Open access peer-reviewed chapter

Helminths Derived Immune-Modulatory Molecules: Implications in Host-Parasite Interaction

Written By

Koushik Das, Shashi Upadhyay and Neeraj Mahindroo

Submitted: 20 December 2021 Reviewed: 28 January 2022 Published: 19 October 2022

DOI: 10.5772/intechopen.102927

From the Edited Volume

Parasitic Helminths and Zoonoses - From Basic to Applied Research

Edited by Jorge Morales-Montor, Victor Hugo Del Río-Araiza and Romel Hernandéz-Bello

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The parasitic life cycle of helminths greatly relies on sophisticated manipulation of host environment and successful evasion of host defense. Helminths produce a repertoire of secretory molecules (including, extracellular vesicles and/or exosomes) to invade and generate habitable host-environment, and also to modulate the host immune responses in such a way that ensures their prolonged survival within host. An outline on helminths derived immune-modulatory molecules and their implications in host-parasite crosstalk have been presented. Queries with regard to the new direction of investigation to reveal specific molecular strategies, used by helminths to manipulate the host systems are also discussed.


  • helminthiasis
  • host parasite interaction
  • secretory molecules

1. Introduction

Helminth parasites infect their hosts for an extended period, demonstrating their capacity to induce a new immunological and physiological equilibrium, which accommodates the invader [1]. Over parasites have evolved a unique arsenal of finely-tuned biochemical adaptations that control, block, or initiate modification in pathways or distinct host cells in order to maximize the success of parasites through eons of evolutionary time [2, 3]. In this book chapter, we look at some of the most current and intriguing advances in the field of host-parasite interaction with molecular pathways where the parasitic worms are known as helminths that belong to the phyla of roundworms (nematodes) and flatworms (platyhelminthes), which are lower invertebrate’s phyla. A vast range of helminth species may colonize a wide range of habitats and host organisms, evading host defense and expulsion systems in each case. Helminths’ goal is to regulate and manipulate immunity in order to disarm immunological defenses, resulting in the host failing to eradicate parasites [4]. Helminths fundamentally gain hold by going undetected, primary disabling host recognition techniques that would otherwise trigger an alarm, and then infecting tolerance of parasite antigens by the immune system, as well as suppressing reactions to bystander antigens in allergy or autoimmune [5]. Where, the helminth’s soft textured technique has consequences for the manner in which they engage with their hosts and their immune systems, implying that constant dialog is required to preserve the tolerance condition. Because stable populations of long-lived parasites characterize the disease, it is plausible to believe that the products secreted on a regular basis by live parasites that target different immune system components [2]. Supported this notion by the fact that most of the molecular mechanism of helminth infections are reversed after drug-mediated parasite clearance [6, 7, 8]. As a result, the antigens of helminths that are “excretory-secretory” (ES) have received a lot of attention, a practical method for collecting combinations of released proteins that have been around for over 60 years [9]. Of course, more recently, the use of mass spectrometry, transcriptomic, and genomics has revolutionized their knowledge to diverse preparations and compound by identifying parasites to release particular molecular components to change their surroundings [2]. Some, products like glycan, nucleic acids, and lipids, including miRNAs, as well as tiny molecules and metabolites, are released in a variety of “packages,” one of which being lipid vesicles, as discussed below.


2. Parasite identification by the host system

The first meeting of host and parasite usually breaches the surface (like, epithelium of intestinal or skin) that incites the “alarmin” discharge [10] and is recognized through pattern recognition receptors (PRRs), as an example, Toll-like receptors (TLRs) which initiate the production of inflammatory cytokine. Alarmins such as thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33) [11, 12], where together stimulate a Type 2 immune response that is anti-helminth and pro-allergic, are strongly related with helminth-mediated tissue damage. Yet, helminths have option to avoid entirely or partially this warning (Figure 1); as an example, Nippostrongylus brasiliensis compounds effectively prevent dendritic cells (DCs) from responding to TLR ligation and other helminths, with interleukin-12 (IL-12) production being particularly suppressed [13, 14, 15, 16, 17]. While the release of IL-33 from the epithelial cell, is directly obstructed through the released products from Heligmosmoides polygyrus [18]. Some of the chemical mediators that prevent innate activation are now being identified, as mentioned in the next section.

Figure 1.

