Schistosoma mansoni

This article is about the organism. For the infection, see Schistosomiasis.
Schistosoma mansoni
Schistosomes copulating
Scientific classification
Kingdom: Animalia
Phylum: Platyhelminthes
Class: Trematoda
Order: Strigeidida
Family: Schistosomatidae
Genus: Schistosoma
Species: S. mansoni
Binomial name
Schistosoma mansoni
Sambon, 1907

Schistosoma mansoni is a significant parasite of humans, a trematode that is one of the major agents of the disease schistosomiasis which is one type of helminthiasis, a neglected tropical disease. The schistosomiasis caused by Schistosoma mansoni is intestinal schistosomiasis.

Schistosomes are atypical trematodes in that the adult stages have two sexes (dioecious) and are located in blood vessels of the definitive host. Most other trematodes are hermaphroditic and are found in the intestinal tract or in organs, such as the liver. The lifecycle of schistosomes includes two hosts: a definitive host (i.e. human) where the parasite undergoes sexual reproduction, and a single intermediate snail host where there are a number of asexual reproductive stages. S. mansoni is named after Sir Patrick Manson, who first identified it in Formosa (now Taiwan).[1][2]

Morphology of adult schistosomes

Schistosomes, unlike other trematodes, are long and slim worms. The male S. mansoni is approximately 1 cm long (0.6–1.1 cm) [3] and is 0.1 cm wide. It is white, and it has a funnel-shaped oral sucker at its anterior end followed by a second pediculated sucker. The external part of the worm is composed of a double bilayer, which is continuously renewed as the outer layer, known as the membranocalyx, and is shed continuously.[4] The tegument bears a large number of small tubercules. The suckers have small thorns in their inner part as well as in the buttons around them. The male genital apparatus is composed of 6 to 9 testicular masses, situated dorsally. There is one deferent canal beginning at each testicle, which is connected to a single deferent that dilates into a reservatory, the seminal vesicle, located at the beginning of the gynacophoric canal. The copula happens through the coaptation of the male and female genital orifices.[5]

The female has a cylindrical body, longer and thinner than the male's (1.2 to 1.6 cm long by 0.016 cm wide). The female parasite is darker, and it looks gray. The darker color is due to the presence of a pigment (hemozoin) in its digestive tube. This pigment is derived from the digestion of blood. The ovary is elongated and slightly lobulated and is located on the anterior half of the body. A short oviduct conducts to the ootype, which continues with the uterine tube. In this tube it is possible to find 1 to 2 eggs (rarely 3 to 4) but only 1 egg is observed in the ootype at any one time. The genital pore opens ventrally. The posterior two-thirds of the body contain the vittelogenic glands and their winding canal, which unites with the oviduct a little before it reaches the ootype.

The digestive tube begins at the anterior extremity of the worm, at the bottom of the oral sucker. The digestive tube is composed of an esophagus, which divides in two branches (right and left) and that reunite in a single cecum. The intestines end blindly, meaning that there is no anus.

Physiology

Feeding and Nutrition

Developing Schistosoma mansoni worms that have infected their definitive hosts, prior to the sexual pairing of males and females, require a nutrient source in order to properly develop from cercariae to adults. The developing parasites lyse host red blood cells to gain access to nutrients; the hemoglobin and amino acids the blood cells contain can be used by the worm to form proteins.[6] While hemoglobin is digested intracellularly, initiated by salivary gland enzymes, iron waste products cannot be used by the worms, and are typically discarded via regurgitation.[7]

Kasschau et al. (1995) tested the effect of temperature and pH on the ability of developing S. mansoni to lyse red blood cells.[6] The researchers found that the parasites were best able to destroy red blood cells for their nutrients at a pH of 5.1 and a temperature of 37 °C.[6]

Locomotion

S. mansoni is locomotive in primarily two stages of its life cycle: as cercariae swimming freely through a body of freshwater to locate the epidermis of their human hosts, and as developing and fully-fledged adults, migrating throughout their primary host upon infection.[7] Cercariae are attracted to the presence of fatty acids on the skin of their definitive host, and the parasite responds to changes in light and temperature in their freshwater medium to navigate towards the skin.[8] Ressurreicao et al. (2015) tested the roles of various protein kinases in the ability of the parasite to navigate its medium and locate a penetrable host surface.[8] Extracellular signal-regulated kinase and protein kinase C both respond to changes in medium temperature and light levels, and the stimulation of p38 mitogen-activated protein kinase, associated with recognition of parasite host surface, results in a glandular secretion that deteriorates the host epidermis, and allows the parasite to burrow into its host.

