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responses in Corriedale and Crioula Lanada sheep following natural infection with Haemonchus contortus. Small Ruminant Res., 51(1): 75–83. Cachat E ...

Journal of Immunology and Immunopathology Vol. 17, No. 2, July-December, 2015: 79-85 DOI: 10.5958/0973-9149.2015.00011.8

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Review Article

Immune Responses to Haemonchus Contortus in Sheep MK Vijayasarathi1*, A Sheeba1, Manikkavasagan2, C Sreekumar3 and K Dhama4 1

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PG Scholar, Department of Veterinary Parasitology, Madras Veterinary College, Vepery, Chennai-600007, Tamil Nadu, India 2 Assistant Professor, College of Food and Dairy Technology, Koduvalli, TANUVAS, Chennai -600052, Tamil Nadu, India 3 Professor, Post Graduate Research Institute in Animal Sciences, TANUVAS, Kattupakkam, Kancheepuram-603203, Tamil Nadu, India 4 Principal Scientist, Division of Pathology, ICAR-Indian Veterinary Research Institute (ICAR-IVRI), Izatnagar, Bareilly-243122, Uttar Pradesh, India *Corresponding author email id: [email protected]

ABSTRACT Vijayasarathi MK, Sheeba A, Manikkavasagan, Sreekumar C and Dhama K (2015). Immune Responses to Haemonchus Contortus in Sheep. J. Immunol. Immunopathol. 17(2): 79-85. Sheep, called as ‘museum of parasites’, is susceptible to many nematodes. Among the nematodes, Haemonchus contortus is an important voracious blood sucking helminth, which causes alteration in pH of abomasum and blood parameters like PCV. The host produces some immune mechanism against H. contortus to limit the pathogenic effect produced by the parasite. However, the parasite escapes the host immune response in order to survive within the host, which is called ‘evasion’ mechanism. Keywords: Haemonchus contortus, Immune response, Antigen, Immunoprophylaxis, Evasion, Sheep, Pathogensis

INTRODUCTION

RESISTANCE AND RESILIENCE

Gastroenteric nematode is a disease with a great economic impact on sheep farms located in humid areas including tropical and subtropical regions of the world (Mugambi et al., 1997). Among the nematodes, Haemonchus contortus is the most important gastroenteric nematode of sheep in many countries, including India. Because of its ubiquity, virulence and blood-sucking ability in the abomasums, it causes a disease known as haemonchosis (Quiroz, 1984; Fernando Alba-Hurtado et al., 2013). There are certain breeds of sheep that are relatively resistant to the parasite including Gulf Coast Native sheep. Understanding the protective nature of the immune response that helps these breeds of sheep control infection could enable the development of vaccines to enhance control programmes (Shakya et al., 2009).

Nematode resistance includes the initiation and maintenance of a host response that prevents, reduces or clears parasitic infection (Hooda et al., 1999; Bricarello et al., 2004). Resistant animals do not completely reject the disease, but they have a lower parasitic load than susceptible animals, as measured by fewer eggs in their faeces. This resistance is based on the immunological capabilities of each individual when challenged with parasite (Gill, 1991). Resilience is the capacity of an animal to compensate for the negative effects of parasitism by the maintenance of productive parameters (Paolini et al., 2005). Sheep in general show simultaneously high resistance and resilience to haemonchosis. Some breeds have moderate or low resistance with relatively high resilience, allowing them to have productivity 79

MK Vijayasarathi, A Sheeba, Manikkavasagan, C Sreekumar and K Dhama

similar to those that are naturally resistant (AlbaHurtado et al., 2010). Differences between sheep breeds in their susceptibility to infection by abomasum-inhabiting nematodes were first reported by Stewart et al. (1937), who described higher resistance to Ostertagia circumcincta (currently Teladorsagia circumcincta) in Romney Marsh lambs compared with lambs of the Rambouillet, Shropshire, Southdown and Hampshire breeds and their crosses. Ross et al. (1959) reported the first evidence for heritable resistance to haemonchosis in sheep.