Recognition of helminth infection by immune system. Innate immune system releases alarmins (IL-33, TSLP) in response to tissue invasion, which might elicit a type 2 immune response; helminth have ability to either inhibit the release of alarmins or block the respective receptors (e.g., IL-33R and ST2). The C-type lectin receptors (CLRs) or Toll-like receptors (TLRs) can recognize pathogen-associated molecular patterns, either presented directly by helminths or by bacteria, moved through damaged epithelium. In the second situation, immune modulators released by helminths suppress the Th1 response, induced by IL-12.

The prototypical PRRs respond to microbiological substances like lipoteichoic acid and lipopolysaccharide (LPS) by releasing pro-inflammatory cytokines like IL-12, which promote the Th1 response. The consistent ability of various helminth products to inhibit the release of IL-12 in response to TLR stimulation could be a mechanism aimed not so much at blocking anti-parasite immunity as it is at avoiding collateral inflammation at barrier sites where, for example, bacterial translocation may accompany helminth invasion. While the key role of TLRs in pathogen pattern recognition via the host is now well recognized, it is surprising that no analogous recognition mechanism for Th2-inducing species like helminths has yet been defined. However, helminth TLR ligands have been discovered, including the RNA activating TLR3 [19] and the lysophosphatidylserine glycolipid [20] from Schistosoma mansoni (S. mansoni), and additional receptor like C-type lectin receptors (CLRs) may fulfill the role of innate detection in different situations [21, 22, 23].


3. Host-parasite molecular interaction

In the extracellular environment, simple protein-protein interactions, involving with either exposed receptors or fluid-phase host components on the surfaces of host cells can be considered the first stage communication between the host and the parasite. H. polygyrus, secretes a functional mimic of the immunomodulatory cytokine TGF-, which binds to mammalian surface receptors and sends an inhibitory signal to the T cells (Johnston et al. submitted to be published). Space blocks further conversation of the numerous singular proteins currently observed to be associated with have helminth cooperation, yet maybe the most fascinating are individuals’ superfamily of the cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) (Pfam00188) which are significantly extended across all helminth parasite heredities [24, 25], and profoundly addressed in the emitted protein sections [26, 27]. One member of this family, a hookworm named Necator americanus, was one among the first to be identified as a potential partner as NIF, an emitted integrin restriction inhibitor that stops neutrophils [28].

While functional roles for members of the CAP gene family other than NIF are sparse, a homolog attaches to a tomato plant innate defense protein, limiting resistance systems, and triggering infection in a plant-parasitic worm [29]. As a result, helminth-released proteins are not limited to cooperating at the host cell surface, but can also play functions inside cells, raising the question of how they enter the cell.

3.1 Helminth derived proteins and their intracellular functions

Two well documented helminth glycoproteins infiltrate the host cells and have immense implications. The S. mansoni egg-inferred glycoprotein ω1 is a ribonuclease with Lewis X glycan side chains that bind to the surface lectin of dendritic cells, interfering with take-up into the phone and causing the protein moiety to serve as a protein blend obstructer [30, 31]. DCs treated with ω1 activate the type 2 immune pathway, causing immature T cells to mature into Th2 effector cells. The major secreted glycoprotein of the filarial nematode Acanthocheilionema viteae (A. viteae) is a distinct mediator of ES-62 could be 62-kDa component with N-linked phosphoryl choline (PC) side chains. Through interaction with ES-62 enters the cell via TLR4 on the surface, and the PC moiety disrupts the downstream signaling of both the B cell receptor and TLR4 within the intracellular milieu, effectively blocking cell activation [32]. Although TLR3 is an intracellular pathogen sensor, and the FheCL1 cysteine protease from Fasciola hepatica (F. hepatica) kills TLR3 in host macrophages, limiting activation; despite the fact that TLR3 is an intracellular pathogen sensor, FheCL1 can reach the endosome and degrade the receptor in situ [17].

The filarial cystatin molecule CPI-2 is used to target a distinct route. This protein contains two blocking sites that are resistant to cysteine proteases and asparagine endo peptidase (AEP) [33]. Human B cells that have been exposed to CPI-2 from Brugia malayi (B. malayi) (a human filarial parasite) are no longer able to practice presenting protein antigen to T cells, a process that is dependent on AEP activity in the endosome [33]. Advance research on a closely related cystatin from A. viteae show that it is taken up by mouse macrophages and activates ERK and p38 kinases, resulting in the production of immune regulation interleukin-10 (IL-10), which is linked to the activation of the CREB and STAT3 signaling pathways [34].

