TREPAR 1495 No.

of Pages 11

Review
Genomic Regions Associated
with Sheep Resistance to
Gastrointestinal Nematodes
Magda Vieira Benavides,1,* Tad S. Sonstegard,2 and
Curtis Van Tassell3
Genetic markers for sheep resistance to gastrointestinal parasites have long
Trends
been sought by the livestock industry as a way to select more resistant individ-
Gastrointestinal parasitic infections are
uals and to help farmers reduce parasite transmission by identifying and remov- the main health problem for grazing
ing high egg shedders from the flock. Polymorphisms related to the major animals.

histocompatibility complex and interferon (IFN)-g genes have been the most Parasite resistance to drugs is now
frequently reported markers associated with infection. Recently, a new picture is widespread, and the first reports of
emerging from genome-wide studies, showing that not only immune mecha- host resistance to gastrointestinal
infections have triggered great interest
nisms are important determinants of host resistance but that gastrointestinal in determining the genetic basis for
mucus production and hemostasis pathways may also play a role. host resistance.

Host Resistance and its Importance for Animal Selection New information brought from quanti-
tative trait loci and genome-wide asso-
Gastrointestinal infections are the main health problem for grazing animals, especially small
ciation studies suggests that three
ruminants such as sheep, causing weight loss ([1] for a short review), stunted growth [2], and mechanisms could determine host
death in extreme situations [3]. In addition to these symptoms, the nematode Haemonchus resistance to gastrointestinal parasitic
contortus is also known to cause severe anemia in lambs, with daily intake of up to 30 ml of infections: innate and acquired immune
responses, gastric mucosal protection,
blood per infected sheep [4]. The cost of parasite treatment alone has been estimated to be in
and hemostasis pathways.
the order of tens of billions of dollars worldwide [5,6]. While farmers had effective antiparasitic
drugs in the 1980s and 1990s, parasite resistance to anthelmintics developed quickly for all Innate and acquired immune cell
pharmaceutical drugs [7] widely used in leading sheep-producing countries. Effective treatment responses are required to boost type
2 helper cytokine production and to
can only be achieved when new, potentially more expensive formulations become available. deliver effector cells and IgE to the site
Hence, finding alternatives for gastrointestinal parasite control remains an urgent area of of infection.
ruminant health research.
Mucin biosynthesis plays an important
role in gastric mucosal protection, act-
The first reports of host resistance to gastrointestinal parasites [8–10] triggered great interest in ing as a barrier and triggering swift
determining the genetic basis for host resistance. Fortunately, gastrointestinal resistance is not parasite expulsion.
an absolute trait nor it is confined to breeds because between- and within-flock variability has
Hemostasis pathways, required for
been reported [11]. The longer animals are exposed to infective larvae in the pasture, the more
blood clotting, can obstruct parasite
likely host resistance will develop. However, some animals will be unable to mount a strong feeding and maintain host packed cell
immune response to parasite infection even in adult life. Host resistance is measurable through volume levels, important for host recov-
the performance of individuals after parasite challenges. The performance of an animal can be ery after infection.
assessed by packed cell volume (PCV) [12,13] for H. contortus infections, immunoglobulin A
(IgA) levels in Teladorsagia circumcincta challenges [13–16], Trichostrongylus colubriformis- 1
Embrapa, Brasília, DF, Brazil
2
specific IgG [17], and eosinophil counts [18]. Fecal egg count (FEC), in other words the number Recombinetics, Saint Paul, MN, USA
3
Animal Genomics and Improvement
of worm eggs in feces, is an indirect trait of parasite burden but is far less invasive to measure, Laboratory, US Department of
hence it is the preferred method in most studies [19]. Agriculture (USDA)/Agricultural
Research Service (ARS) Beltsville
Agricultural Research Center,
Sheep resistance information was put to a practical use when breeding programs that included Beltsville, MD, USA
FEC in their selection objectives were established in Australia, New Zealand, and Uruguay

Trends in Parasitology, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.pt.2016.03.007 1

© 2016 Elsevier Ltd. All rights reserved.
 TREPAR 1495 No. of Pages 11

{Nemesis [20], WormFec (www.sheepimprovement.co.nz/getdoc/7cd2a417-fc4a-4ec0-888e- *Correspondence:

magda.benavides@embrapa.br
b85d9e66f12a/Internal-Parasites-WormFEC-Pro.aspx), and [21], respectively}. These programs (M.V. Benavides).
provided farmers with the option to use selective breeding to enhance host resistance to parasite
infections in their flocks.