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PATHOGENESIS Many factors are involved in the pathogenesis of haemonchosis. In terms of the development of disease, the most important factors are parasite virulence and host–response. The main pathogenic mechanisms of H. contortus are direct lesion on the gastric mucosa and haematophagy. The effects of pathogenic mechanisms during intra-host parasite development and the subsequent response of infected ruminants provoke morpho-functional changes particularly in abomasum (Figure 1a). Also variations appear in some blood parameters, resulting in the appearance of both anaemic and impaired digestion– absorption syndromes. Haemonchosis is acquired by ingesting pasture contaminated with the third stage larvae (L3) of H. contortus. L3 penetrates the abomasal glands, where they molt into L4. The presence of larvae induces abomasal gland hyperplasia (Figure 1b), inflammatory cell infiltration (Figure 1c) and the substitution of wall cells secreting HCL with young non-secreting cells. Consequently, the abomasal pH increases, which in turn reduces the transformation of pepsinogen to pepsin, reduces protein digestion, increases mucosa permeability and increases the loss of endogenous proteins in the abomasum. Adult parasites are found in the abomasum lumen, and they are voracious haematophagous parasites, daily consuming 0.05 mL of host blood per worm. H. contortus causes notable blood loss with a reduction of packed cell volume (PCV). This parameter has been used as marker of parasite virulence and indirect estimation of parasite burden in haemonchosis. A reduction of plasma protein 80

concentrations has been found in haemonchosis due to blood loss and haemorrhagic gastritis. In addition, leakage of proteins to the gastric lumen occurs as a result of the disruption of inter-cellular unions and increased requirements for protein synthesis by the immune system (Amarante et al., 2005). SYMPTOMS OF HAEMONCHOSIS IN SHEEP The negative effects of haemonchosis on the biological and economic efficiency of sheep herds include malnutrition, low feed conversion, anaemia, loss of appetite, reduction in milk and wool production, presence of pale mucosa, oedemas, diminution of PCV, haemoglobin, plasma proteins and increase in the number of circulating eosinophils in peripheral blood (Balic et al., 2006). Besides these, there is an increase in level of serum pepsinogen and gastrin, low fertility indices and in certain cases death may be accompanied by emaciation and death. HOST IMMUNE RESPONSES The immunological mechanisms by which sheep acquire resistance to haemonchosis are not very clear. Resistance is an individual characteristic that has been associated with age, breed and previous exposure to the parasite (infection or reinfection). Both innate and adaptive immunities protect the host from H. contortus infection. Clearance of the nematode in immunised sheep requires several events, including the activation of non-specific defence mechanisms, the recognition of parasitic somatic and excretion/ secretion antigens, and the initiation of an appropriate acquired response (Meeusen et al., 2005). The mechanisms underlying immunity are still not completely understood. Antibodies, in particular local IgA and IgE, certainly play a role. The role of IgG is less clear. Lymphocyte proliferation responses seem to correlate to immunity. Sheep that have high antigen-induced lymphocyte responses have a low susceptibility to infection. Furthermore, several studies have demonstrated that immunity against H. contortus is associated with mastocytosis and hypersensitivity reactions (McClure et al., 1996). More recently, increasing attention is being paid to the role of cytokines (interleukins and gamma-interferon) in the activation of specific defence mechanisms (Schallig, 2000). Vol. 17, No. 2, July-December, 2015

Immune Responses to Haemonchus Contortus in Sheep

(b)

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(a)

(c) Figure 1 (a): Congested abomasal mucosa with numerous minute hair-like Haemonchus contortus worms (green arrow), (b) Thickening of abomasal mucosa due to hyperplasia of mucous and gastric gland, (c) Eosinophilic Infiltration in the mucous and gastric gland of abomasum

Host immune response to haemonchosis is com plex and shows cellular, humoral and inflammatory mechanisms (McClure et al., 1996; Meeusen, 1999) that can vary depending on the parasitic phase present (Yong et al., 1985). The parasitic Ag interact with innate immune system cells like macrophage, dendritic cells, natural killer cells and basophils which releases cytokines, mainly IL4, that provide instructions to T and B cells of the acquired immune system to generate a specific response (Haward et al., 1999; London et al., 1998). Infection with helminths induces the liberation of cytokines associated with T helper cells (Th2) response, accompanied by eosinophils, Journal of Immunology and Immunopathology

