos to the host defense against helminth parasites is nity. Furthermore, it is possible to conclude that eosinophilia is a
crucial (40). In agreement with this, in vitro studies have dem- sign of helminthic infection and that Eos are critically involved in
onstrated that Eos use ADCC mechanisms to directly eliminate immunoregulatory and/or host protective effects during parasitic
a variety of helminthic species through the action of Eos granule worm infections.
proteins. Furthermore, in vivo studies have shown that Eos can Macrophages from rats have been involved in the in  vitro
directly kill helminthic larvae (41, 42), exept for the adult forms ADCC of newly encysted juvenile (NEJ) worms of the trematodes
of the parasites, which are more relevant to the infection (43). F. hepatica through nitric oxide-dependent killing (Figure  2).
Antibody-dependent cellular cytotoxicity by Eos degranula- Similarly, Mo and Eos from sheep have been shown to be able
tion occurs as a consequence of the interaction of Eos FcεRI with to eliminate juvenile larvae from F. gigantica through the release
the Fc portion of specific-IgE bound to the parasite. The Eos gran- of superoxide radicals (48). However, this latter mechanism was
ules mainly contain cytotoxic proteins such as the major basic shown to be ineffective when ovine peritoneal cells were cultured
proteins (MBP-1 and MBP-2), eosinophil peroxidase, eosinophil with F. hepatica NEJ, suggesting the ability of this parasite to
cationic protein (ECP) and EDN, which cause cytolysis of the resist elimination by reactive oxygen species, possibly through
parasite when released into the extracellular space (Figure  2) the release of antioxidant enzymes (48).
(15, 44). Mouse models of Eos depletion have demonstrated The predominant cell in the early response to schistosomula
the protective role of these cells in secondary infections with is the neutrophil, and the earliest histologic signs of parasite
helminths, with the depletion of Eos inducing an increase in damage involve larval–neutrophil interactions (49). Besides, the
the parasite burden of N. brasiliensis and Trichinella spiralis in killing of schistosomula by neutrophils (50, 51) or Mo (52, 53)
murine models (45). Moreover, it has recently been reported has been reported. Also, ADCC by lung cells from rats infected
with T. spiralis was demonstrated to be effective against newborn
larva (NBL) with the FcεRI receptor present in Mo and neutro-
phils with Eos playing a critical role in cytotoxic attack (54). In
addition, Bass and Szejda reported that neutrophils are at least as
effective as Eos in the killing of NBL of T. spiralis, which appeared
to be mediated by the generation of hydrogen peroxide (55).
Despite considerable pieces of evidence from in  vitro assays
showing the killing of helminth parasites by ADCC (15), there
are few reports about whether this mechanism occurs in  vivo.
However, it has been demonstrated in helminth infections that
the absence of antibodies or effector cells, crucial in ADCC,
has a significant impact on the resistance to infection. In this
regard, depletion of Eos, neutrophils, or Mo in studies of mice
infected by helminths has revealed the importance of these cells
in controlling infection levels (44, 56). In a similar way, antibody
production was shown to correlate with protection in mice hel-
minth infections (57, 58). In agreement with this, mice lacking
antibodies (JH−/−) or activating Fc receptors (FcRγ−/−) have shown
increased numbers of larvae when infected with Heligmosomoides
polygyrus bakeri, highlighting the relevant role of antibodies in
Figure 2 | Mechanism of cellular cytotoxicity mediated by antibodies
the protective mechanism against helminth parasites (59).
against helminth parasites. The interaction of the antibodies that cover the
parasite with the Fc receptors present in eosinophils (Eos), neutrophils, or
Some mechanisms identified in helminth infections to prevent
macrophages (Mo) induces degranulation and the release of lysosomal/ the immune system attack have been reported. One example that
granular content, hydrogen peroxide (H2O2) or nitric oxide (NO), causing lysis shows an inefficient ADCC is the ability of F. hepatica, on the
of the helminth. Eos granules contain parasite toxic proteins, such as major one hand, to cleave IgG and IgE through the release of cathepsin
basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein
L-protease and, on the other hand, to induce apoptosis of Eos and
(ECP), and eosinophil-derived neurotoxin (EDN).
Mo (60–62). Furthermore, the release of antioxidant enzymes