The parasite's nervous system contains bilobed ganglia and several nerve cords which splay out to every surface of the body; serotonin is a transmitter distributed widely throughout the nervous system and plays an important role in nervous reception, and stimulating mobility.[9]

Life cycle

Schistosoma mansoni life cycle

After the eggs of the human-dwelling parasite are emitted in the faeces and into the water, the ripe miracidium hatches out of the egg. The hatching happens in response to temperature, light and dilution of faeces with water. The miracidium searches for a suitable freshwater snail (Biomphalaria glabrata, Biomphalaria straminea, Biomphalaria tenagophila or Biomphalaria sudanica[10]) to act as an intermediate host and penetrates it. Following this, the parasite develops via a so-called mother-sporocyst and daughter-sporocyst generation to the cercaria. The purpose of the growth in the snail is the numerical multiplication of the parasite. From a single miracidium result a few thousand cercaria, every one of which capable of infecting a human.

Libora et al. (2010)[11] have detected in Venezuela, that a land snail Achatina fulica can also serve as a host of Schistosoma mansoni.[11]

The cercaria emerge from the snail during daylight and they propel themselves in water with the aid of their bifurcated tail, actively seeking out their final host. When they recognise human skin, they penetrate it within a very short time. This occurs in three stages, an initial attachment to the skin, followed by the creeping over the skin searching for a suitable penetration site, often a hair follicle, and finally penetration of the skin into the epidermis using cytolytic secretions from the cercarial post-acetabular, then pre-acetabular glands. On penetration, the head of the cercaria transforms into an endoparasitic larva, the schistosomule. Each schistosomule spends a few days in the skin and then enters the circulation starting at the dermal lymphatics and venules. Here, they feed on blood, regurgitating the haem as hemozoin.[12] The schistosomule migrates to the lungs (5–7 days post-penetration) and then moves via circulation through the left side of the heart to the hepatoportal circulation (>15 days) where, if it meets a partner of the opposite sex, it develops into a sexually mature adult and the pair migrate to the mesenteric veins.[13] Such pairings are monogamous.[14]

Male schistosomes undergo normal maturation and morphological development in the presence or absence of a female, although behavioural, physiological and antigenic differences between males from single-sex, as opposed to bisex, infections have been reported. On the other hand, female schistosomes do not mature without a male. Female schistosomes from single-sex infections are underdeveloped and exhibit an immature reproductive system. Although the maturation of the female worm seems to be dependent on the presence of the mature male, the stimuli for female growth and for reproductive development seem to be independent from each other.

The adult female worm resides within the adult male worm's gynaecophoric canal, which is a modification of the ventral surface of the male, forming a groove. The paired worms move against the flow of blood to their final niche in the mesenteric circulation, where they begin egg production (>32 days). The S. mansoni parasites are found predominantly in the small inferior mesenteric blood vessels surrounding the large intestine and caecal region of the host. Each female lays approximately 300 eggs a day (one egg every 4.8 minutes), which are deposited on the endothelial lining of the venous capillary walls.[15] Most of the body mass of female schistosomes is devoted to the reproductive system. The female converts the equivalent of almost her own body dry weight into eggs each day. The eggs move into the lumen of the host's intestines and are released into the environment with the faeces.