mastocytosis and production of IgE. The cells that recognise parasitic Ag send molecular signals that induce T helper (Th) cells to secrete IL (McClure et al., 1996; Meeusen, 1999). Interleukins stimulate B cells to produce and secrete antibodies (IgE, IgG and IgA); these antibodies bind to antigens. The complex formed is recognised by mastocytes, eosinophils and neutrophils, which release the content of their granules like histamine, leukotrienes, prostaglandins and other mediators. This induces an inflammatory process, increases mucous production and provokes the contraction of smooth muscle and expulsion of the parasite or death (Yong et al., 1985; Gill, 1994; London et al., 1998; Meeusen, 1999; Mulcahy et al., 2004; Terefe et al., 2007; Francisco 81

MK Vijayasarathi, A Sheeba, Manikkavasagan, C Sreekumar and K Dhama

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et al., 2007). In ruminants, elimination of adult nematodes from the GI tract commonly occurs as a consequence of the development of adaptive immunity (Terefe et al., 2007). The increase of complement receptors on the eosinophils surface and the complement protein deposits on helminth surface cause cell degranulation and a direct effect on the parasite as well as an indirect effect through the complement classic pathway (London et al., 1998). CD4 lymphocytes are effecter and regulator cells, performing collaborative functions which increase in number after H. contortus infection in the abomasums mucosa and regional lymph nodes (Terefe et al., 2007). CD8 lymphocytes are considered effecter and regulatory cell of immune system carrying out suppressing and cytotoxic functions. In H. contortus infections, their role is less important as observed by lack of effect of CD8 reduction on HPG, parasitic burdens in lambs and cell infiltration in abomasal mucosa during the parasitic infection (Mulcahy et al., 2004; Amarante et al., 1999). Mastocytes are markers of helminth infection. They are generated in the bone marrow from a haematopoetic precursory cell that expresses CD34 on its surface, similar to eosinophils and basophils and must mature in the target organ. Mastocytes play an effecter role in resistance against gastrointestinal nematodes, and their proliferation, recruitment and differentiation are regulated by cytokines released by lymphocytes CD4 (Balic et al., 2006). The hyperplasia of mastocytes in the abomasums mucosa is associated mainly with the presence of adult parasites and is greater in reinfections, requiring a continuous stimulation on the part of parasitic antigen. The increase in the number suggests local inflammatory response implied in the protective response against re-infection. With regard to humoral response, it has been shown in different papers that H. contortus infection cause an increase in specific immunoglobulin slightly in primary infection and strongly in re-infection (Ross et al., 1959). These immunoglobulin increases are associated with the immediate hypersensitivity response by means of the binding of IgE to parasitic antigens with the subsequent degranulation of effecter cells. The result is the expulsion or death, thus regulating parasitic 82

burden. The specific local response of IgA and IgG is consistently associated with reduction of the helminth size and parasitic fecundity by metabolic enzyme neutralisation (Francisco et al., 2007). THE NON-SPECIFIC IMMUNE MECHANISMS H. contortus larvae must inhabit an appropriate gastrointestinal niche that nourishes their development and growth and protects them from mechanical (peristaltic movement) and chemical (abomasum mucous) host barriers. Parasite colonisation of the host abomasum initially depends on the motility of the larvae and the parasite load. Some host individuals, after sensitisation via previous infections, can modify the micro-environmental conditions of the niche to expel the parasite (Miller, 1996). HAEMONCHUS CONTORTUS IMMUNE EVASION Parasites are exposed to host immune system attack, which is why they must develop efficient immune evasion strategies (Hartmann and Lucius, 2003). The mechanisms used by H. contortus to diminish the host local response efficacy are location in the abomasum lumen and parasite mobility. In addition, the helminth produces a number of inhibitory proteases as well as immune modulator components that block host effecter mechanisms (Mulcahy et al., 2004). Cystatins of H. contortus are inhibitors of proteases involved in the process of antigen presentation, reducing the T lymphocytes response. They modulate cytokine response, by reducing the co-stimulator molecule expression on macrophage surface, thus contributing to an anti-inflammatory micro-environment induction with a strong diminution of cellular proliferation (Hartmann and Lucius, 2003). Type C lectin, identified in H. contortus and other nematodes, inhibits leukocyte adhesion to endothelial cells by competing with selectin and their subsequent migration to infected tissue, reducing the inflammation. It has been determined that another E/S protein of adult H. contortus called calreticulin, in addition to inhibiting blood clotting and facilitating haematophagy, binds with and inhibits complement C1q component, which facilitates helminth survival (Suchitra et al., 2005). Vol. 17, No. 2, July-December, 2015

