Dicrocoelium dendriticum: Difference between revisions

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{{CZ:Biol_201:_General_Microbiology/EZnotice}}
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{{Taxobox  
{{Taxobox
| color=violet
| color = cyan
| name = Myxoma Virus
| name = ''Lancet fluke/Small liver fluke''
| image = myxoma_virus.jpg
| image = Dicrocoelium_dendriticum3.jpg‎
| virus_group = Group I dsDNA virus, no RNA stage
| regnum = Animalia
| familia = Poxviridae, subfamily: Chordopoxvirinae
| phylum = Platyhelminthes
| genus = Leporipoxvirus}}
| classis = Trematoda
 
| ordo = Plagiorchiida
== Classification: ==
| familia = Dicrocoeliidae
'''
| genus = Dicrocoelium
ICTVdB Virus Code: 00.058.1.05.001. Virus accession number: 58105001. Obsolete virus code: 58.1.5.0.001; superceded accession number: 58150001. NCBI Taxon Identifier NCBI Taxonomy ID: 10273. Type of the genus: 00.058.1.05. [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.058.1.05.htm]poripoxvirus]|Leporipoxvirus subfamily 00.058.1. [Chordopoxvirinae]|[http://www.ncbi.nlm.nih.gov/ICTVdb/Ictv/index.htm] in the family 00.058. Poxviridae.]
| species = D. dendriticum
 
| binomial = ''Dicrocoelium dendriticum''
Viruses: Group I dsDNA viruses, no RNA stage;  Family: Poxviridae;  SubFamily: Chordopoxvirinae;  Genus: Leporipoxvirus
| binomial_authority =  Rudolphi, 1819
 
}}
'''[[Image:Leporipoxvirus edited.jpg]]
 
== Description and significance: ==
''' 
Myxoma virus is a member of the [[Poxviridae]] family. It causes a benign infection in [[rabbits]] of the [[Sylvilagus]] [[genus]], but induces a fatal disease known as [[myxomatosis]] in the European rabbit, [[Oryctalagus cuniculus]]. <ref>Stanford, MM, Barrett, JW, Nazarian, SH, Werden, S and McFadden, G. (2007). Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells. Journal of Virology, 81: 1251–1260.</ref>
Myxoma [[virions]] have two types of structures, either enveloped or not, a surface membrane, a core, and lateral bodies. The envelope contains [[lipids]] derived from the host and [[glycolipids]] that are self synthesized. Over the course of its life cycle, myxoma virions produce both extracellular and intracellular particles. They can have two [[phenotypes]] and they can be enveloped during their extracellular phase. The extracellular virions are the ones to initiate viral infection. Myxoma virions may be segregated within [[inclusion bodies]]. They typically contain one enveloped [[nucleocapsid]], are somewhat [[pleiomorphic]], brick–shaped, and measure approximately 250 nm in diameter, 250–300 nm in length, and 200 nm in height. The core is biconcave with two lateral bodies. It lies either between the core membrane or the surface membrane. Myxoma virions mature by budding through the membrane of the host cell.<ref>Stanford, MM, Werden, SJ and McFadden, G. (2007). Myxoma virus in the European rabbit: interactions between the virus and its susceptible host. Vet Res 38: 299–318</ref>
The Myxoma virus was important enough to have its genome sequenced is because it encodes [[proteins]] designed to circumvent the host's cellular [[immune response]] to the viral infection. This induces extensive [[immunosuppression]] in infected rabbits.<ref>Stanford‌, MM, and McFadden, G. (2007) Myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer. Expert Opinion on Biological Therapy, Vol. 7, No. 9, Pages 1415-1425.</ref>
 
'''
 
== Natural Host: ==
'''
Domain Eucarya, Kingdom Animalia, Phylum Chordata, Subphylum Vertebrata, Class Mammalia, Order Lagomorphia, purportedly only in Oryctolagus cuniculus, Lepus Europaeus, S. Bachmani, and S. floridanus.  
 