Genome

Schistosoma mansoni has 8 pairs of chromosomes (2n = 16)—7 autosomal pairs and 1 sex pair. The female schistosome is heterogametic, or ZW, and the male is homogametic, or ZZ. Sex is determined in the zygote by a chromosomal mechanism. The Schistosoma genome is approximately 270 MB with a GC content of 34%, 4–8% highly repetitive sequence, 32–36% middle repetitive sequence and 60% single copy sequence. Numerous highly or moderately repetitive elements have been identified, and their frequency in genomic sequence data also suggests at least 30% repetitive DNA. Chromosomes range in size from 18 to 73 MB and can be distinguished by size, shape, and C banding. There are estimated to be 15–20 thousand expressed genes.[16]

In 2000, the first BAC library of Schistosome was constructed.[17] In June 2003, a ~5x whole genome shotgun sequencing project was initiated at the Sanger Institute. Together with the shotgun data being generated by TIGR, an ~8x coverage of the genome will be obtained, assembled and annotated.[18] Also in 2003, 163,000 ESTs (expressed sequence tags) were generated (by a consortium headed by the University of São Paulo) from six selected developmental stages of this parasite, resulting in 31,000 assembled sequences and an estimated 92% of the 14,000-gene complement.[19]

In 2009 the genomes of both S. mansoni and S. japonicum were published, with each describing 11,809 and 13,469 genes, respectively. Analysis of the S. mansoni genome highlighted expansions in protease families and deficiencies in lipid anabolism; both observations can be directly related to S. mansoni's parasitic lifestyle. The former included the invadolysin (host penetration) and cathepsin (blood-feeding) gene families, while the latter encompassed several enzymes required for the de novo synthesis of fatty acids and sterols (so the worm must rely on its host for these products). The results open the way for research on new targeted treatments.[20][21]

In 2012, an improved version of the S. mansoni genome was published, with only 885 scaffolds and more than 81% of the bases organised into chromosomes. In the same study, the authors have also used transcriptome sequencing (RNA-seq) from four time points in the parasite’s lifecycle to refine 45% gene predictions and profile their expression levels.[22]

Pathology

A Schistosoma mansoni egg with the characteristic lateral spine

Schistosome eggs, which may become lodged within the hosts tissues, are the major cause of pathology in schistosomiasis. Some of the deposited eggs reach the outside environment by passing through the wall of the intestine; the rest are swept into the circulation and are filtered out in the periportal tracts of the liver, resulting in periportal fibrosis. Onset of egg laying in humans is sometimes associated with an onset of fever (Katayama fever). This "acute schistosomiasis" is not, however, as important as the chronic forms of the disease. For S. mansoni and S. japonicum, these are "intestinal" and "hepatic schistosomiasis", associated with formation of granulomas around trapped eggs lodged in the intestinal wall or in the liver, respectively. The hepatic form of the disease is the most important, granulomas here giving rise to fibrosis of the liver and hepatosplenomegaly in severe cases. Symptoms and signs depend on the number and location of eggs trapped in the tissues. Initially, the inflammatory reaction is readily reversible. In the latter stages of the disease, the pathology is associated with collagen deposition and fibrosis, resulting in organ damage that may be only partially reversible.

Granuloma formation is initiated by antigens secreted by the miracidium through microscopic pores within the rigid egg shell, and there is strong evidence that the vigorous granulomatous response, rather than the direct action of parasite egg antigens, is responsible for the pathologic tissue manifestations in schistosomiasis.[23] The granulomas formed around the eggs impair blood flow in the liver and, as a consequence, induce portal hypertension. With time, collateral circulation is formed and the eggs disseminate into the lungs, where they cause more granulomas, pulmonary arteritis and, later, cor pulmonale. A contributory factor to portal hypertension is Symmers' fibrosis, which develops around branches of the portal veins. This fibrosis occurs only many years after the infection and is presumed to be caused in part by soluble egg antigens and various immune cells that react to them.

Recent research has shown that granuloma size is consistent with levels of IL-13, which plays a prominent role in granuloma formation and granuloma size. IL-13 receptor α 2 (IL-13Rα2) binds IL-13 with high affinity and blocks the effects of IL-13. Thus, this receptor is essential in preventing the progression of schistosomiasis from the acute to the chronic (and deadly) stage of disease. Synthetic IL-13Rα2 given to mice has resulted in significant decreases in granuloma size, implicating IL-13Rα2 as an important target in schistosomiasis.[24]

Evasion of host immunity

Adult and larval worms migrate through the host's blood circulation avoiding the host's immune system. The worms have many tools that help in this evasion, including the tegument, antioxidant proteins, and defenses against host membrane attack complex (MAC).[25]

Tegument

The tegument coats the worm and acts as a physical barrier to host antibodies and complement.