Despite the benefits of challenging young ruminants for selection purposes, this process is
laborious and lambs are particularly susceptible to parasitic infections [22]. High parasite
burdens are likely to cause loss of production while lambs have their resistance status assessed.
However, it is important that all animals follow parasite challenges to eliminate false resistant
animals owing to lack of pathogen exposure. Consequently, scientists and the livestock industry
have been searching for genetic markers associated with host resistance as one strategy to
tackle parasite problems. With these markers in hand, selection programs could be more
effective and straightforward. By using DNA markers, blood or tissue samples could be taken
from young animals and selection performed based on their genotypes, although a low level of
phenotyping would still be necessary to cull individuals with undesirable morphological traits.

There have been several reviews in the host resistance field [19,23–27], therefore the main
objective of this paper is to focus on the new information brought from quantitative trait loci (QTL)
and genome-wide association study (GWAS) reports.

Markers Associated with Host Gastrointestinal Parasite Resistance

Candidate gene investigation, in other words studies of associations between variants of
preselected genes related to the host immune response, was the first approach used to search
for genetic markers associated with host resistance [28–30].

Among the genetic markers that have been reported so far using the candidate gene approach,
the most frequently cited are those from the major histocompatibility complex (MHC) region on
Ovis aries chromosome 20 (OAR20) [12,13,15,30–42]. Genes that belong to MHC are highly
polymorphic [43] and play important roles in presenting processed antigens to host T lympho-
cytes, causing T cell activation and an immunological cascade of events building host immunity.

Second to the MHC region is the interferon g (IFNG) gene on OAR3 [14,15,17,18,44–51]. This
Th1 proinflammatory cytokine is involved in recruiting cellular responses [52]. Evidence from
murine models shows that high levels of IFNg may negatively interfere with the development of a
Th2 protective immune response against gastrointestinal parasites [53].

QTL Studies and GWAS

The concepts used to conduct QTL searches and GWAS are quite similar. Both methods are
used to identify regions of a genome that have effects on economic traits. Typically, QTL studies
in livestock have been conducted in pedigreed populations (with known sire and dam informa-
tion) for a trait that is quantitative in measure, such as weight gain or litter size, and polygenic in
nature, using a modest number (100–200) of genetic markers (mainly microsatellite markers).
QTL studies typically localize the causative variant to a fairly large region. GWAS can fit pedigreed
populations but it can also be used in case–control studies with no pedigree information. It
employs thousands of -polymorphismSNP markers to unveil genomic regions associated with
the trait of interest.

In all ovine chromosomes, 126 significantly associated markers and marker intervals spread
across the genome were found to be associated with FEC and related traits for the main parasite
species that affect sheep (H. contortus, T. circumcincta, and T. colubriformis) [54]. The pano-
rama that emerges from the latest compiled QTL and GWAS literature for sheep resistance to
gastrointestinal parasites is an intricate one, and is undoubtedly rendered even more complex

2 Trends in Parasitology, Month Year, Vol. xx, No. yy

 TREPAR 1495 No. of Pages 11

owing to the number of software packages and algorithms available for analysis of QTL and
GWAS results.

However, a clearer pattern can be observed by looking to specific regions in four ovine
chromosomes: 1, 3, 6, and 20 (Tables S1–S4 in the supplemental information online) where
66 relevant markers were detected. Of interest will be the practical application of the results
reviewed here (see Outstanding Questions), where the main challenge will be to test markers and
obtain the best possible combination of polymorphisms to establish a panel that characterizes
resistant individuals, if not for all sheep breeds, at least for groups of them.

