Molecular Mechanisms Used by Adult Schistosoma Worms to Survive in the Bloodstream - Essay Example

Molecular Mechanisms used by Adult Schistosoma Worms to Survive in the Bloodstream By: Ahmed Aljeraisi Advanced Molecular and Medical Parasitology Id Number: 2011113503 Location: University of Hull Date of submission: 16/11/2012 Introduction Schistosomes consist of a genus of trematodes, which belong to the Platyhelminthes phylum. They are parasites that live in the vascular system, and mature as separate-sex entities in the veins of birds and mammals. Schistosomes are the causative agent of Schistosomiasis or bilharzia, which is approximated to affect more than two hundred million individuals in seventy six developing nations. Schistosome eggs often become lodged in the tissues of the host, and they are the major cause of pathology in the condition. A number of the deposited eggs can pass through the intestinal wall and reach the outside environment. The remaining eggs often go into circulation and get filtered in the periportal tracts within the liver, and this causes periportal fibrosis. According to Ashton and Wilson (2001), the major schistosome species that affect individuals are: Schistosoma haematobium, Schistosoma mansoni and Schistosoma japonicum. These parasites experience remarkable physiological and morphological changes throughout their life as a means of survival and adaptation to their varying living conditions in different hosts. These parasites are unique because they exhibit unique adaptations both to free-living, as well as parasitic living. The adaptations exhibited by these parasites allow movement between intermediary hosts and the ultimate host. Schistosomes survive within the host by adopting mechanisms that counter the effect of the hosts’ defense mechanisms. These adaptations occur both at the molecular and structural levels. Schistosomes have various adaptations at the molecular level and these include anti-oxidant production and glycoproteins secretion among others. Structural adaptations also help facilitate survival, and these include tails or cilia for swimming, secretory glands for penetration into the host, a glycocalyx for host immuno-modulation or protection of the parasite, a gynaecophoric canal for continued coupling between sexes, and a well-organized reproductive system for proper egg fertilization, as well as muscular suckers for feeding and attachment. This paper reviews these adaptation strategies, and how they are employed in survival. Additionally, possible interventions are proposed to counter the effect of these adaptations so as to make the parasites vulnerable to the host’s immune system and possible elimination. Evasion Strategies Adaptations for survival among schistosomes entail evasive strategies that enable the parasites to survive within the host without being affected by the hosts’ immunity. The evasion tactics, which allow survival, are complex and some of them are not fully understood. The major evasion tactic used by schistosomes entails the generation of antigens that are analogous to the endogenous components of the host’s system. This adaptation enables the schistosome surface membrane to evade immune recognition, which may lead to its destruction. Schistosomes also produce antioxidant proteins, which are part of their evasive mechanisms. The hosts of schistosoma are produce superoxide, which has the ability to destroy the worm. However, the worm evades the potential destruction from superoxide by producing antioxidant proteins, which are capable of blocking the superoxide destructive effect. The parasites have four superoxide dismutases, and the protein levels of the dismutases increase with the maturation and development of the schistosomes. The ability to inhibit antioxidant pathways has been identified as the major choke-point for schistosomes and it has been employed in eliminating the worms. The inhibition of antioxidant pathways makes the worms vulnerable to the defense mechanism responses kill the worms through superoxide. Schistosomes are capable of protecting themselves from host membrane attack complex by blocking complement proteins from the host. Studies on immunocytochemistry have shown that the parasite’s tegument protein has a decay accelerating factor. The decay accelerating factor is often found on the cells of the host, and it protects the cells of the host from damage by blocking the formation of the membrane attack complex. Additionally, studies have revealed that the genome of schistosomes contains the human CD59 homolog, which is responsible for the inhibition of the membrane attack complex. This ability to mimic the hosts’ immunological adaptation functions allows the parasites to survive within the host without being detected as foreign bodies. Schistosoma also secrete and synthesize a wide range of glycoproteins, which have antioxidant activity against the defense systems of mollusks, which are intermediary hosts. This protects them against oxidative killing exhibited by the defense system of intermediary hosts. This evasive mechanism enables them to survive before they can reach their ultimate host. These glycoproteins are not only produced in the intermediary hosts, but also in the ultimate host where they serve the same survival purpose. Schistosomes also secrete and excrete products that alter the immune system of their hosts in a manner that down-regulates the immune responses of their hosts, and thus preventing their destruction. For example, the secretions by schistosomes larval forms, cercarie, are known to down-regulate the immune response of their hosts. Similarly Schistosoma mansonii secretes products, which are coupled by Sm 16.8 protein, which is has an anti-inflammatory action that prevents the activation of the host’s immune responses (Gryseels and Kestens, 2006, p163). This mechanism is also displayed by eggs of Schistosoma mansonii and adult worms-miracidia. Mechanisms of survival The Tegument of the Adult Worm The structural nature of the schistosomes’ surface also plays a significant role in the worm’s survival and evasion of the immune responses of the host.  Adult schistosomes have a thick syncytium, which is 2-4 m. The syncytium is known as a tegument and it covers the worm’s entire surface. The tegument of adult worms and schistosomula is fascinating. It comprises of a solitary multinucleated cytoplasmic layer, known as syncytium, which covers the whole worm. This is connected to nucleated cell bodies, below it, by cytoplasmic links that cover the musculature. The apical exterior of the tegument experiences dynamic proceedings and has a distinctive architecture consisting of two strongly aligned lipid bilayers, the proximal membranocalyx of the host and the plasma membrane. Image 1: The tegument of an adult Schistosome This surface is quite essential in immune modulation and evasion, as well as nutrient absorption. Therefore, it guarantees the survival of the Schistosome. In addition the tegument plays vital roles in the elimination of dissipate lactate from mature Schistosomes. There are several proteins found in the tegument of these mature Schistosomes that influence their survival in the host. These proteins are linked with the valuable targets of drug/vaccine in relation to their proximity to the blood of the host. For instance, S. mansoni contain approximately 51 proteins. These includes enolase, a protein concerned with the metabolism of energy; the molecular chaperone heat shock proteins 19, 17 and 20, a range of molecular motor and cytoskeletal proteins consisting of severin, actin and dynein light chains, calmodulin; proteins of the mitochondria like Adenosine Tri-phosphate synthase; plasma membrane transporters, and vesicle proteins; structural molecules and enzymes such as glucose transport protein, calcium ATPase, annexin, alkaline phosphatases, and tetraspanins A, B, and C (Burke & McManus, et al. 2009, p. 172). Quite a good number of these proteins are normally expressed in both S. japonicum and S. mansoni species. The absorption of nutrients is from hosts is important for survival of parasites. Schistosomes are known to use their tegument in absorption of some essential nutrient elements such as iron. According to Glanfield et al. (2007, p. 585) iron uptake as well as other minerals’ absorption in schistosomes occurs through the tegument. The iron uptake is proposed to occur through non-specific binding of transferrin (Tf)-host iron carrier. According to the hypothesized absorption Ferric iron is cleaved and reduced by ferric reductase to a ferrous form. This is then carried across the tegument by a divalent metal transporter (DMT1) (Glanfield et al., 2007, p. 585). The ability to easily acquire nourishing nutrient supplies from the blood through absorption across the tegument and its membranes ensures that schistosomes are able to conveniently survive within the hosts’ vascular system. The tegument also enables the parasites to acquire amino acids from the host’s blood through hemoglobin degradation. This processes is least understood, but it is suggested that it may involve a number of proteases. The transport of nutrients across membranes requires mediation of transporter molecules, which include cathepsin B and schistosome alkaline phosphatase (SmAP) (Glanfield et al., 2007, p. 585). These