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Motran et al. Innate Cells Shaping Immunity Against Helminths

such as superoxide dismutase or glutathione transferase could infections by nematodes, such as Litomosoides sigmodontis, an
inhibit the superoxide anion, which is potentially toxic for the inflammatory infiltrate rich in Mo in the pleural cavity appears
parasite larvae (63). It has also been recently demonstrated that because of the proliferation of these cells due to the effect of IL-4,
a TGF-β-like molecule from F. hepatica called FhTLM, which is rather than by a recruitment of monocytes (70). By contrast, dur-
expressed by the NEJ stage of the parasite, inhibits the ability of ing S. mansoni infection in mice, the majority of Mo in the liver
Mo-dependent ADCC by using the TGF-β receptor (64). In this was demonstrated to be monocyte-derived, with CCL2 being
way, the parasite is able to inhibit each of the different components involved in the recruitment process (71). A possible explanation
of the ADCC mechanism (such as effector cells, antibodies, and for this difference could be the fact that in the schistosomiasis
toxic molecules), resulting in its escape from the immune system model, the classical inflammation due to TLR activation can
and allowing its survival in the host. occur due to the leakage of bacterial ligands from the intestinal
Early studies by James et al. and Moser and Sher, have shown lumen to the circulation, with the resulting passage of the eggs
the ability of different granulocytes such as Mo, Eos, and neutro- from the vasculature to the lumen. In contrast, in infection with
phils to kill the schistosomula. These granulocytes play a critical L. sigmodontis, which resides in sterile tissues such as lung, the
role in the antigen-antibody specific interaction on the surface of recruitment of Mo to the pleural cavity is mainly a consequence
the larvae with the resulting death of these parasites (65, 66). In of local Mo proliferation (70).
line with these findings, CBA mice immunized with an irradiated Tissue damage caused by the migration of helminth parasites
cercariae showed subdermal inflammatory foci around the dead through different organs of the host triggers a “type-2” inflamma-
Schistosoma larvae, with eosinophils and mononuclear cells the tory response characterized by the recruitment of cells, including
main infiltrating cells (67). basophils, Eos, and Th2-type CD4 lymphocytes. The secretion of
Mast cells are inflammatory cells that respond to different cytokines IL-4 together with IL-13 from these cells promotes the
signals from innate and adaptive immunity by the release of accumulation and activation of Mo toward an M2 (also known
inflammatory mediators. Thus, the phenotype and function of as alternatively activated phenotype). Numerous examples of
mast cells is modified by Th2-type cytokines, such as IL-4 and murine models of helminth infection (S. mansoni, H. polygyrus, N.
IL-5. Activation of mast cells is associated with the aggregation brasiliensis, Tenia crassiceps, T. spiralis, L. sigmodontis, F. hepatica,
of FcεR1 by the antigens recognized by bound IgE. The density Ascaris suum, and the filarial parasite B. malayi) show the recruit-
of FcεR1 on these cells is upregulated by higher levels of free IgE ment of M2 Mo after a few days of infection (30).
or the presence of IL-4 (49). Moreover, mast cells are activated Interestingly, it has recently been demonstrated that alterna-