'''
== When was your organism discovered? ==
'''
Myxoma virus was first discovered when it killed imported European rabbits in Guiseppe Sanarelli's lab in Uruguay in 1896 at the Institute of Hygiene in Montivideo. <ref>Stanford, MM, Werden, SJ and McFadden, G. (2007). Myxoma virus in the European rabbit: interactions between the virus and its susceptible host. Vet Res 38: 299–318</ref>
 
'''
 
== How and where it was isolated: ==
'''
The Lausanne strain of the virus was isolated by a team of Canadian scientists at the Department of Microbiology, The University of Western Ontario, London, Ontario, Canada.  However, only a partial sequencing of the California MSW strain was achieved by a team associated with School of Biochemistry and Molecular Biology, Faculty of Science, Australian National University, Canberra, Australia.  There they cloned EcoRI and SalI restriction fragments of viral DNA and sequenced the ends.<ref>Labudovic, A., Perkins, H. van Leeuwen, B. and Kerr, P. (2004) Sequence mapping of the Californian MSW strain of Myxoma virus. Archives of Virology, Vol. 149, Number 3/March, 553-570.</ref>
'''
 
== Genome structure: ==
'''  
 
The [[genome]] is not segmented and consists of a single molecule of linear double-stranded DNA, ie. [[dsDNA]]. Sequence has the [[accession number]] [M93049]. The genome is 161,773 [[nucleotides]] long and has a central region of highly conserved enzymatic and structural genes that control essential viral functions. At both ends however, are terminal sequences with cross-linked single-stranded loops which form one continuous polynucleotide chain.  These sequences include two copies of 12 genes which encode nonessential factors that affect the host's response to infection. These factors include [[serine proteinase]] inhibitors, such as SERP1, Serp2, and Serp3, and a scrapin.  They are responsible for major [[histo-compatibility]] complex class I down regulation.  Additionally, the genome has a guanine + cytosine content of approximately 40%. <ref>Cameron, C, Hota-Mitchell, S, Chen, L, Barrett, J, Cao, JX, Macaulay, C et al. (1999). The Complete DNA Sequence of Myxoma Virus. Virology 264: 298–318.</ref>
 
'''
[[Image:Myxoma Genome.jpg]]
 
== Interesting Features: ==
'''
Myxoma virus subverts the host immune response using two distinct viral mechanisms, each delivered by viral proteins. Most significantly, the virus produces encoded proteins known as [[viroceptors]] or [[virokines]] which mimic host receptors or [[cytokines]]. These viroceptors or virokines act to block extracellular immune signals, thereby providing effective clearance and producing a "virus friendly" environment. Secondly, the virus uses intracellular viral proteins to impede innate antiviral responses such as [[apoptosis]], and to thwart an infected cell's mechanisms to communicate with its immune system. Additionally, the [[M128L]] myxoma virus gene expresses a five-membrane spanning cell surface protein that has amino acid homology to cellular [[CD47]] proteins.  CD47 proteins are associated with determining leukocyte adhesion, motility, activation, and phagocytosis.  M128L is necessary for the production of a lethal infection in rabbits. However it is not essential for the dissemination of virus within the host. The M128L protein is a novel CD47-like immunomodulatory gene of myxoma virus required for full [[pathogenesis]] of the virus.  Without it, [[monocyte]] /[[macrophage]] activation is increased during infection.<ref>Iannello,A., Debbeche,O., Martin, E., Habiba Attalah, L., Samarani, S. and Ahmad, A., Viral strategies for evading antiviral cellular immune responses of the host. J. Leukoc. Biol. 2006 79: 16-35. </ref> <ref>Cameron, C. M., Barrett, J. W., Mann, M., Lucas, A., McFadden, G..  Myxoma virus M128L is expressed as a cell surface CD47-like virulence factor that contributes to the downregulation of macrophage activation in vivo. Virology ,  2005  (Vol. 337)(No. 1) 55-67</ref>