Although the entrance pathway cannot always be determined, other products have been found to modulate intracellular signaling in host cells. The ALT-2 protein, for example, is generated from a large larval transcript of the filarial parasite B. malayi, when this protein was given to macrophages or introduced into macrophages via the intracellular protozoan Leishmania mexicana (L. mexicana), it induced the signaling proteins GATA3 and SOCS1, which are active to generate type 2 responses and inhibit IFN-dependent intracellular inflammatory signaling [35].

3.2 Identification of exosomes and their implications in host-parasite interactions

Apparently, particularly exosomes and extracellular vesicles appear to play an important role in cellular communication. Exosomes are nano vesicles with a diameter of around 50–100 nm that are secreted by all cells to allow the transfer of specific cargo, primarily lipids, proteins, and RNA species, as well as other phenotypic markers from their cell of origin [36, 37]. Exosomes are formed by the inward budding of multi-vesicular endosomes within a cell, and include components of the original cell, such as RNAs or proteins, that may be trafficked into the same compartment. The extracellular vesicles have been discovered from kinetoplastids growths, and microorganisms’ group, the hypothesis that exosome-interceded correspondence could work on a cross-animal categories stage, by which parasite-inferred exosomes could associate with, and conceivably adjust, the host invulnerable framework [38]. Exosomes have just recently been discovered as integral products of extracellular organisms such as helminths [38, 39].

According to the recent research, exosomes are produced by parasitic helminths. The excretory-secretory portions of the trematodes F. hepatica, and Echinostoma caproni, which contaminate the liver and gastrointestinal system individually, were the first to disclose this [40], as well as the nematode H. polygyrus, which contaminates the small intestinal tract [41]. Information derived from the trematode concentrates additional advises that ES inferred exosomes are fit for arriving at the host climate, as they seem, by all accounts, to be discovered unblemished on the para destinations’ covering. The capacity of helminth exosomes to cross-phylum communication between mammals, and helminths is further supported by their uptake by host intestinal epithelial cells.

Exosome formation in free-living nematodes was first demonstrated in helminths, with the demonstration that a novel secretion pathway from the apical membrane of Caenorhabditis elegans co-secretes multi vesicular bodies containing exosome-like vesicles with peptides that normally promote cuticle growth [42]. Helminths and protozoa exosomes have similarities in various specific markers. In heat-shock protein 70 (HSP70), endosomal sorting components like surface tetraspanins, and Alix, including CD63 and CD9 are all found in mammalian exosomes [37]. As an example, when exosomes secreted by macrophages, which are Leishmania-infected experience a series of phenotypic alterations followed by infection, and they hold some exosome markers, with CD63, TsG101, and Alix [43]. Furthermore, transcriptome investigation of the cestode, Echinococcus granulosus, revealed the existence of other CD63-like tetraspanin family members [44]. Tetraspanins have been chosen as a vaccine against Echinococcus multilocularis, a tapeworm that causes alveolar echinococcosis, a highly lethal illness that has spread throughout areas of Central Europe, China, and Siberia [45, 46]. This tetraspanin-targeting vaccination is also being investigated as a potential treatment for the human pathogen S. mansoni [47, 48].

Earlier, it was seeming that H. polygyrus, a mouse gastrointestinal nematode, has previously been demonstrated to release exosomes containing various miRNA types as well as a significant number of proteins, accounting for around 10% of an adult worm’s total protein secretion [41]. The enrichment of a number of important components within the exosomes was also established by a proteomic analysis of the released products represented in the soluble and vesicular fractions using ultracentrifugation separation. Interestingly, some of these proteins have previously been found in the region of C. elegans’ intestinal epithelial apical membrane cells; electron microscopy revealed multi-vesicular bodies in the intestinal tissues of H. polygyrus adults, as well as exosome-like structures freed into the lumen [41], strongly implying that the parasite releases exosomes from its alimentary tract (Figure 2a).

Figure 2.