by TLR ligands through damage-associated molecular patterns tive activation of Mo could be induced in an antibody-dependent
and the binding of IgG to FcγR1 and C3a and C5a through and an IL-4Rα-independent way. Thus, during infection with
CD88. An example of the effector function of mast cells against the murine parasite H. polygyrus bakeri, helminth antigens can
helminths is their participation in IgE-mediated immediate develop a new type of Mo called helminth-antibody activated
hypersensitivity reactions, for example, against enteropatho- macrophages, which are involved in the resistance mechanism
gens (49), thereby contributing to diarrhea production and at against the helminth and in the avoidance of tissue damage (59).
the same time assisting in parasite expulsion. The immediate Different markers such as IL-4Rα, MR (CD206), and argi-
hypersensitivity is a consequence of the presence of high levels nase-1 activity together with its metabolic products (such as
of non-specific IgE generated by the Th2-type cytokine milieu urea and proline) are characteristic of M2 Mo (30). In addi-
as a result of worm infection. This cytokine binds FcεRI on mast tion, soon after infection with helminth parasites, the M2 Mo
cells, inducing degranulation (anaphylactic degranulation) and produce high levels of the proteins Ym1 and Fizz, which are
the release of inflammatory factors when they are cross-linked both secreted after the activation of these cells by Th2 cytokines
by cross-reactive antigens on the surface of the larva or adult (72). Ym1, a lectin with an affinity for chitin, is a member of
worms (49, 68). Intriguingly, ES-62, a molecule secreted by mammalian proteins that share homology with chitinase family
filarial helminths, is able to inhibit the FcεRI-induced release proteins and has been described as an Eos chemotactic factor
of allergy mediators by selectively blocking key signal transduc- (73, 74). A role in cell-to-cell and cell-to-extracellular matrix
tion events in mast cells, thus protecting the mice from cell- (ECM) interactions has been attributed to Ym1 due to its ability
dependent hypersensitivity (69). to bind heparin (75), and deposit ECM involved in the wound
healing process (73).
Another abundant protein secreted after a nematode infec-
Mo IN HELMINTH INFECTIONS: tion, Fizz1 (also known as resistin-like molecule α) has also
RECRUITMENT, ACTIVATION, AND been implicated in the process of deposition of ECM (76), which
CONTROL OF TISSUE DAMAGE has angiogenic properties and the capacity to stimulate actin
and collagen synthesis. M2 Mo also promote increased levels of
A subject of recent controversy is related to the origin of the Mo vascular endothelial growth factor, insulin-like growth factor
that expand during helminth infections. In the case of viral, bac- 1 (IGF-1), and MMPs, and trigger receptor expression on the
terial, or fungal infections and even protozoa, the Mo of tissues myeloid cells 2 (TREM2), TGF-β and growth factors such as
have been reported to be derived from monocytes. However, it platelet-derived growth factor (PDGF). All these factors have
is not that clear this is the case during helminth infections. As been shown to be involved in different stages of the wound
regards the origin of the Mo, there is a report showing that in healing responses. Also increased levels of these mediators