'''
'''Dicrocoelium dendriticum''' is a small liver fluke, that is, a parasitic organism. It benefits from its relationship to the host while contributing nothing to the survival of that host such that it in most cases may lower host fitness. Theory and mechanisms on parasite manipulation of host fitness is a current topic of much controversy (see ‘Small Liver Fluke Manipulation of Host Behavior’ section below).Dicrocoeliosis is a globally present parasitic infection caused by ''Dicroceolium'', which infect the bile ducts and gall bladder of wild and domestic animals. Since it is not as pathogenic as other flukes very little is known about this parasite. Moreover, since it has two intermediate hosts Dicrocoeliosis is difficult to reproduce under experimental conditions.
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== How does this organism cause disease? ==
==Morphology  ==                                                        
'''
Dorso-ventrally flattned (lance shaped), adult lancet flukes are semi transparent ~8-14mm in length and ~2-3mm in width, oval shaped with the anterior slightly more narrow in shape compared to its posterior, both ends being slightly tapered <ref name=Desmond>Desmond, James introduction to animal parisitology p. 214 Figure 14.14</ref>. At its tip the anterior contains an oral sucker. A hermaphrodite, the adult lancet fluke contains two lobed testes, in its anterior region, juxtaposed to its ovary, and the uterus lies below in its midsection. Vitellaria glands flank its reproductive organs, and are important in egg production. The digestive components (gut and bladder) lie in the posterior portion of its body<ref name=Krull>Krull, W. H., and C. R. Mapes. "Studies on the biology of Dicrocoelium dendriticum (Rudolphi, 1819) Looss, 1899 (Trematoda: Dicrocoeliidae), including its relation to the intermediate host, Cionella lubrica II. Collection of the snail, Cionella lubrica, and its maintenance in the laboratory." Cornell Vet 41 (1951): 433-44.</ref>
Myxoma virus (MV) is a [[poxvirus]] and a prototypical member of the [[Leporipoxvirus]] genus. It is the causative agent of [[myxomatosis]], a lethal and severely deblilitating disease of European rabbits (Oryctolagus cuniculus).  The disease is characterized by systemic cellular [[immunosuppression]] which prompts respiratory complications and death. The myxoma virus encodes multiple proteins capable of [[downregulating]] the host innate and acquired immune responses. Other virus-encoded proteins enable replication in host [[lymphocytes]] and [[monocytes]] by inhibiting apoptosis. Specifically, Myxoma virus prevents [[apoptosis]] in [[RK-13]] cells and forms thick dermal lesions. MV encodes the virulence factor SERP2, a serine proteinase inhibitor. Virulence may depend on inhibition of pro-inflammatory [[proteinases]] by SERP2.  
However, notwithstanding the increasingly detailed molecular knowledge of myxoma virus, relatively little is known about the dynamics of the interaction of the virus with the integrated host-immune system during infection.<ref>MacNeill AL, Turner PC, Moyer RW, (2006) Mutation of the Myxoma virus SERP2 P1-site to prevent proteinase inhibition causes apoptosis in cultured RK-13 cells and attenuates disease in rabbits, but mutation to alter specificity causes apoptosis without reducing virulence. Virology. 2006 Dec 5-20;356(1-2):12-22. Epub 2006 Sep 7</ref><ref>Kerr P, McFadden G. (2002) Immune responses to myxoma virus. Viral Immunol. 15(2):229-46.</ref>


'''
==Parasitic Reservoirs: ''inside and outside the Definitive Host''[[Image:Zebrina Conchology A.jpg]][[Image:Intermediate hosts.jpg]]==
''Dicrocoelium dendriticum’s '' habitat includes lowland or mountain pastures, of dry and alkaline consistency, providing appropriate conditions for its definitive and intermediate hosts (shown above).<ref name=Krull/> <ref name=Otranto>Otranto, Domenic  Dicrocoeliosis of ruminants: a little known fluke disease Trends in Parasitology 2003</ref>  The adult lancet fluke necessarily inhabits the liver of its definitive host, specifically the bile ducts and gall bladder of domesticated and wild ruminating animals (sheep, goat and cattle). Although, they can also be found in the liver of dogs, rabbits, horses, humans and some rodents <ref name=Otranto/>.  Endogenous host and environmental conditions are critical for its survival, whereby each intermediate host must be favored in the collective biotope, making it difficult to model similar conditions in the laboratory. Since its continuance into the liver of its definitive host for sexual reproduction is dependent on prior passage through two other distinct host organisms, conditions must favor each part of this biological community. Once an adult, it uses its hermaphroditic body plan to propagate itself several orders of magnitude, but to get their the fluke must be ingested by specific intermediate hosts, which allow it to carry out the different stages of its life cycle <ref name=Otranto/>.