Host-helminth molecular cross-talk. (a) Helminths communicate with host systems by releasing a repertoire of molecules, such as proteins, glycan, and extracellular vesicles/exosomes containing miRNA. (b) Helminth triggers the Foxp3+ Treg population by producing short-chain fatty acids (SCFAs) and also stimulates the gut-microbes, those secrete SCFAs.

Exosomes from external helminths were also found to have immunomodulatory properties. Exosomes from H. polygyrus dominate the innate immune response to the fungus Alternaria alternata, which is linked to respiratory allergies, mostly through modulating type 2 innate lymphoid cells (ILC2s) [41]. Helminths communicate with host systems by releasing a repertoire of molecules, such as proteins, glycan, and extracellular vesicles/exosomes containing miRNA (Figure 2b). Both in-vitro and in-vivo, H. polygyrus exosomes demonstrate a lower expression of IL1RL1/ST2 transcript in mouse cell types. This gene encodes the IL-33 receptor, which is essential for ILC2s to trigger the type 2 immune response, which is compatible with exosomes’ in vivo protection from allergic inflammation. The role of the IL-33 ligand-receptor axis in anti-parasite responses is also well established [18, 49]. As a result, our findings support the ability of H. polygyrus derived exosomes to evade parasite clearance by altering a critical element of the host immune system.

Exosomes were identified in the culture media of the digenean trematode livestock parasite Dicrocoelium dendriticum, which included over 80 protein components and at least 30 miRNA species with similarity or near-identity to known sequences [50]. Despite the lack of functional studies, the scientists noted similarities with the key Schistosoma miR-3479, miRNAs Bantam, and miR-10, which are visible indicators in the plasma of infected animals [51].

Moreover, Nowacki et al. identified over 200 miRNAs, 20 tRNA-derived short RNAs, and over 100 proteins in 30–100 nm exosome-like vesicles released by S. mansoni schistosomula that are enriched in certain non-coding RNAs and proteins [52]. Furthermore, it was discovered that the B. malayi L3 infective stage secretes 50–120 nm vesicles rich in miRNA species, as well as a protein complement that includes not only conventional exosome-associated products, but also those that could interfere with host cell responses, like Cathepsin L [53]. Importantly, the adult worm stage was shown to produce less exosomes than the infective stage, which is likely due to the demands of converting from vector to host at this point in the life cycle. Adult S. mansoni worms also release 50–130 nm-sized exosome vesicles with approximately 80 identifiable proteins, five of which are tetraspanins, and an abundant saposin-like protein, according to Sotillo et al. [54]. It is also shown that a number of recognized schistosome vaccine candidate antigens, including the tetraspanins, are key components of the exosomes, as previously mentioned. Wang et al. reported that adult worms of the similar parasite S. japonicum emit 30–100 nm vesicles after being cultivated in-vitro for 5 h, which can be detected using ultracentrifugation of the culture solution [55]. Although this work did not identify the protein cargo of the exosomes, these scientists discovered that S. japonicum exosomes boosted the production of nitric oxide in the murine macrophage-like cell line RAW264.7, along with other markers of a Type 1 pathway. The presence of many important proteins and RNA species in secreted vesicles emphasizes both the complexity and diversity of cargo within exosomes, as well as the broad range of potential connections between recipient cells [56].

Investigations of the liver fluke Opisthorchis viverrini, a trematode common in regions of Southeast Asia and causally connected to cholangiocarcinoma (bile duct cancer) have revealed a larger chance for helminth exosomes. Exosomes (measured 40–180 nm) were found in secretory material from the species mentioned above, along with a similar spectrum of related proteins, including tetraspanins [57]. In the bile fluid of infected hosts, some proteins linked to exosomes were discovered. Anti-tetraspanin antibodies prevented exosomes from entering host cells, implying that this protein is likely to be represented on the vesicular surface in the same way that mammalian exosomes. Suggestively, exosomes from O. viverrini were shown to stimulate cell proliferation and induce the generation of the pro-inflammatory cytokine interleukin-6 (IL-6) in a human cholangiocyte cell line in a way that was partially inhibited by an anti-tetraspanin antibody. Taken together, these findings support the theory that O. viverrini energies cause tumorigenic alterations in the host bile duct, which could explain the parasite’s carcinogenic effects.