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Motran et al. Innate Cells Shaping Immunity Against Helminths

have been reported in helminth infections, suggesting that they to what was observed in the liver, where Eos are the majority of
might contribute to the control of the tissue damage induced by the cells recruited (15).
these parasites (77–79). In addition to promoting tissue repair, M2 Mo also play a role
The early stage of tissue repairing (up to hours or few days in the inhibition of the pro-inflammatory responses mediated by
after tissue damage occurs) involves events including bleeding M1 Mo and Th1 and Th17 responses, which in turn can exacerbate
and inflammation with the recruitment of mast cells, neutrophils, tissue damage if not controlled. A demonstrative study from Ref.
platelets, as well as monocytes, which play a role in the control of (84) shows that IL-4Rα signaling in Mo is essential for mice sur-
bleeding. Different events of tissue damage and hemorrhages take vival during acute schistosomiasis. Thus, the absence of IL4R-α in
place during the life cycle of S. mansoni as follows: Mo was responsible for the death of mice due to increased levels
of Th1 cytokines, NOS-2 activity and immunopathology in the
1. The cercariae penetrate the skin of the host by means of the liver and gut as well as increased egg expulsion. These results
secreted proteases. highlight the key role played by M2 Mo in protection against
2. Immature schistosomula can cross capillaries to enter the tissue damage. In the same line, results from a human study
arterial flow. show the importance of the Th2 response to down modulate the
3. Adult parasites mate in the mesenteric veins and the female inflammatory response in acute schistosomiasis (85). In addi-
lays eggs. tion, an Arg-1 Mo-dependent suppressive mechanism to control
4. The eggs from the veins enter the gut wall and some reach excessive fibrosis (characteristic of the severe human disease) has
lumen. been recently reported. However, this is a surprising finding, con-
5. Some eggs are dragged by the blood flow into the liver where sidering that Arg-1 is involved in the synthesis of proline (amino
they are trapped in the small sinusoidal vessels, inducing a acid precursor of collagen), and therefore in the promotion of
strong granulomatous response. fibrosis and tissue repair. At the same time, Arg-1-derived M2 Mo
help in the resolution of Th2-type-dependent inflammation and
Thus, all stages of the parasite produce relevant tissue damage fibrosis by acting as suppressor cells (86).
and hemorrhages in the host (78). Another example of tissue
damage occurs during the life cycle of F. hepatica, where NEJ
cross the intestinal wall, fall into the peritoneum and then go ROLE OF PHAGOCYTES DURING
through the liver parenchyma leaving tunnels that cause necrosis ORCHESTRATION OF THE INTESTINAL
(80). Among the nematodes, A. lumbricoides and N. brasiliensis IMMUNE RESPONSE IN HELMINTH
cause damage to the lung tissue during their migration through INFECTIONS
the host (15).
In the healing process after tissue damage, the proliferation of Intestinal helminth parasites interact with the host intestinal
fibroblasts and remodeling takes place. In particular, neutrophils barrier producing damage related to different causes, such as the
and Mo are important cells because of their phagocytic capacity attachment of the parasite to epithelial cells, migration through
to help in debris removal. In addition, Mo and fibroblast induce the host tissue, worm feeding events, or secondary opportunistic
fibroblast proliferation and promote fibrogenesis and collagen bacterial infections (87). Damage to host tissues induces the
production through the release of different molecules, such as release of alarmins including the cytokines IL-33, IL-25, and TSLP
TGF-β and PDGF (81, 82). Interestingly, an opposing role can by intestinal epithelial cells (IECs), among others. Furthermore,
be attributed to Mo during an inflammatory process after tissue helminth infection promotes the early recruitment of the phago-
damage. On the one hand, these cells are able to activate a pro- cytes Eos, mast cells, and basophils at the site of infections, which
fibrotic process by promoting the recruitment of inflammatory provide the rapid secretion of the Th2-type cytokines IL-4, IL-13,
cells, which stimulate the activity of fibroblasts and the deposition and TSLP (88). In addition to IECs, Mo, Eos, neutrophils, and
of ECM (83). On the other hand, Mo are able to terminate the mast cells can also secrete endogenous inflammatory media-
inflammation by the elimination of the debris coming from the tors or alarmins, which can function as chemotactic factors or
rupture of tissue including dead inflammatory cells (82). induce DC maturation (88, 89). These alarmins include EDN,
Tissue damage can cause upregulation of the alarmin IL-33. cathelicidins, defensins, and high-mobility group box protein 1
This is a strong positive stimulus for innate lymphocyte T  cell with a suggested role of EDN in the initiation and maintenance
2 (ILC2) accumulation and cytokine production, which can of the Th2-type response (90). However, the mice models using
support tissue-protective M2 Mo differentiation. Recent data anti-IL-5 or anti-CCR3 antibodies for Eos depletion have shown
suggest the possibility that ILC2, M2 Mo, amphiregulin (AREG), the dispensable role of these cells in the promotion of the Th2
and IGF-1 may collaborate in promoting wound healing at the response against helminth parasites (91).
mucosal barrier surfaces. A dominant Th2-type cytokine response in infected hosts
Interestingly, Mo are also involved in the immunopathology influences the development of intestinal and systemic immune
of schistosomiasis, since in both mice and humans infected with and immunopathological changes. These include strong periph-
S. mansoni many of these cells are recruited to the granulome in eral and intestinal IgE-type responses, eosinophilia, goblet
response to trapped eggs in the liver, intestinal or bladder tissues. cell (GC) hyperplasia, villous atrophy and crypt hyperplasia,
In a mouse model of S. mansoni, it was demonstrated that Mo are increased muscle contractility, and mastocyte hyperplasia in
the predominant cell population in gut granulomas, in contrast the intestinal mucosa. In addition, profound changes in the