== What makes it biologically interesting? ==
==Life Cycle: ''A Definitive Host and Two Intermediate Hosts''==
'''
A trifecta of successful host:parasite adaptation, the small liver flukes’ life cycle and mode of transmission have been well described by the work of Krull and Mapes. Collectively their work showed that infection of the definitive host is initiated by ingestion of infected ants and cannot be bypassed by eating the slimeballs of infected snails, the first intermediate host.<ref name=Krull/><ref name=Otranto/><ref name=Desmond/>Adult flukes in the bile ducts, lay dark brown eggs each containing a miracidium, which are expelled with the bile into the intestine and later incorporated into the feces. These eggs are viable embryos, which are only hatched upon ingestion by the appropriate species of snail, Cionella lubrica in North America (There are many other possible host snail species depending on geographical location i.e. In France, Cochlicella acuta) <ref name=Otranto/>. The hatching mericidia penetrate the glandular intestinal epithelium and then undergo several rounds of asexual replication into daughter sporocysts <ref name=Krull/><ref name=Otranto/>. These daughter sporocysts mature into motile larva, called mature cercariae and travel to the snails’ respiratory chambers, a process that can take 5 months depending on season or age of the snail.<ref name=Krull/> <ref name=Otranto/> The cercariae contain glands which are speculated to be involved in the formation of slimeballs. Several ~500-5000 cercariae are collected in these slime accumulations but little is known about the mechanism of their formation.<ref name=Krull/><ref name=Otranto/> Slimeballs stick to nearby plants and debris, each snail usually produces one but can produce more.<ref name=Krull/>  These slimeballs are ingested by a specific species of ant, in North America Formica fusca (Again, several species are capable of being intermediate host, differences being dependent on location). The larva then transform into metacercariae which grow in the abdomen of the ant. After a period of about a month <ref name=Desmond/>, at the expense of its own survival, a single  metacercariae will become localized in the subesophageal ganglion, which results in changes in normal behavior of the ant, when temperatures are low <ref name=Krull/>. In this parasite adaptive state the infected ant climbs to the tips on blades of grass where they are exposed to grazing mammals such as sheep, goats and cows<ref name=Krull/> <ref name=Otranto/><ref name=Desmond/>. Finally, the metacercariae have arrived at their destination in the definitive host, where they are encysted in the duodenum <ref name=Otranto/>. The larva excyst and migrate to the bile ducts and then the gall bladder. In the bile ducts they develop into cross fertilizing and hermaphroditic adult flukes, capable of releasing new eggs into the environment, in the host excrement.<ref name=Krull/><ref name=Otranto/> <ref name=Desmond/>
'''Its application to Biotechnology... its medical importance... major research findings made with it... what's cool about myxoma virus as an organism:'''
[[Image:Dicrocoelium LifeCycle.gif]]


*Myxoma virus has potential as an [[oncolytic]] [[virotherapeutic]] agent against human malignant [[glioma]] because of: 1) the nonpathogenic nature of myxoma virus outside of its host, 2) its capacity to be genetically modified, 3) its ability to produce a long-lived infection in human tumor cells, and 4) the lack of preexisting antibodies in the human population.<ref>Yang, WQ, Lun, X, Palmer, CA, Wilcox, ME, Muzik, H, Shi, ZQ, Dyck, R, Coffey, M, Thompson, B, Hamilton, M, Nishikawa, S, Brasher, P, Fonseca, K, George, D, Rewcastle, NB, Johnston, R, Stewart, D, Lee, P, Senger, D, Forsyth, P, (2004) Efficacy and Safety Evaluation of Human Reovirus Type 3 in Immunocompetent Animals, Clinical Cancer Research Vol. 10, 8561-8576</ref><ref>Lun, X, Yang, W, Alain, T, Shi, ZQ, Muzik, H, Barrett, JW et al.(2005). Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas. Cancer Res 65: 9982–9990.</ref>
==Epidemiology==
''D. Dendriticum'' transmission depends on the presence of its intermediate hosts and the conditions that favor their survival. These conditions and thus the occurrence of ''D. dendriticum'' are dependent on; dry and alkaline soils <ref name=Otranto/>. Overall dicrocoeliosis is present sporadically in Europe, China, Japan, North Africa, South America, and some parts of North America, Australia and Africa. Although, it is endemic in parts of Spain, Brazil and a few Mediterranean countries.<ref name=Broglia>Broglia, A. Experimental ELISA for diagnosis of ovine dicrocoeliosis and application in a field survey Parasitology  Research 2009</ref> These small liver flukes are found in dry lowland or mountain pastures, which provide sufficient conditions for the survival of snails and ants<ref name=Otranto/>. The prevalence of infection varies with season and the snail  which is parasitized <ref name=Otranto/>.