3.3 Exosomes contain helminth miRNAs

It’s been a while, all around archived that micro-RNAs and non-coding RNAs specifically, move among cells and life forms through their epitome inside exosomes and other vesicles found outside of the cell [58]. Certainly, this gives a piece of machinery for RNA protection from destruction outside the cell, and appears to provide an absorption pathway to transfer RNA to the recipient’s proper cellular compartment. Many of the investigations mentioned above, including those from the nematodes B. malayi [53] and H. polygyrus [41], as well as the trematodes D. dendriticum [50] and S. mansoni, identified short RNAs within parasite exosomes [52].

We were able to show a collection of RNA species bundled inside exosomes, including miRNAs such as let-7, miR200, and diminutive [41], which may block the mouse phosphatase Dusp1 using a quantitative measure, thanks to H. polygyrus. New information differentiating wide miRNA collections in parasitic helminths is rapidly emerging, albeit the circulation of these released conservative exosomes inside parasitic helminths has yet to be established.

Most importantly, definitive proof for helminth-derived miRNAs acting on host genes has yet to be discovered; however, the circumstantial evidence remains enticing; not only are extensive seed sequences shared between helminth and host miRNAs, but the miRNA-rich exosomes (at least of H. polygyrus) also contain worm Argonaut protein [41, 59]. Indicating that a functional gene repression package is being delivered to the targeted cells.


4. Host-parasite communications through small molecules

Mechanisms of tiny molecules, hormones, molecular cues, and metabolites, which are closely involved in intercellular communication, draw much attention. As an example, short-chain fatty acids (SCFAs, butyrate, acetate, and propionate), for example, which are commensal derivatives at the level that promote regulatory T cells, are not generated by mammalian organisms [60]; dysbiosis is thus considered harmful for the disruption of this path [61, 62]. Surprisingly, these chemicals can also be produced by helminths [63], implying that commensal bacteria can produce a significant amount of SCFAs [64].

Another tiny molecules produced by filarial parasites B. malayi and Onchocerca volvulus, as well as skin-invasive cercariae of S. mansoni, include prostaglandins D2 and E2 [65, 66, 67]. In addition to tiny chemicals and metabolites, helminths change small ligands derived from the host, such as acetylcholine (through acetylcholinesterase) [68], the enormous discussion of platelet-activating factor (PAF hydrolase [69]) and ATP (apyrase [70]), among many others, is beyond the scope of this paper.


5. Microbiome-mediated interactions

In the gastrointestinal system, particularly, helminth parasites contribute their position with numerous microorganisms, predominantly numerous bacterial species recognized as microbiota [71, 72, 73]. Remarkably, helminth contamination depend on excessive range on the existence of these parasites: as an illustration, in the lack of caecal bacteria, Trichuris eggs do not mature in the gut [74]. The majority of microbiota study in mice infection with gut helminths have discovered important and sometimes comprehensive alterations in species arrangement, mainly within Lactobacillus populations and Bacteroides [71, 72, 73]. Newly, it was declared that BALB/c mice infected with H. polygyrus showed enlargement of the L. taiwanensis species, and the degree of colonization with this bacterium was found to be positively linked with both adult worm populations and Treg activation [75]. Surprisingly, mice administered L. taiwanensis before receiving H. polygyrus larvae were shown to be more susceptible to infection, implying that the bacteria and helminth species work together to promote infection.

It has also been suggested that the immune-modulating capabilities of helminth infection could be aided in part by altering the microbiome of the intestine. To date, fascinating research have shown that infected mice’s intestinal contents (which comprise bacteria as well as a variety of host and parasite products) can lessen allergy symptoms when transmitted to recipient mice [64]. It will be interesting to investigate this consequence minutely and mostly if L. taiwanensis, specific bacteria is responsible.

Considerably, a recent study showed that fecal miRNAs produced from intestinal epithelial cells might influence the microbiome, possibly by interacting directly with bacterial genes [76]. Feasibly these miRNAs could potentially be found in extracellular vesicles, raising the possibility that the helminths and host both might modify the microbiome through this innovative mechanism, and indeed as stated below, that host exosomes might have an impact on the helminth organism, parasitizing the intestinal tract.