Antioxidant proteins

Host immune defenses are capable of producing superoxide, which has a tremendous detrimental effect on the worm. However, they are able to produce a number of antioxidant proteins that block the effect of superoxide. Schistosomes have four superoxide dismutases, and levels of these proteins increase as the schistosome develops and matures.

Antioxidant pathways were first recognised as a chokepoints for Schistosomes [26] and later extended to other trematodes and cestodes. Targeting of this pathway with different inhibitors of the central antioxidant enzyme Thioredoxin Glutathione Reductase (TGR) results in reduced viability of worms [27]

Defense against host MAC

Schistosomes have evolved ways to block host complement proteins. Immunocytochemistry techniques have found decay accelerating factor (DAF) protein on the tegument. DAF is found on host cells and protects host cells by blocking formation of MAC. It has also been found that the schistosome genome consists of human CD59 homologs. CD59 inhibits MAC.

Epidemiology

Main article: Schistosomiasis

Schistosoma mansoni infects about 83 million people worldwide (data from 1999),[28] causing the disease intestinal schistosomiasis (schistosomiasis caused by all the Schistosoma species infects over 200 million people.)[29][30]

S. mansoni is the most widespread of the human-infecting schistosomes, and is present in 54 countries. These countries are predominantly in South America and the Caribbean, Africa including Madagascar, and the Middle East.

S. mansoni is commonly found in places with poor sanitation. Because of the parasite's fecal-oral transmission, bodies of water that contain human waste can be infectious. Water that contains large populations of the intermediate host snail species is more likely to cause infection. Young children living in these areas are at greatest risk because of their tendency to swim and bathe in cercaria-infected waters longer than adults .[31] Any one travelling to the areas described above, and who is exposed to contaminated water, is at risk of schistosomiasis.

History

Schistosoma mansoni reached Egypt via infected slaves and baboons from the Land of Punt through migrations that occurred possibly as early as the Vth Dynasty.[32]