Genomic Regions Exclusively Associated with One Parasite

Two genomic regions associated to H. contortus FEC were identified in OAR3 [49,50,54] (F and
H segments, Table 1): a wide region (F, Table 1) where markers are either closely located to or
overlapped immune response genes for biosynthesis of interleukins [50,54], and a second
region (H, Table 1) [49] containing several interleukin receptors and receptor-like genes. Parasite
infections, especially those caused by the pathogenic H. contortus, are characterized by a type
2 helper T cell (Th2) response showing increased number of mucopeptic cells [55], eosinophilia,
mastocytosis, and immunoglobulin E (IgE) production, triggered by secretory factors produced
by parasites attached to the mucosa [22,52,56,57], and even before mucosal attachment [53].
Because mastocytosis, eosinophilia, and IgE production are also interleukin-driven processes,
the identification of genes involved in biosynthesis of interleukins is understandable.

Exclusive regions associated to T. circumcincta host resistance are located in chromosomes 1

[42] and 3 [14,15,36,44,46] (C, J, and K, Table 1). Several candidate gene studies demonstrated
the role of IFNg in sheep resistance to T. circumcincta [14,15,17,44,46–48]. Significant interval
markers were also found close to the IFNG region in QTL studies of sheep resistance to
T. circumcincta [15,18,51], suggesting that IFNG neighboring genes may also be of interest in
host resistance.

The first association between IFNG and sheep resistance to T. circumcincta was described
using a candidate gene approach [14], and it was later followed by several candidate gene
studies focusing this gene [44,46,47] and confirmed by genome-wide methodologies
[15,17,48]. This IFNG polymorphism was associated with IgA in lambs, and the authors
hypothesized that this allele was capable of downregulating IFNg, therefore leading to a stronger
Th2 response and hence more resistance [14]. However, to date there are no studies clearly
associating this allele with lower expression of IFNg and host resistance.

The IFNG polymorphism argument should also work for H. contortus; nonetheless GWAS failed
to identify associations with host resistance to this parasite. The fact that the IFNG gene was
associated with T. circumcincta and not with H. contortus is a puzzling finding. The pathology of
these two abomasal parasites might differ because T. circumcincta produces substantial injury
to the abomasal mucosa [58] and H. contortus causes local mucosal damage at the site of
parasite attachment [59]. Resistance to both parasites depends on Th2 cell responses; however,
their immunological profiles may differ. Haemonchus contortus infections elicit rapid changes in
effector cells in the abomasal mucosa and lymph nodes [22], and also produce swift and strong
IL5 responses that could downregulate IFNg at local lymph nodes in resistant sheep [60]. On the
other hand, IFNg expression was reported to be high in lambs infected with T. circumcincta
[61,62], possibly due to low IL5 levels in early infection. Cattle studies with Ostertagia ostertagi
infection corroborate the high levels of IFNg expression after infection [63,64]. This prolonged
IFNg expression could be an explanation why IFNg seems to be more important to T. circum-
cincta than to H. contortus, where a strong Th2 response at the beginning of infection minimizes
the effect of IFNg.

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TREPAR 1495 No. of Pages 11

Table 1. Summary of Relevant Genomic Regions for FEC and Related Traits, in Ovine Chromosomes 1, 3, 6, and 20, and Genes Located Within Regions
Trends in Parasitology, Month Year, Vol. xx, No. yy

Chromosome 1 3 6 20

Segment A B C D E F G H I J K L M N O P

From ([8_TD$IF]Mbp) 15.274271 [9_TD$IF]108.571005 171.428022 179.527190 216.348958 12.409183 [10_TD$IF]58.879027 83.766686 125.982479 [1_TD$IF]151.527165 171.249925 193.294649 16.880386 55.942491 7.197476 12.326227

To ([8_TD$IF]Mbp) 44.730409 [9_TD$IF]168.948404 175.114220 196.951219 273.044608 50.846078 [10_TD$IF]58.879027 99.683489 134.722893 [1_TD$IF]153.851070 188.007557 212.354024 36.651734 112.817744 7.281659 40.705933

Haemonchus [41,54] [49] [50,54] [50,54] [49] [49,54] [51] [50,51] [51,54] [12] [12,41[13_TD$IF]]
contortus[1_TD$IF]
[12_TD$IF][refs]

Teladorsagia [16,42] [16] [42] [42] [14,15,36, [15] [15] [42] [16,48] [15,34] [15,33,35,
circumcincta 44,46] 36,39,42]
[refs]

[14_TD$IF]Trichostrongylus [93] [45] [45] [45]

colubriformis
[[15_TD$IF]refs]