6. Host-helminth interaction is bi-directional process

While this analysis has focused on how helminths communicate with the immune system of hosts, there are several enthralling examples of how helminths detection and response towards host immune state. Adult N. brasiliensis worms acclimate towards an immunized host through adjusting secreted acetylcholinesterase expression levels and isoforms, according to previous research [77]. All the more as of late, identification of cytokines from host, has been found in schistosomes, which need the existence of TNF from host to develop to laying of egg [78] and filarial parasites reacting towards high IL-5 levels present in-vivo by speeding up the development and off-spring formation [79]. Helminth receptor illustration is ready to ligate host cytokine was set up on account of S. mansoni TGF-β family receptor [80].

An appealing chance of extracellular vesicles from the host may offer of communications of network, which accelerates the helminth parasites, although it is still not proved that, parasites can directly receptive to vesicle-mediated signals. There are a developing literature representing the how host-derived extra-mobile vesicle effect against defense in opposition of pathogens. As an instance, in recipient infected cells, IFN-α, exosomes derived from stimulated cell could induce the antiviral activity and bound viral replication [81, 82]. Additionally, semen exosomes from human is associated in resistant to HIV-1 resulting their uptake into immature cells by reducing viral fitness [83]. Innate response towards protozoan parasite Cryptosporidium parvum is also established as an instance of exosome-mediated host defense. Activation of host epithelium through TLR mediation enhances the secretion of antimicrobial exosomes, which contains peptides that limits infection rate of pathogen in the intestinal environment [84]. The progress of a targeted host exosomes anti-pathogen response has also been examined the usage of a clinical setting, in which host exosomes collected from parasite antigen-primed dendritic cells encourage protection against various protozoan contaminations, counting Toxoplasma gondii infection [85] and Leishmania major [86].


7. Exploitation of helminth-induced immune modulation as novel therapeutic strategy

With people parasitic, helminths have coevolved with centuries, unpredictably filtering and fostering a variety in instruments to smother or slant the host’s invulnerable framework, accordingly advancing their drawn-out endurance. A few helminths, like hookworms, make minimal no obvious pathology when present in unobtrusive numbers and can even give profits to their hosts humans. Clinical studies on helminth infection of humans have been conducted and analyzed for the protection and efficiency of a variety of immune dysfunction to take advantage of this evolutionary phenomenon, with mixed results [87]. It was shown that treatment of live helminth on mice and larger animals resulting excretory/secretory products, having drug-like properties of anti-inflammation, represent an updated pharmacopeia. Such molecules include proteins, glycans, and extracellular vesicles, modifications after the translation process, several metabolites. Helminth-motivated treatments grips guarantee, this adds a test to the medication improvement local area, which is for the most part new to unfamiliar biologics that do not act like antibodies. The identification and characterization of helminth compounds and vesicles, as well as the molecular pathways they target in the host, provides a unique opportunity to produce customized therapeutics stimulated through nature that is safe, efficacious, and immunogenic [88].


8. Conclusions and future perspectives

Throughout evolution, helminths have conveyed a wide variety of host species, emerging sophisticated links, also regulate channels with, and even control of, their hosts’ immune systems. In host-parasite biology, there is the fast invention that several helminth species mediate cross-phylum interactions by releasing exosomes which leads to the importance of this pathway. Classification as helminths, how large the extracellular parasites, may be capable to “reach in” into the host cells intracellular mechanism, rebuilding the behavior through every possible way. The absorption of exosomes is not a receptor-dependent process; this is hard for the host to grow countermeasures to inhibit properties of exomes on parasites, whereas this would be easier for the parasite for abusing the tracking exosome for operative interfering particles, from enzymes to small RNAs, proteins and other modifiers of gene expression. Additionally, these vesicles suggest vigorous machinery to the parasites, which might transport their “message” through extracellular spaces present in diverse nature and quite probably through cells and tissues.

More information from exosomes of helminths would lead towards balancing their effects, gaining our prevailing knowledge about immunomodulatory proteins and glycan. If we can produce antibody reactions towards components of the surface membrane, which are needed for cell entry, exosomes could be a good vaccine target. Additionally, new drug aims may appear from elaborating the paths needed for the biogenesis of exosome in helminths, and the cellular events of a host cell, which occurs after helminth exosome uptake. Hereafter, a new opening has unlocked on how helminths overthrow the immunity system and how they deal works by defeating the strategy of the helminth.


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Written By

Koushik Das, Shashi Upadhyay and Neeraj Mahindroo

Submitted: 20 December 2021 Reviewed: 28 January 2022 Published: 19 October 2022