References

  1. ↑ Birch, CA (1974). "Schistosoma mansoni. Sir Patrick Manson, 1844-1922.". The Practitioner 213 (1277): 730–2. PMID 4156405.
  2. ↑ Swanner, Yann A. Meunier ; with contributions from Michael Hole, Takudzwa Shumba & B.J. (2014). Tropical Diseases : a Practical Guide for Medical Practitioners and Students. Oxford: Oxford University Press, USA. p. 40. ISBN 9780199997909.
  3. ↑ Machado-Silva JR, Galvao C, Oliveira RMF, Presgrave AF, Gomes DC (1995). "Schistosoma mansoni sambon, 1907: Comparative morphological studies of some Brazilian Strains". Rev. Inst. Med. Trop. Sao Paulo 37 (5): 441–447. doi:10.1590/s0036-46651995000500010. PMID 8729755.
  4. ↑ Braschi S, Borges WC, Wilson RA (September 2006). "Proteomic analysis of the schistosome tegument and its surface membranes". Memórias Do Instituto Oswaldo Cruz 101 (Suppl 1): 205–12. doi:10.1590/S0074-02762006000900032. PMID 17308771.
  5. ↑ Rey, Luíz (1991). Parasitologia. Rio de Janeiro, RJ: Editora Guanabara Koogan S.A. pp. 351–62. ISBN 85-277-0189-8.
  6. 1 2 3 Kasschau, Margaret R. et al. (1995). “Influence of pH and temperature on hemolysis by adult Schistosoma mansoni membranes.” Journal of Experimental Zoology 271(4): 315-322. DOI: 10.1002/jez.1402710409
  7. 1 2 Wilmer, Pat, Graham Stone, and Ian Johnston (2005). Environmental Physiology of Animals. United Kingdom: Blackwell Publishing. pp. 677-692. ISBN: 9781405107242
  8. 1 2 Ressurreicao, Margarida et al. (2015). “Sensory Protein Kinase Signaling in Schistosoma mansoni Cercariae: Host Location and Invasion.” Journal of Infectious Diseases 212(11): 1787-1797. DOI: 10.1093/infdis/jiv464
  9. ↑ Patocka, Nicholas et al. (Jan 2014). “Serotonin Signaling in Schistosoma mansoni: A Serotonin-Activated G Protein-Coupled Receptor Controls Parasite Movement.” PLoS Pathogens 10(1): e1003878. DOI:10.1371/journal.ppat.1003878
  10. ↑ Gatlin MR, Black CL, Mwinzi PN, Secor WE, Karanja DM, Colley DG (2009). King, Charles H., ed. "Association of the Gene Polymorphisms IFN-γ +874, IL-13 −1055 and IL-4 −590 with Patterns of Reinfection with Schistosoma mansoni". PLoS Neglected Tropical Diseases 3 (2): e375. doi:10.1371/journal.pntd.0000375. PMC 2631135. PMID 19190772.
  11. 1 2 (Spanish) Libora M., Morales G., Carmen S., Isbelia S. & Luz A. P. (2010). "Primer hallazgo en Venezuela de huevos de Schistosoma mansoni y de otros helmintos de interés en salud pública, presentes en heces y secreción mucosa del molusco terrestre Achatina fulica (Bowdich, 1822). [First finding in Venezuela of Schistosoma mansoni eggs and other helminths of interest in public health found in faeces and mucous secretion of the mollusc Achatina fulica (Bowdich, 1822)]. Zootecnia Tropical 28: 383-394. PDF.
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  14. ↑ Beltran S, Boissier J (September 2008). "Schistosome monogamy: who, how, and why?". Trends in Parasitology 24 (9): 386–91. doi:10.1016/j.pt.2008.05.009. PMID 18674968.
  15. ↑ Loverde PT, Chen L (November 1991). "Schistosome female reproductive development". Parasitology Today 7 (11): 303–8. doi:10.1016/0169-4758(91)90263-N. PMID 15463396.
  16. ↑ "Schistosoma mansoni Genome Project". Sanger Institute. Retrieved 2007-06-14.
  17. ↑ Le Paslier MC, Pierce RJ, Merlin F, et al. (April 2000). "Construction and characterization of a Schistosoma mansoni bacterial artificial chromosome library". Genomics 65 (2): 87–94. doi:10.1006/geno.2000.6147. PMID 10783255.
  18. ↑ "Schistosoma mansoni Genome Project". The Institute for Genomic Research. Retrieved 2007-06-14.