*Myxoma virus selectively infects and kills human tumor cells. This capability is linked to dysregulated intracellular signalling pathways found in the majority of human cancers.<ref>Lun, XQ, Zhou, H, Alain, T, Sun, B, Wang, L, Barrett, JW et al.(2007). Targeting human [[medulloblastoma]]: oncolytic virotherapy with myxoma virus is enhanced by rapamycin. Cancer Res 67: 8818–8827.</ref>
==Pathology==
[[Image:D dendriticum egg wtmt JCG C.jpg]]
Disease occurrence in humans is rare, but infection by eating plants covered with infected ants (image of larval metacecariae egg, found in infected ant abdomen, is shown above or parasite manipulated ant on blade of grass shown below) or through ingestion of uncooked infected liver is possible. Although, in general livestock are at higher risk for infection. The small liver fluke has little identifiable clinical manifestations in infected hosts, compared other liver flukes i.e. ''Fasciola''. Even in heavily infected hosts they are asymptomatic, often suffering from anaemia, oedema or emaciation <ref name=Otranto/>. Also, the pathogenic effects of ''D. dendriticum'' can become confounded by simultaneous infections with other nematodes. Still some have been able to detect its effect on the liver <ref name=Otranto/>. In this case sheep liver was examined ''post mortum'' which appeared to have heavy scarring on its surface, hardening due to calcification and fibrosis, and displayed disruption of the bile ducts as a result of irritation caused by the presence of the small liver flukes <ref name=Otranto/>.


*Myxoma virus appears to be an effective oncolytic agent against medulloblastoma. Whether used alone or in combination with rapamycin, myxoma virus was found to be effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine out of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection.  Additionally, it was found that the oncolytic potential myxoma virus was enhanced by combination therapy with [[signaling inhibitors]] that modulate activity of the [[phosphatidylinositol 3-kinase/Akt pathway]]. Apparently, the susceptibility of human cancer cells to be infected and killed by an oncolytic poxvirus, myxoma virus (MV), is related to the basal level of endogenous phosphorylated Akt.<ref>Lun, XQ, Zhou, H, Alain, T, Sun, B, Wang, L, Barrett, JW et al.(2007). Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin. Cancer Res 67: 8818–8827.</ref>
==Small Liver Fluke Manipulation of Host Behavior==
Out on the open plains, in the evening or just before sunrise a keen observer might see something quite remarkable. Several ants with their mandibles attached firmly to blades of grass. If their timing is right, they will later find themselves in a fatal journey culminating with their special hitchhikers (metacercariae) being transmitted successfully into the definitive hosts liver. If no livestock graze on these particular grasses then the ant will return to its normal duties in its colony<ref name=Krull/>. This manipulation of the second intermediate host is carried out when a mature cercaria in the ant abdomen matures into a
metacercariae which is now motile and able to travel to the ant's subesophageal ganglion. As a result, the ant and the parasite (localized in the brain) are sacrificed<ref name=Krull/><ref name=Otranto/>. Clearly, there is a conflict of interest between host and parasite which only makes sense to the parasite. But, while the eggs of the parasite are passed on to the terminal host, the parasite which traveled to the ant brain had to sacrifice itself in the process. Thus this single motile parasite does not have the ability to pass on its genes.  There is no model to explain this behavior but some have proposed that kin selection may be taking place and that the altruistic ant may share genes with other larva in the ant which will survive<ref name=Gandon>Gandon, Sylvain Parasitic manipulation: a theoretical framework may help</ref>. This behavior has gotten the attention of many biologist and those with scientific interest. Some have seen this as an example of how some adaptations while perfectly natural are clearly not beneficial to the intermediate host (the ant). This example of parasite manipulation of host behavior has been used by Biologist, Richard Dawkins and Philosopher, Dan Dennett, to explain how some adaptations while harmful, still propagate themselves quite readily from individual to individual. The latter conceptual example was used by these authors, in connection with how memes, units of cultural inheritance may transmit themselves, throughout the human population.
[[Image:800px-Ant on leaf.jpg]]