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Motran et al. Innate Cells Shaping Immunity Against Helminths

function of the IECs have been observed, including alterations cell type), which in turn are capable of secreting IL-25, and
in permeability, proliferation, and differentiation (92). All these together with IL-33 promotes the secretion of IL-13 by ILC2 cells
mechanisms together contribute to the expulsion of the parasite (Figure 3). In this circuit, the Th2 cytokines IL-4 and IL-13 are
from the intestinal lumen. also capable of inducing tuft cell hyperplasia (98). In fact, IL-13
The hypercontractility of the intestinal smooth muscle in an produced by activated ILC2s and Th2 cells has been shown to
IL-4/IL-13-dependent manner is a characteristic of nematode promote an active renewal of IECs, a process that acts as an “epi-
infections. Furthermore, the involvement of M2 Mo in the thelial escalator” and helps to expel parasites from the intestine
regulation of intestinal contractility has been demonstrated. The (99). In addition, IL-13 induces GC differentiation, which results
expulsion of worms from the lumen appears to be mediated by in the secretion of mucus and anti-helminthic molecules, such as
the expression of Arg-1 in M2 Mo, as a regulator of this function RELMβ (97).
(93). By contrast, innate lymphoid cells (ILCs) perform crucial Zaiss et  al. have reported the involvement of AREG, origi-
functions in different tissues, particularly at the mucosa surface nally described as an epithelial cell-derived factor, which has a
of the intestine and lung, where they are important regulators of critical role in helminth resistance and shows its relevance in
the innate immune response. Among these, the ILC2s are local- the expulsion of the nematodes T. muris through the promotion
ized mainly in mucosa-associated tissues with IL-25 together of IEC replacement. Although non-lymphoid gut cells might
with IL-33. These innate immune responses contribute to the produce AREG, the exact cellular sources of this molecule are
elimination of parasites such as N. brasilienses (a gastrointestinal still unknown (100).
nematode that infects mice and has a life cycle similar to that of Considering a scenario where helminth infection causes the
hookworms in humans) (94). In line with this, it has also been recruitment of different cell populations, it is logical to speculate
reported that IL-33 has a crucial role in resistance against other how ILC2s interplay with phagocytes. In this way, Bouchery et al.
nematodes including S. venezuelensis in mice (95) and T. muris (101) reported that ILC2s and T cells cooperate with M2 Mo in
(96). After being activated by IL-33, the ILC2s increase their the lung during infection with N. brasiliensis, thereby trapping
IL-13 production, which in turn mediates two mechanisms that and killing the larvae in re-infected mice. Furthermore, they
contribute to the rodent hookworm N. brasiliensis being expelled showed that IL-33- or IL-2-dependent ILC2 activation stimulates
from the intestinal lumen: M2 Mo to reduce worm burden in the lung of re-infected mice.
Nevertheless, it is important to emphasize the role of mast cells
(1) The induction of the anti-nematode protein resistin-like mol- in the immunity against intestinal helminths, since the accu-
ecule beta or Fizz2 (RELMβ) expression, a protein released mulation of these cells or mastocytosis is a feature of infections
by GCs which are able to inhibit worm nutrition (97). caused by these parasites. The proteases of mast cells promote
(2) Eos recruitment, a key cell for eliminating intestinal nema- the breakdown of the narrow joints of the IECs, allowing the
todes from infected hosts. discharge of fluids into the intestinal lumen. In line with this,
mast cell-deficient mice (by a mutation in the c-kit gene) have
Interestingly, after N. brasiliensis infection, the activation of been demonstrated to have difficulty in eliminating the T. spiralis
ILC2s induces the hyperplasia of tuft cells (a secretory intestinal nematode (102). In addition, a crucial role of mast cells has been