[16_TD$IF]No parasite [94] [18] [[18_TD$IF]94]

specified [[17_TD$IF]refs]

Genesa[19_TD$IF] (from TAL1 (h)b[20_TD$IF] FCER1A (i) PHLDB2 MYLK (h) RAP2B DAB2IP (i) IL18RAP (i) ATP2B1 (h) IFNG (i) MYH9 (h) VWF (h) NFKB1 (i) TLR10 (i) DYA (i) TREM2
proximal to
distal in the LRP8 (h) FCER1G (i) MUC13 (m) P2RY1 ADAM17 (i) IL18R1 (i) SOCS2 (i) IL2RB (i) GALNT8 (m) SPP1 (h) TLR1 (i) TAP1 (i) IL17A (i)
chromosome) PPAP2B (h) MUC20 (m) P2RY12 TRIB2 (i) IL1RL1 (i) ZNF385A (h) TLR6 (i) IL17F (i)

MUC4 (m) CPA3 (i) GALNT14 (m) IL1RL2 (i) GALNT6 (m) RHOH (h) DRB1 (i)

GP5 (h) PIK3CB (h) ANXA4 (i) IL1R1 (i) PDGFRA (i/h) TNFA (i)

PLEK (i) IL1R2 (i) KIT (i) MUC21 (i)

MUC7 (m) HIST1H2BF (i)

IL8 (i) HIST1H2BI (i)

PPBP (h) HIST1H2BE (i)

CXCL9 (i) UBE2N (i)

CXCL10 (i/h)

CXCL11 (i)

CXCL13 (i)

a
[2_TD$IF]Abbreviations, ADAM17, ADAM metallopeptidase domain 17; ANXA4, annexin A4; ATP2B1, plasma membrane calcium-transporting ATPase 1; CPA3, carboxypeptidase A3; CXCL10, chemokine (C-X-C motif)
ligand 10; CXCL11, chemokine (C-X-C motif) ligand 11; CXCL13, chemokine (C-X-C motif) ligand 13; CXCL9, chemokine (C-X-C motif) ligand 9; DAB2IP, DAB2 interacting protein; DRB1, major histocompatibility
complex class II DR b1; DYA, MHC class II antigen DY/; FCER1A, Fc fragment of immunoglobulin E (IgE) – high-affinity I receptor for / polypeptide; FCER1G, Fc fragment of IgE – high-affinity I receptor for g
polypeptide; GALNT14, polypeptide N-acetylgalactosaminyltransferase 14; GALNT6, polypeptide N-acetylgalactosaminyltransferase 6; GALNT8, polypeptide N-acetylgalactosaminyltransferase 8; GP5, platelet
glycoprotein V; HIST1H2BE, histone cluster 1 H2be; HIST1H2BF, histone cluster 1 H2bf; HIST1H2BI, histone cluster 1 H2bi; IFNG, interferon gamma; IL17A, interleukin 17A; IL17F, interleukin 17F; IL18R1, interleukin
18 receptor 1; IL18RAP, interleukin 18 receptor accessory protein; IL1R1, interleukin 1 receptor 1; IL1R2, interleukin 1 receptor 2; IL1RL1, interleukin 1 receptor-like 1; IL1RL1, interleukin 1 receptor-like 1; IL1RL2,
interleukin 1 receptor-like 2; IL1RL2, interleukin 1 receptor-like 2; IL2RB, interleukin 2 receptor beta; IL8, interleukin 8; KIT, v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog; LRP8, low-density
lipoprotein receptor-related protein 8 – apolipoprotein E receptor; MUC13, mucin 13; MUC20, mucin 20; MUC4, mucin 4; MUC7, mucin 7; MYH9, myosin heavy chain 9 non-muscle; MYLK, myosin light chain kinase;
NFKB1, nuclear factor of k light polypeptide gene enhancer in B cells 1; P2RY12, G-protein coupled 12; P2RY1, purinergic receptor P2Y G-protein coupled 1; PDGFRA, platelet-derived growth factor receptor /;
PHLDB2, pleckstrin homology-like domain family B member 2; PIK3CB, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit b; PLEK, platelet pleckstrin; PPAP2B, phosphatidic acid phosphatase type
2B; PPBP, pro-platelet basic protein (chemokine C-X-C motif ligand 7); RAP2B, ras-related protein RAP-2B; RHOH, ras homolog family member H; SOCS2, suppressor of cytokine signaling 2; SPP1, osteopontin
precursor; TAL1, T cell acute lymphocytic leukemia 1; TAP1, ATP-binding cassette, subfamily B; TLR10, toll-like receptor 10; TLR1, toll-like receptor 1; TLR6, toll-like receptor 6; TNFA, tumor necrosis factor /;
TREM2, triggering receptor expressed on myeloid cells 2; TRIB2, tribbles pseudokinase 2; UBE2N, ubiquitin-conjugating enzyme E2N; VWF, von Willebrand factor; ZNF385A, zinc finger protein 385A.
[20_TD$IF] b
Pathways related to (i)[3_TD$IF] immune system; (h) hemostasis; (m) mucin regulation.
 TREPAR 1495 No. of Pages 11