*All [[rhabdoid]] tumor cell lines tested in vitro were found to be susceptible to lethal infections by myxoma virus.  Intraturmoral injection of live MV substantially reduced the size of subcutaneous rhabdoid tumor xenografts compared with control animals.<ref>Wu Y, Lun X, Zhou H, Wang L, Sun B, Bell JC, Barrett JW, McFadden G, Biegel JA, Senger DL, Forsyth PA.Authors' Affiliations: Departments of Oncology, Clinical Neurosciences, and Biochemistry and Molecular Biology, University of Calgary, the Tom Baker Cancer Centre, and the Clark H. Smith Brain Tumour Research Centre, Calgary, Alberta, Canada. Clinical Cancer Research, 2008 Feb 15;14(4):1218-27.</ref>
===Controversy: ''Cultural Diversity an Evolutionary Fluke?''===
The above mentioned example of parasite manipulation of host behavior has been cited by Richard Dawkins and Dan Dennett,In Dawkin's book ''The Extended Phenotype'' to explain how some adaptations while harmful, still propagate themselves quite readily from individual to individual <ref name=Dawkins>Dawkins, Richard The Extended Phenotype 1982, 1999 With a new afterword by Daniel Dennett</ref>. The concept of host manipulation was used, in connection with how memes, units of cultural inheritance (first mentioned in Dawkins' ''the Self Gene''), might transmit themselves amongst humans. Still this particular case of behavioral manipulation in ants is difficult to extrapolate to parasitic manipulation in humans. Especially, since this effect on ant behavior is only characterized in terms of physiological changes that take place in the ant once infected by the parasite and behavior and cognitive function in humans is highly complex. In any case, the field of Memetics is developing quickly and while still highly controversial it appears ideas and cultural practices, like religions, may also evolve by the process of natural selection (see Dan Dennetts TED talks [http://www.ted.com/index.php/talks/dan_dennett_on_dangerous_memes.html]and [http://www.ted.com/index.php/talks/dan_dennett_s_response_to_rick_warren.html].


*Myxoma virus has been used successfully to treat human glioma xenografts in [[immunodeficient]] mice.  Several mouse tumor cell lines, including B16 [[melanomas]], are permissive of MV infection.  Multiple intratumoral injections of MV resulted in substantial tumor growth inhibition.  Moreover, with systemic injection of MV in a lung [[metastasis]] model with [[B16F10LacZ]] cells substantially reduced lung tumors.<ref>Stanford, MM, Shaban, M, Barrett, J, Werden, SJ, Gilbert, PA, Bondy-Denomy, J, MacKenzie, L, Graham, K, Chambers, F, and McFadden, G, Myxoma Virus Oncolysis of Primary and Metastatic B16F10 Mouse Tumors In Vivo. Molecular Therapy (2007) 16 1, 52–59.</ref>
==Current Research==


'''
=== Experimental ELISA for diagnosis of ovine dicrocoeliosis and application in a field survey  A. Broglia et al. 2009===
This group demonstrated that it was more efficient to serotype infected livestock versus waiting for a coprological sample. The latter being almost a month less sensitive post infection compared to the ELISA assay. The antigen, a small liver specific antigen, derived from an infected sheep's bile ducts, was previously isolated by another group and used for this study.