Figure 3 | Innate immune response in intestinal helminth infection. Tissue damage caused by intestinal helminths induces an ATP increase that is recognized by
P2X7R on the surface of mast cells, which in turn are activated secreting IL-33. This cytokine together with other alarmins such as stromal lymphopoietin (TSLP)
activate ILC2 and induce their proliferation. Activated ILC2 cells secrete IL-13 thereby increasing mucus secretion in goblet cells (GC). The activation of ILC2s
induces the hyperplasia of tuft cells and the release of IL-25, which together with IL-33 promotes the secretion of IL-13 by ILC2 cells. IL-1β produced by lamina
propria (LP) cells inhibits IL-25 and IL-33, thereby controlling the expansion of the Th2-type response.

Frontiers in Immunology  |  www.frontiersin.org 8 April 2018 | Volume 9 | Article 664


Motran et al. Innate Cells Shaping Immunity Against Helminths

recently demonstrated in eradicating H. polygyrus in the early it is not clear whether these mechanisms occur in vivo. However,
stage of infection. These cells secrete IL-33 that activates an ILC2 there is growing evidence showing the importance of these cells
response after the recognition of tissue damage-derived ATP in the mechanisms of protection against parasitic helminths in
through the P2X7 receptor (103) (Figure 3). different settings of cell depletion or vaccination in mice.
Finally, a recent mechanism for Th2 immunity constriction Some interactions between phagocytes with other cell types
has been demonstrated. Early post-infection with H. polygyrus (e.g., ILC2) during helminth infection have been demonstrated.
bakeri, intestinal lamina propria (LP) cells secrete IL-1β, which However, further studies are still required to elucidate the fac-
inhibits the helminth-induced IL-25 and IL-33 and results in a tors that modulate the maturation of DCs to promote the Th2
reduced Th2 protective immune response, thus allowing the response in naive T cells and possible interaction between other
parasite chronicity (104) (Figure 3). phagocytic cells such as Mo, neutrophils, basophils, and mast
cells during infection by helminth parasites.
CONCLUSION
AUTHOR CONTRIBUTIONS
In the last decade, there have been important advances in the
knowledge about how helminth parasites are recognized by DCs CM and LC wrote the manuscript, LS and DC designed the
and also regarding the capacity of these cells to induce a Th2-type figures, LSC and MT critically revised the manuscript, and LA
response. However, other phagocytes are necessary to generate an and XV revised the manuscript.
intricate network of cytokines, soluble factors, and danger signals
arising from the damage produced by parasite migration, which ACKNOWLEDGMENTS
promotes a Th2-type response. This response in turn drives the
alternative activation of Mo, and the activation of Eos, basophils, This work was supported by grants from the Consejo Nacional de
and mast cells, which contribute to the expulsion of intestinal Investigaciones Científicas y Técnicas of Argentina (CONICET)
nematodes. Among the phagocytes, M2 Mo play a key role in pro- PIP 2015-2017 GI, 112201 501002 60CO, Agencia Nacional de
viding factors for rapid and efficient tissue repair and to complete Promoción Científica y Técnica (PICT-2015-1179 and 2488),
the process of wound healing. and Secretaría de Ciencia y Técnica-Universidad Nacional de
Although an undeniable involvement of phagocytes, such as Mo, Córdoba (grants to CM and LC). CM, LC, LSC, and MT are
neutrophils, Eos, basophils, mast cells, and antibodies in in vitro members of the Scientific Career of CONICET. DC, LA, and XV
death mechanisms against helminths, have been demonstrated, thank CONICET for the fellowships granted.

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