are important transporter molecules used by the schistosomes in nutrient acquisition. The ability to easily acquire virtually all its nutrient requirements from the blood makes schistosomes well adapted for survival within the vascular system without requiring any special structural elements for seeking nourishment. Image 2: Absorption of iron nutrients across the tegument of schistosomes The tegument of the infective larvae facilitates penetration and activation of survival mechanisms within the host. According to Kusel et al, (2007, p. 1479), the tegument undergoes changes that facilitate the penetration and prevention of haematosis. The parasite and its eggs are foreign bodies, which may in ideal circumstances prompt the formation of blood clots around them. However, there are no clots that form around the migrating parasites, and therefore, it can be concluded that that the parasites have a molecular, biological mechanism, which hinders the activation of blood coagulation or haematosis within the host. In essence, this action prevents the parasite and its eggs from being recognized as foreign bodies, and therefore, averting destruction. Apart from serving as a nutrient uptake site, the tegument also serves as a waste secretion site that allows adults schistosomes to eliminate lactate waste produced during their metabolic processes. The worm’s tegument also serves a reproductive role because female worms are able to signal male worms for pairing through a chemical mechanism initiated by the worm’s tegument. The signal facilitates pairing and consequent reproductive processes that allow proliferation (Glanfield et al., 2007, p. 588). Schistosomes’ Variant Nature within a Host Schistosomes vary their molecular appearance through genetic mechanisms so as to facilitate survival within the host. In S. mansoni, the snail host, mucins are produced. These mucins are regulated by a multi-gene family unit. The family members of this unit normally recombine. There also exist multiple splice variations for every gene. As a result, the polymorphism of mucin occurs and this facilitates versatility and survival under different environments. In addition, tetraspanin-2, the tegument protein found in S. japonicum, has been established to be different from the sequence variation on the molecule’s surface. On the other hand, S. mansoni elucidates a differential micro-exon gene transcript splicing that is generated by a protein variation mechanism (Van Riet & Yazdanbakhsh, 2007, p. 103). The expressed gene-based polymorphism and protein variation allows survival under varying environments. The development of this genetic understanding on the nature of schistosomes’ polymorphism and protein variation has significant implications in the search for vaccines against these parasites. According to Walker (2003), the genetic understanding developed on schistosomes may be used in developing vaccines and drugs that could be used in the treatment of the condition caused by the parasites. The Sensory System of Schistosome The search hosts and the ability to move and find appropriate host site requires a sensory system in all parasites. The schistosomes’ sensory system serves the parasites in the search for pairing partners and appropriate sites within the host for survival. Schistosomes utilize their sensory system to sense the existence of their definitive and intermediate hosts, to react to environmental signals and move within the body of their hosts to locations where they develop fully. The ability to sense their hosts enables them to effectively identify and invade targets for survival. In addition, they employ this sensory system in the recognition of one another, sustaining their close relationship, as well as coupling. The sensory structures are located on the exterior layer of the mature Schistosomes’ tegument and on different areas such as the terebratorium of particular larval stages (Jones & Loukas, 2008, p. 204). Nonetheless, the signals that are obtained at the parasite’s exterior surface and modulate its behavior are complex. The schistosomes’ sensory system relies on ciliated sensory papillae, which are the main sensory organs used by the worms. There exists a network of neurotransmitters with regard to the presence of the neuronal system. There are also receptors which are coupled with a number of G-proteins. There is a molecular contact between these components that is essential in the Schistosome’s behavioral reactions such as the larvae’s motility and the contraction of the muscles. Molecular communication, which occurs, is important for behavioral responses, which include muscle contraction and the facilitation of