  19. ↑ Verjovski-Almeida S, DeMarco R, Martins EA, Guimarães PE, Ojopi EP, Paquola AC, Piazza JP, Nishiyama MY Jr, Kitajima JP, Adamson RE, Ashton PD, Bonaldo MF, Coulson PS, Dillon GP, Farias LP, Gregorio SP, Ho PL, Leite RA, Malaquias LC, Marques RC, Miyasato PA, Nascimento AL, Ohlweiler FP, Reis EM, Ribeiro MA, Sá RG, Stukart GC, Soares MB, Gargioni C, Kawano T, Rodrigues V, Madeira AM, Wilson RA, Menck CF, Setubal JC, Leite LC, Dias-Neto E. (Oct 2003). "Transcriptome analysis of the acoelomate human parasite Schistosoma mansoni.". Nature Genetics 35 (2): 148–157. doi:10.1038/ng1237. PMID 12973350.
  20. ↑ Berriman M, Haas BJ, LoVerde PT, Wilson RA, Dillon GP, Cerqueira GC, Mashiyama ST, Al-Lazikani B, Andrade LF, Ashton PD, Aslett MA, Bartholomeu DC, Blandin G, Caffrey CR, Coghlan A, Coulson R, Day TA, Delcher A, DeMarco R, Djikeng A, Eyre T, Gamble JA, Ghedin E, Gu Y, Hertz-Fowler C, Hirai H, Hirai Y, Houston R, Ivens A, Johnston DA, Lacerda D, Macedo CD, McVeigh P, Ning Z, Oliveira G, Overington JP, Parkhill J, Pertea M, Pierce RJ, Protasio AV, Quail MA, Rajandream MA, Rogers J, Sajid M, Salzberg SL, Stanke M, Tivey AR, White O, Williams DL, Wortman J, Wu W, Zamanian M, Zerlotini A, Fraser-Liggett CM, Barrell BG, El-Sayed NM. (July 2009). "The genome of the blood fluke Schistosoma mansoni". Nature 460 (7253): 352–8. doi:10.1038/nature08160. PMC 2756445. PMID 19606141.
  21. ↑ "Killer parasites' genes decoded". BBC News. July 16, 2009. Retrieved 2009-07-16.
  22. ↑ Anna V. Protasio, Isheng J. Tsai, Anne Babbage, Sarah Nichol, Martin Hunt, Nishadi De Silva, Tim J.C. Anderson, Richard C. Clark, Claire Davidson, Gary P. Dillon, Nancy E. Holroyd, Philip T. LoVerde, Christine Lloyd, Jacquelline McQuillan, Guilherme Oliveira,Thomas D. Otto, Sophia J. Parker-Manuel, Michael A. Quail, R. Alan Wilson, Adhemar Zerlotini, David W. Dunne, Matthew Berriman. (Jan 2012). "A systematically improved high quality genome and transcriptome of the human blood fluke Schistosoma mansoni.". PLoS Neglected Tropical Diseases 6 (1): 1455. doi:10.1371/journal.pntd.0001455. PMC 3254664. PMID 22253936.
  23. ↑ Boros DL (July 1989). "Immunopathology of Schistosoma mansoni infection". Clinical Microbiology Reviews 2 (3): 250–69. PMC 358119. PMID 2504481.
  24. ↑ Mentink-Kane MM, Cheever AW, Thompson RW, et al. (January 2004). "IL-13 receptor α 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis". Proceedings of the National Academy of Sciences of the United States of America 101 (2): 586–90. doi:10.1073/pnas.0305064101. PMC 327191. PMID 14699044.
  25. ↑ Wilson RA, Coulson PS (September 2009). "Immune effector mechanisms against schistosomiasis: looking for a chink in the parasite's armour". Trends in Parasitology 25 (9): 423–31. doi:10.1016/j.pt.2009.05.011. PMID 19717340.
  26. ↑ Sayed AA, Simeonov A, Thomas CJ, Inglese J, Austin CP, Williams DL (April 2008). "Identification of oxadiazoles as new drug leads for the control of schistosomiasis". Nat. Med. 14 (4): 407–12. doi:10.1038/nm1737. PMC 2700043. PMID 18345010.
  27. ↑ Ross F, Hernández P, Porcal W, et al. (2012). "Identification of thioredoxin glutathione reductase inhibitors that kill cestode and trematode parasites". PLoS ONE 7 (4): e35033. doi:10.1371/journal.pone.0035033. PMC 3335049. PMID 22536349.
  28. ↑ Crompton DW (June 1999). "How much human helminthiasis is there in the world?" (PDF). The Journal of Parasitology (The Journal of Parasitology, Vol. 85, No. 3) 85 (3): 397–403. doi:10.2307/3285768. JSTOR 3285768. PMID 10386428.
  29. ↑ Oliveira, G.; Rodrigues, N. B.; Romanha, A. J.; Bahia, D. (February 2004). "Genome and genomics of schistosomes". Canadian Journal of Zoology 82 (2): 375–390. doi:10.1139/z03-220.
  30. ↑ Jamison et al., eds. (2006). Disease Control Priorities in Developing Countries (2nd ed.). ISBN 0-8213-6179-1.
  31. ↑ "DPDx - Schistosomiasis risk and Epidemiology Factors". CDC. Retrieved 2013-11-05.
  32. ↑ Abou-El-Naga IF (2013) Biomphalaria alexandrina in Egypt: Past, present and future. J Biosci 38(3):665-672

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