Immune Responses to Haemonchus Contortus in Sheep

HAEMONCHUS CONTORTUS ANTIGENS

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During the infection of sheep, H. contortus progresses through various life-cycle stages (L3, L4, L5 and adult), among which there are differences in surface molecule expression. Some antigens specific to L3 and L4 are not expressed during the adult stage. The frequent changes in surface antigens make an effective adaptive response difficult in the initial stages of infection; therefore, each developmental stage is immunologically a different organism. Thus, the larval antibody response does not cross-react with the adult stage (Meeusen et al., 2005). Hidden antigens from the H. contortus intestine have been used to elicit a Th2-type response and the production of host serum antibodies, which are subsequently ingested when nematodes feed on the host’s blood. The ingested antibodies recognise the nematode’s intestinal antigens and alter its digestion. The best-characterised and most effective intestinal antigens are the enzyme complexes H11 and H galGP. The first is a family of m icrosomal aminopeptidases, and the latter is an aspartyl protease and metalloprotease complex. Together, these antigens, which have been obtained directly from adult worms, provide substantial protection against natural infection by H. contortus in sheep (Bowles et al., 1995; Knox et al., 2003; Smith et al., 2001). Immunisation with H-gal-GP results in the production of host antibodies that inhibit the haemoglobinase activity of the endogenous enzyme, leading to H. contortus malnutrition due to decreased blood digestion. However, the induced protection is short lived, and the difficulties of large-scale production of immunogens limit their commercial development. Sheep immunised with the same recombinant antigens expressed in Escherichia coli and insect intestinal cells have been unsuccessful in providing protection from infection (LeJambre et al., 2008; Cachat et al., 2010). Immunisation with cysteine protease-enriched protein fractions obtained from adult H. contortus worms protected sheep and goats against experimental infection with the parasite. The 70–83 kDa surface antigens obtained from exsheathed Journal of Immunology and Immunopathology

larvae, and the 15 and 24 kDa excretion/secretion antigens produce some degree of protection (LeJambre et al., 2008). Infection with different nematodes induces the abomasal and intestinal production of IgG antibodies against a carbohydrate larval antigen (Car LA) present on the surface of various strongylid nematodes (Cachat et al., 2010). CONCLUSION H. contortus is an important blood-sucking nematode which has produced anaemia and hypoproteinaemiain small ruminants that may be fatal particularly to young animals. Anaemia is the major feature responsible for pathogenesis haemonchosis infection. There are numerous elements that may or may not favour the appearance of haemonchosis, whose clinical manifestation is not only caused by parasite pathogenesis but also by different host responses to infection. This complex situation requires the planning of different control strategies in order to reduce parasitic action and stimulate host resistance and thus increases the productivity of ovine flocks. REFERENCES Alba-Hurtado F, Romero-Escobedo E, Munoz-Guzman MA, Torres-Hernandez G and Becerril-Perez CM (2010). Comparison of parasitological and productive traits of Criollo lambs native to the central Mexican Plateau and Suffolk lambs experimentally infected with Haemonchus contortus. Vet. Parasitol., 172(3–4): 277–282. Amarante AFT, Bricarello PA, Huntley JF, Mazzolin LP and Gomes JC (2005). Relationship of abomasal histology and parasite-specific immunoglobulin A with resistance to Haemonchus contortus infection in three breeds of sheep. Vet. Parasitol., 128: 99– 107. Amarante AFT, Craig TM, Ramsey WS, Davis SK and Bazer FW (1999). Nematode burdens and cellular responses in the abomasal mucosa and blood of Florida native, Rambouillet and crossbreed lambs. Vet. Parasitol., 80: 311–324. Balic A, Cunningham CP and Meeusen ENT (2006). Eosinophil interactions with Haemonchus contortus larvae in the ovine gastrointestinal tract. Parasite Immunol., 28: 107–115.

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