A single study [45] showed that only one region in chromosome 1 (E, Table 1) is exclusively
associated to T. colubriformis FEC. This region overlaps several genes involved with platelet
activation and aggregation, and with wound healing. However, these are important processes at
the site of parasite attachment to the mucosa, and would be important for H. contortus
infections because hematophagous parasites secrete proteins to inhibit host thrombosis so
as to facilitate blood ingestion and digestion at the site of attachment [65].

Genomic Regions Associated With Two or More Parasites

Six genomic regions located in chromosomes 1, 3, 6, and 20 (B, D, L, M, O, and P in Table 1)
show common results between H. contortus and T. circumcincta, both of which are abomasal
parasites. Some of the genes found within these segments are implicated in wound healing,
platelet adhesion, and blood clotting (Table 1) that are important response mechanisms for H.
contortus. This associates with anemia, an important clinical symptom in H. contortus infections
[66] owing to the hematophagous nature of this parasite, causing decrease in red blood cell
counts that are easily measured as a reduction in PCV.

Other genes identified are involved in the production of IL-3 and IL-6, key cytokines in the IgE
production cascade, and in mounting the Th2 immune response against gastrointestinal
parasite infection [52,57]. Genes linked to mucin biosynthesis and glycosylation were found
mostly in OAR1 (D, Table 1), but also in OAR3 (L, Table 1). Genes implicated in MHC-mediated
antigen processing and presentation, and lymphocyte signaling pathways were found in
OAR20 (O, Table 1).

Still in OAR20, we found the positions of IL17A and IL17F to be relatively close to DRB1. These
interleukin genes have not been yet described in sheep resistance studies; however, there are
interesting results showing their involvement in immunological responses of cattle and mouse
parasite infections. IL-17 is the leading inflammatory cytokine in Th17 cell populations [67] and
IL-17 transcripts have been shown to be strongly upregulated in cattle after a single challenge
with the bovine abomasal nematode Ostertagia ostertagi [68]. IL-17 was found to stimulate
acute inflammation after Nippostrongylus brasiliensis infection in mice [69].

Likewise, the TNFA gene, which encodes a Th1 cytokine produced by macrophages, is located
1 [8_TD$IF]Mbp from the DRB1 region and has been reported in sheep parasite infections. Schafer et al.
[70] observed severe clinical signs in sheep infected with H. contortus when this cytokine was
produced in combination with IL-1, showing that Th1 cytokines increase pathological signs when
sheep are infected with helminths. It is our belief that IL-17 and TNF/ could contribute to severe
inflammation, hampering a protective immune response against parasites.

The region common to H. contortus and T. colubriformis (I, Table 1) overlaps the SOCS2 gene
[45,49,54] which is responsible for IL-3 regulation [71]. This gene has also been reported
as being differentially expressed in the abomasal lymph nodes of lambs resistant to T. circum-
cincta infection versus control individuals [72]. Together with IgE and eosinophilia, mastocy-
tosis is another typical helminth infection host response, and the latter mechanism is stimulated
by IL-3 [73], suggesting that SOCS2 could be important for improving sheep immune
response.

Genomic Regions Common to All Main Parasite Species

Two genomic regions affect H. contortus, T. circumcincta, and T. colubriformis (A and N,
Table 1). Several important genes related to hemostasis are located on OAR1 (A, Table 1),
including TAL1 that is important for platelet formation and the regulation of mast cell differentia-
tion, PPAP2B involved in regulating wound healing, and LRP8 that is related to the platelet
hemostasis pathway (www.genecards.org/Search/).