motility for schistosome larvae. The integration of signals to provide coordination is least understood and needs further exploration because this is one of the least understood areas in the study of the parasite. Immunopathogenic Characteristics of Schistosome Eggs Schistosome eggs are a significant determinant of the survival of parasite in human hosts. Their survival and capability to hatch within the human body facilitates the survival and furtherance of the parasites’ existence. Schistosome eggs pose an immunogenic challenge to the host because they form inflammatory granulomas on the egg surfaces, and as result the eggs become embolized within the tissue of the host. Image 3: Schistosoma egg enclosed within an embolized and developing structure. The embolism commonly occurs in the lungs, intestine and liver as well as urogenital organs. The embolized surrounding around the eggs protects them from adverse effects of the host immune responses and allows their survival and proliferation of the parasite. In addition to this mechanism, the schistosome eggs secrete glycoprotein antigens, which protect the eggs from adverse immune responses of the host. The eggs specifically secrete omega-1, a 31 kDa glycoprotein antigen. The antigen presents ribonuclease activity and favors the survival of eggs within the host. According to Kusel, Al-Adhami and Doenhoff (2007, p. 1479), the role of the produced omega-1 has not been fully established, but a number of other identified ribonucleases have an immunomodulatory and cytotoxic properties meant to enhance the immune properties of the host so as to favor the survival of the parasite. Conclusion Schistosomes are able to survive in their intermediary and ultimate hosts through various mechanisms, which enable them to evade the immune responses of the host that may kill the worms of their eggs. The adaptations enable the worms to survive, proliferate and seek conducive sites within their host environment. The major evasion tactic used by schistosomes entails the generation of antigens that are analogous to the endogenous components of the host’s system. Schistosomes also produce antioxidant proteins, which are part of their evasive mechanisms. The antioxidants prevent destruction by superoxide produced by the hosts’ immune system. Schistosomes are also capable of protecting themselves from host membrane attack complex by blocking complement proteins from the host. Additionally, studies have revealed that the genome of schistosomes contains the human CD59 homolog, which is responsible for the inhibition of the membrane attack complex. Schistosoma also secrete and synthesize a wide range of glycoproteins, which have antioxidant activity against the defense systems of mollusks, which are intermediary hosts. Schistosomes also secrete and excrete products that alter the immune system of their hosts in a manner that down-regulates the immune responses of their hosts, and thus preventing their destruction. These adaptations help the parasites to effectively cope with the host immune system. Additionally, the structural nature of the schistosomes’ surface also plays a significant role in the worm’s survival and evasion of the immune responses of the host. The tegument, which forms the exterior covering of the parasite serve sensory purposes and protective purposes that enable the parasites to survive and move within the host to appropriate sites and even find pairing mates for reproduction. Molecular appearance variation, which is genetically mediated, facilitates polymorphism and protein variation, which allows survival under varying environments. Research on Schistosomes’ fundamental biology is driven purposefully by the necessity to manage human Schistosomiasis. The research centers on developing means that may counter the defenses exhibited by the parasites so as to make their survival within hosts impossible. Therefore, special areas of modern functional studies on Schistosomes may be established by investigating the major advances done in the past decade. Based on this, the subject of schistosome biology, which is ready for investigation, may then be considered. Additionally, research on schistosome survival and development as well as modulation of cell signaling pathways is necessary for the development of anti-schistosome drugs or vaccines. The fact that a detailed annotation of S. mansoni kinome has been obtained creates a favorable ground for research into schistosome kinases, which can help in understanding and manipulating schistosomes’ development and survival mechanisms. Studies into the genome of the parasite are also another leading and promising front, which may