Abstract
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.
Keywords
- 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,
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
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.
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
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
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
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
Exosome formation in free-living nematodes was first demonstrated in helminths, with the demonstration that a novel secretion pathway from the apical membrane of
Earlier, it was seeming that
Exosomes from external helminths were also found to have immunomodulatory properties. Exosomes from
Exosomes were identified in the culture media of the digenean trematode livestock parasite
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
Investigations of the liver fluke
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
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
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
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
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,
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
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
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
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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