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Several toll-like receptor (TLR) genes (TLR1, 10, and 6), members of the TLR signaling pathway,
NF-kB family, and Th17 differentiation pathways, are present on chromosome OAR6 (N, Table 1).
TLRs are innate immune proteins that detect pathogen invasion in the gastrointestinal mucosa
and are essential for mounting Th2 responses [74]. These TLRs are located in a large chromo-
somal region (55.9–112.8 [8_TD$IF]Mbp) reported by several studies [16,48,51,54] as being of impor-
tance for host resistance to gastrointestinal parasite infection.

The same region encodes several other genes involved in the immune response to infection,
such as PDGFRA [48] and KIT [16,48], which encode proteins implicated in MHC class I
mediated antigen processing and presentation, and genes encoding the IFNg-induced chemo-
kines CXCL9, 10, 11, and 13. MUC7, involved in mucin biosynthesis, is also located within this
region.

Despite some genomic regions having been exclusively found for one or other parasite species,
we highlight that genes related to the immune system, mucosal protection, and hemostasis are
common to all three main species.

Other Chromosomes
Sixty other genes or chromosomal regions were found to be scattered across the ovine genome
outside chromosomes 1, 3, 6, and 20. Some of these regions are worth mentioning, mainly
because they contain genes related to those already mentioned.

The SNP marker OAR12_69606944 (63 088 234 bp [54]) is located close to the laminin g1 chain
precursor gene (LAMC1; 62.16–62.28 [8_TD$IF]Mbp). Laminins are active in the integrin pathway,
degradation of the extracellular matrix, cell adhesion/plasmin signaling, and hemostasis. It
has been suggested Trypanosoma cruzi surface proteins modulate laminin expression to move
through the extracellular matrix and promote cellular infection [75].

MUC15, encoding a cell surface-associated protein (54.529 [8_TD$IF]Mbp) belonging to the O-linked
glycosylation pathway, is located near the OAR15_59871543 (55.404–55.417 [8_TD$IF]Mbp [54]) and
PGA5 (pepsinogen) markers on OAR21 [41], corroborating earlier results [55] that found an
increase in plasma pepsinogen resulting from H. contortus and Ostertagia circumcincta
infections.

Finally, it is of significance that earlier results [76] (7–22.5 [8_TD$IF]Mbp) overlap for two important genes
on OAR23: CD226, encoding a protein related to class I MHC-mediated antigen processing and
presentation, and GALNT1, encoding a mucin-type O-glycosylation enzyme involved in mucin
biosynthesis. On this same chromosome, two studies [41,50] found overlapping FEC-associ-
ated marker intervals (15.308–15.880 [8_TD$IF]Mbp). A second region [41] contained MALT1 (57.8–
58.0 [8_TD$IF]Mbp), which encodes a mucosa-associated lymphoid tissue lymphoma translocation
protein that is part of the B cell receptor signaling pathway, among other immune response
functions.

Known and Proposed Mechanisms for Host Response to Infection

By comparing relevant markers for FEC in the literature to the currently available sheep genome
map, it is possible to uncover genes of biological significance for host resistance. It must be
mentioned that the identification of genes located close to relevant markers was possible
through efforts made by the International Sheep Genome Consortium (www.sheephapmap.
org/). The fact that sheep genome is still being improved by proper assembly and annotation
adds an extra challenge to the identification of genes in linkage disequilibrium with significant
markers for host resistance. As the sheep genome becomes more saturated it is likely new
genes will come to light.

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 TREPAR 1495 No. of Pages 11

As expected, most of the genomic regions are flanked by Th2 immune response genes typical of
gastrointestinal infection, such as eosinophilia, mastocytosis, and immunoglobulin E (IgE)
production [22,52,57] (Table 1). Together with the acquired immune response, there is a
growing body of evidence indicating that genes involved in O-linked glycosylation of mucins
(MUC or GALNT) and in hemostasis are found almost ubiquitously around reported markers,
and these too may play a major role in fighting parasite infections [77,78] (Table 1). Interestingly,
genes involved in the mucin-type O-glycosylation pathway appear to segregate near to genes
involved in hemostasis (Table 1). Figure 1 summarizes the proposed host resistance mecha-
nisms for H. contortus infection, showing the putative implication of the mucin and hemostatic
pathways, the known acquired host immune response, and their interactions.