be used in developing drugs that may combat the parasite. In silico approaches relying on genomic information obtained from the study of the parasites’ genome have been used in prioritizing potential schistosoma mansoni drug targets. It is therefore, anticipated that the integration of bio-informatic and experimental approaches may help in the development of anti-schistosome vaccines or drugs. In essence, the most effective attack on these parasites should rely on their defense mechanisms so as to make them vulnerable to the host’s defense mechanism. Additionally, other approaches such as the inhibition of nutrients uptake should be researched. References List Ashton, D., & Wilson, R. et al. 2001. The Schistosome egg: Development and secretions. Parasitology, Vol. 22, No. 1, pp. 329-338. Burke, M., & McManus, D. et al. 2009. Immunopathogenesis of human schistosomiasis. Parasite Immunology, Vol. 31, No. 1 pp.163-176 Collins, J., & Newmark, P. et al. 2011. An atlas for Schistosoma mansoni organs and life-cycle stages using cell type-specific markers and confocal microscopy, PLoS Negl Trop Dis 5, pp. 1009 Connors, V., & Yoshino, P. 1991. Identification of a Schistosoma mansoni sporocyst excretory-secretory antioxidant molecule and its effect on superoxide production by Biomphalaria glabrata hemocytes. J. Invertebrate, Pathology, Vol. 58, No. 1, pp. 387–395 DeMarco, R., & Verjovski-Almeida, S. 2009. Schistosomes - proteomics studies for potential novel vaccines and drug targets, Drug Discov Today, Vol. 14, pp. 472-478 Dissous, C., & Grevelding, G. 2011. Piggy-backing the concept of cancer drugs for schistosomiasis treatment: a tangible perspective? Trends Parasitology, 27, pp. 59-66 Dorsey, H., & Stirewalt, A. 2002. Ultrastructure of the Schistosoma mansoni cercariae, Micron, 33, pp. 279-323 Driguez, P., & McManus, P. et al. 2010. Schistosomiasis vaccine discovery using immunomics, Parasite Vectors, Vol. 3, pp4 Fallon, G., & Mangan, E. 2007. Suppression of TH2-type allergic reactions by helminthes infection. Nat. Rev. Immunol. Vol. 7, pp.220–230 Glanfield, A. Donald, P.M. Greg, J. A. & Malcolm, K. J. 2007. Pumping iron: a potential target for novel therapeutics against schistosomes. Trends in Parasitology Vol. 23, No. 12, pp. 583–588 Gryseels, B., & Kestens, L. 2006. Human schistosomiasis. Lancet, Vol. 368, pp. 1106-1118 Jenkins, S. J., Hewitson, J. P., Jenkins, G. R., & Mountford, A. P. 2005. Modulation of the hosts immune response by schistosome larvae. Parasite Immunol, Vol. 27, pp. 385–393 Jones, K., & Loukas, A. 2008. Tracking the odysseys of juvenile schistosomes to understand host interactions. PLoS Negl Trop Dis, 2, pp. 257 Kusel, J. R. Al-Adhami, B. H. & Doenhoff, M. J. 2007. The schistosome in the mammalian host: understanding the mechanisms of adaptation Parasitology, Vol. 134, No. 11, pp. 1477-526 Lightowlers, M. W., & Rickard, M. D. 1988. Excretory-secretory products of helminth parasites: effects on host immune responses. Parasitology, Vol. 96, (suppl.) S123–S166. Lodes, M. J., & Yoshino, T. P. 1989. Characterization of excretory-secretory proteins synthesized in vitro by Schistosoma mansoni primary sporocysts. J. Parasitol, 75, pp. 853–862 LoVerde, T., & Oliveira, G. 2009. Signal transduction regulates schistosome reproductive biology. Curr Opin Microbiol, 12, pp. 422-428 Matthews, B.E. 2005. An Introduction to Parasitology, Cambridge University Press, McLaren, D. J. 1984. Disguise as an evasive stratagem of parasitic organisms. Parasitology, 88, pp. 597–611. McLaren, D. J., & Terry, R. J. 1982. The protective role of acquired host antigens during schistosome maturation. Parasite Immunology, vol. 4, pp. 129–148 Ribeiro, P., & Geary, G. 2010. Neuronal signaling in schistosomes: current status and prospects for post genomics. Can J Zoology, 88, Pp1-22 Roberts, L. & Janovy, J. 2009. Foundations of Parasitology, 8th ed., McGraw-Hill, Salzet, M., Capron, A., & Stefano, G. B. 2000. Molecular crosstalk in host-parasite relationships: schistosome- and leech-host interactions. Parasitol Today 16, Pp536–540 Samuelson, C., & Caulfield, P. 1984. Hatching, chemokinesis, and transformation of miracidia of Schistosoma mansoni. J Parasitol, Vol. 70, pp. 321-331 Van Riet, E., Hartgers, F. C., & Yazdanbakhsh, M. 2007. Chronic helminth infections induce immunomodulation: consequences and mechanisms. Immunobiology, Vol. 212, pp. 475–490 Walker, J. A. 2011.Insights into the functional biology of schistosomes. Parasites & Vectors, Vol. 4, No. 203  Yoshino, T. P., & Bayne, C. J. 1983. Mimicry of snail host antigens by miracidia and primary sporocysts of Schistosoma mansoni. Parasite Immunology, Vol. 5, pp.317–328 Read More