== Current Research: ==
=== Dicrocoeliosis of ruminants: a little known fluke disease D. Otranto et al. 2003===
'''
This review mentions the lack of overall current study on ''D. dendriticum'' and review general information about the parasite. Briefly, it reviews the life cycle of D. Dendriticum which has two intermediate hosts, its epidemiology, a worldwide disease endemic in only some parts of Spain, South America a few Mediterranean countries. Also, the article mentions that the more practical forms of disease control would be better husbandry practices, pretreatment of free grazing animals likely to be infected and even introduce other animals to prey on the intermediate hosts.
'''Myxoma Virus Oncolysis of Primary and Metastatic B16F10 Mouse Tumors In Vivo'''<ref>Stanford, MM, Shaban, M, Barrett, J, Werden, SJ, Gilbert, PA, Bondy-Denomy, J, MacKenzie, L, Graham, K, Chambers, F, and McFadden, G, Myxoma Virus Oncolysis of Primary and Metastatic B16F10 Mouse Tumors In Vivo. Molecular Therapy (2007) 16 1, 52–59.</ref>
This paper investigates the effectiveness of myxoma virus (MV) in treating primary and metastatic mouse tumors in immunocompetent C57BL6 mice. The authors found several mouse tumor cell lines, including B16 melanomas, to be permissive to MV infection.  They used B16F10 cells to assess MV replication and efficacy in genetically similar primary tumor and metastatic models in vivo.  Multiple intratumoral injections of MV caused substantial inhibition of tumor growth.  Moreover, systemic administration of MV in a lung metastasis model with B16F10LacZ cells dramatically reduced lung tumors. Of particular note, a combination therapy of MV with rapamycin reduced both the size and number of lung metastases, as well as the induced antiviral neutralizing antibody titres.  This study demonstrates that MV is capable of targeting and destroying tumors while causing no significant disease or collateral tissue infection in an immunocompetent host. Moreover when MV is combined rapamycin, the potential of MV is significant in oncolytic cancer therapy.


'''Oncolytic efficacy of recombinant vesicular stomatitis virus and myxoma virus in experimental models of rhabdoid tumors.'''<ref>Wu Y, Lun X, Zhou H, Wang L, Sun B, Bell JC, Barrett JW, McFadden G, Biegel JA, Senger DL, Forsyth PA.Authors' Affiliations: Departments of Oncology, Clinical Neurosciences, and Biochemistry and Molecular Biology, University of Calgary, the Tom Baker Cancer Centre, and the Clark H. Smith Brain Tumour Research Centre, Calgary, Alberta, Canada. Clinical Cancer Research, 2008 Feb 15;14(4):1218-27.</ref>
=== Post parasitic infection ===
This paper investigates the therapeutic potential of two oncolytic viruses, myxoma virus (MV) and an attenuated vesicular stomatitis virus (VSV(DeltaM51)) in models of human rhabdoid tumor. Rhabdoid tumors are highly aggressive pediatric tumors that are typically unsusceptible to treatment. In this experiment, four human rhabdoid tumor cell lines were cultured in vitro and treated with live or inactivated control virus. At various times after infection, the cytopathic effect, the viral gene expression, the infectious viral titers, and cell viability were measured. However, to gain insight into viral oncolysis in vivo, human rhabdoid tumor cells were implanted subcutaneously or intracranially in CD-1 nude mice, which were then treated with intratumoral or i.v. injections of live or UV-inactivated virus.
The paper ''Hepatic marker enzymes, biochemical parameters and pathological effects in lambs experimentally infected with ''Dicroceolium dendriticum'' (Dignea) M.Y. Manga-Gonzalez et al. 200'' studied several qualitative and quantitative parameters post experimental parasitic infection. The authors quantified the levels of, key hepatic enzymes, number of worms post necropsy, and qualitatively examined histological slides of the infected lamb ''post mortum''. The authors found significant increases in hepatic enzyme activity ( ALT & AST), which the authors suspected was a pathogenic response to parasite invasion which produces host-toxic metabolites.
In terms of results: 1) all in vitro rhabdoid tumor cell lines were susceptible to lethal infections by MV and VSV(DeltaM51); and 2)Intratumoral injection of live MV or VSV(DeltaM51) reduced the size of s.c. rhabdoid tumor xenografts "dramatically" when compared with control animals. Consequently, these results indicate  that VSV(DeltaM51) and MV have potential as novel therapies against human rhabdoid tumor.