Abomasal mucus, whose main component is mucin, is considered to be one of the primary
innate immune host defense components, providing the first barrier against gastrointestinal
parasites [74,78] as well as viral, bacterial, and fungal pathogens [79–81]. It was found that
sheep immunized by daily low-dose H. contortus inoculations had unchanged gastric mucin
levels 48 h after infection, showing that hosts are able to control mucus depending on their
immunological status [82]. In vitro studies have shown that larval motility and feeding are
restrained when sheep gastrointestinal mucus samples were co-cultured with parasites [83].
However, each host species may respond differently according to the infective parasite species.

Mucus was also reported to facilitate parasite expulsion in murine models. Trichinella spiralis and
Nippostrongylus brasiliensis parasites were covered in mucus when expelled from the gastro-
intestinal tract [80,83,84]. However, T. colubriformis response to infection may not rely on
alterations of mucins present in the mucus because the host response has been shown to be
mainly dependent on inflammatory mediators and vasoactive factors [85–87].

Hemostasis (control over bleeding and blood vessels injury) could be a third possible mechanism
contributing to sheep resistance to gastrointestinal parasites. The PDGFRA gene (N, Table 1)
encodes a protein involved in wound healing that is located close to FEC markers reported in
T. circumcincta and H. contortus infections [16,48,54]. Other proteins related to blood clotting
(SPP1 [51] and LRP8 [54]) were associated to H. contortus FEC. The SPP1 gene belongs to the
wound-healing pathway (J.R. Wright, PhD thesis, University of Leicester, 2010) and it has been
implicated in the duration of in vivo thrombosis in murine models [88]. These results corroborate
previous findings that hemostasis and platelet hemostasis pathways may play a role in host

Acquired immune response Innate immune response Hemostasis

MHC complex (Class I, DRB1, and DYA) GALNT- 1, 3, 5, 6, 7, 8, 13, and 14 ATP2B1, LRP8, PDGFRA, and SPP1
IFNγ MUC- 4, 7, 13, 15, and 20
Blood clong at the host–parasite
Parasite angens Increase in GI mucus aachment site

Angen presentaon to MHC Class I and II

A R
Reducon of larval molity and feeding
T cell acvaon Parasite feeding restraint
Increase in peristalsis
IgE producon Reorganizaon of mucosal ssue
Parasite expulsion from GI tract
Eosinophil and mast cell migraon Wound-healing process

IgE armed eosinophil and mast cells Steady host packed cell volume level
degranulaon

Mount strong Th2 response

Figure 1. Proposed Host Resistance Mechanisms to Haemonchus contortus Infection. Arrows indicate the flow of interaction among pathways and proteins.
Abbreviations: ATP2B1, plasma membrane calcium-transporting ATPase 1; DRB1, major histocompatibility complex (MHC) class II DR b1; DYA, MHC class II antigen
DY/; GALNT, polypeptide N-acetylgalactosaminyltransferase; GI, gastrointestinal; IgE, immunoglobulin E; IFNg, interferon gamma; LRP8, low-density lipoprotein
receptor-related protein 8 – apolipoprotein E receptor; MUC, mucin; PDGFRA, platelet-derived growth factor receptor /.

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 TREPAR 1495 No. of Pages 11

resistance. Maintaining hemostasis is perhaps more important for host resistance to hema- Outstanding Questions
tophagous parasite infections as a way to control host anemia. In addition, host hemostasis is Can the current genetic markers for
also a paramount process for the parasite because clotting at the infection site can severely FEC be used in animal breeding pro-
grams for host resistance selection
undermine the constant blood supply to adult hematophagous parasites, impairing parasite purposes?
feeding and survival in the host [65].
Considering the wide range of markers
associated to sheep resistance to par-
Concluding Remarks
asite infection, could a single panel of
The path to pinpointing genetic markers strongly associated with host resistance has been long markers be valid for all sheep breeds
and hard. Literature results originate from a wide variety of sheep resource populations (ten and parasite species? If this poses a
breeds and five crossbreds), and from distinct geographical regions (tropical or temperate challenge, would it be possible to
establish different panels for groups
climates), exposed to the main parasite species in the sheep industry (H. contortus, T.
of breeds with similar genetic back-
colubriformis, and T. circumcincta), either under natural or artificial challenge protocols (Box grounds which are infected with a sin-
1), to name the main factors. Considering this genetic and environmental diversity, it is gle parasite?
understandable that numerous molecular markers have been reported to be associated with
Is the IFNG polymorphism associated
FEC and its related traits.
with T. circumcincta infection related to
injury of the abomasal mucosa and
Some genomic regions have been shown to be exclusive to particular parasite species. The prolonged IFNg levels at the beginning
association of IFNG with T. circumcincta is of significance; genome-wide scans failed to of the infection?

associate this specific genomic region with H. contortus or T. colubriformis. However, most Can the role of mucin biosynthesis-
genomic regions were similar between H. contortus and T. circumcincta, two parasites with the and hemostasis-related genes in pro-
abomasum as the site of infection. tection against helminth infections be
confirmed by comparing their expres-
sion in parasite-resistant versus -sus-
Despite the wide range of genomic regions associated with host resistance, several studies ceptible sheep?
seem to be providing results that point toward genes other than those related to immune
response. There is mounting evidence that host resistance is of a quantitative nature, determined Host resistance to gastrointestinal par-
asite infections is characterized by a
by several genes with varied effects, rather than by a limited number of genes with a major role in
Th2 response. How detrimental would
resistance. The literature indicates not only that host acquired immune system mechanisms are it be for FEC-selected sheep to be
important to build host resistance but that genes involved in the gastrointestinal mucus infected with Th1 response diseases?
production, parasite expulsion, and hemostasis regulation are also relevant.

Some remaining questions are the confirmation of mucin production as an important protective
mechanism for helminth infections, either by in vitro assays or stimulation through dietary
ingredients [89], and by looking at its efficacy in parasite expulsion. Nevertheless, mucin-
and hemostasis-related genes are found in gene expression studies comparing parasite-resis-
tant and susceptible sheep. Previous reports [90–92] support a role for several of the genes
listed in Table 1, such as SPP1, CXCL10, and IFNG, proving their involvement in host resistance
mechanisms.

Box 1. Challenge Protocol

Natural and artificial parasite challenges rely on drenching (deworming) all contemporary animals to zero their FEC; the
animals are then run as a single flock in a highly contaminated paddock (natural challenge) or receive oral administration of
infective larvae (artificial challenge). Weekly fecal samples are taken from 5–10% of the animals for FEC counts.

Parasite challenge methodologies (www.sheepimprovement.co.nz/getdoc/7cd2a417-fc4a-4ec0-888e-b85d9e66f12a/

Internal-Parasites-WormFEC-Pro.aspx) are applied early in life to recently weaned lambs to minimize the generation
interval. It is important that lambs graze pasture containing infective larvae from birth to weaning such that host immunity
can gradually increase with age.

If genomic studies are to be carried out, blood samples must be taken from each individual for genotyping. When FEC
average reaches the threshold, all individuals are drenched, fecal samples are taken, and a new round of challenge
ensues (usually two to three rounds of challenge are used). In some regions veterinarians recommend drenching when
flock FEC reaches 500 eggs per gram of feces, but this threshold might differ in other geographic regions.

8 Trends in Parasitology, Month Year, Vol. xx, No. yy

 TREPAR 1495 No. of Pages 11

Most importantly, an interesting aspect of this topic is its application in the sheep industry. This
information can be useful to animal breeding programs soon after a combination of markers are
tested to validate FEC effects and marker panels are established to select for resistant individuals
and measure their effects on FEC. Setting up one group of markers for all ovine breeds and
parasites will be a challenge, and most likely a panel will need to be established for groups of
similar breeds infected with a single parasite.

Finally, it would be useful to test markers for parasite resistance against other diseases such as
those caused by bacteria and viruses, and to confirm that Th1 response diseases would not
display detrimental effects when sheep are selected on the basis of FEC.

[21_TD$IF]Supplemental Information
[2_TD$IF]Supplemental information associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.pt.
2016.03.007.

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