'''Oncolytic Virotherapy Synergism with Signaling Inhibitors: Rapamycin Increases Myxoma Virus Tropism for Human Tumor Cells'''<ref>Marianne M. Stanford, John W. Barrett, Steven H. Nazarian, Steven Werden, and Grant McFadden* Biotherapeutics Research Group, Robarts Research Institute, and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6G 2V4, Canada Journal of Virology, 2007 February; 81(3): 1251–1260.</ref>
==References==
This paper investigates the effect of treating non-permissive human tumor cell lines, which usually restrict myxoma virus replication, with rapamycin.  Aside from being a rabbit-specific poxvirus pathogen, myxoma virus also has a unique tropism for human tumor cells and is substantially oncolytic for human cancer xenografts.  Apparently most tumor cell lines are permissive for myxoma infection as a consequence of activation of Akt kinase.  M-T5, a range factor of myxoma virus, directly interacts with Akt and mediates myxoma virus tumor cell tropism. Rapamycin specifically inhibits mTOR, a regulator of cell growth and metabolism downstream of Akt.  Non-permissive human tumor cell lines were treated with rapamycin. The result was a dramatic increase in virus tropism and transmission in vitro. This increased myxoma replication occurred correspondingly with the effects on mTOR signaling, specifically, an increase in Akt kinase.  However, in contrast, rapamycin does not increase myxoma virus replication in rabbit cell lines or permissive human tumor cell lines with active Akt. This finding is significant in that it indicates that rapamycin increases the oncolytic capacity of myxoma virus for human cancer cells by reconfiguring the internal cell signaling environment to be optimal for virus replication.  It also suggests that a potentially therapeutic synergy exists between kinase signaling inhibitors and oncolytic poxviruses for cancer treatment.
<small>
<references>


'''
</references>
'''Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin.'''<ref>Lun XQ, Zhou H, Alain T, Sun B, Wang L, Barrett JW, Stanford MM, McFadden G, Bell J, Senger DL, Forsyth PA. Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada. Cancer Research, 2007 Sep 15;67(18):8818-27.</ref>
</small>  
This paper investigates and demonstrates that myxoma virus either used alone or in combination with rapamycin is effective and safe experimental models of medulloblastoma in vitro and in vivo.  Nine out of 10 medulloblastoma cell lines tested were found to be susceptible to lethal myxoma virus infection.  However, pretreatment of medulloblastoma cells with rapamycin increased the extent of oncolysis in vitro. In terms of experimental protocal, intratumoral injection of live myxoma virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models as compared to the inactivated virus control. Pretreatment with rapamycin increased the extent of viral oncolysis, effectively "curing" most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Moreover, rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice. Significantly, rapamycin increased the levels of activated Akt in Daoy and D341 cells, a finding that susgests an explanation for its ability to enhance myxoma virus oncolysis. In sum, these findings suggest: 1) that myxoma virus may be an effective oncolytic agent against medulloblastoma, and 2) that therapy with signaling inhibitors that affect the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.


== References: ==
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*Barrett, JW, Sypula, J, Wang, F, Alston, LR, Shao, Z, Gao, X et al.(2007). M135R is a novel cell surface virulence factor of myxoma virus. J Virol 81: 106–114.
*Cameron, C, Hota-Mitchell, S, Chen, L, Barrett, J, Cao, JX, Macaulay, C et al. (1999). The Complete DNA Sequence of Myxoma Virus. Virology 264: 298–318.
*Cameron, C. M., Barrett, J. W., Mann, M., Lucas, A., McFadden, G..  Myxoma virus M128L is expressed as a cell surface CD47-like virulence factor that contributes to the downregulation of macrophage activation in vivo. Virology, 2005 (Vol. 337)(No. 1) 55-67
*Duteyrata, J. et al., (2001) Ultrastructural morphogenesis study of myxoma virus replication cycle. Biology of the Cell 93  349–361.
*Fenner, F. (2000). Adventures with poxviruses of vertebrates. FEMS Microbiol Rev 24: 123–133.
*Iannello,A., Debbeche,O., Martin, E., Habiba Attalah, L., Samarani, S. and Ahmad, A., Viral strategies for evading antiviral cellular immune responses of the host. J. Leukoc. Biol. 2006 79: 16-35.
*Kerr P, McFadden G. (2002) Immune responses to myxoma virus. Viral Immunol. 15(2):229-46.
*Labudovic, A., Perkins, H. van Leeuwen, B. and Kerr, P. (2004) Sequence mapping of the Californian MSW strain of Myxoma virus. Archives of Virology, Vol. 149, Number 3/March, 553-570.
*Lun,X, Yang,W, Alain,T, Shi,ZQ, Muzik,H, Barrett,JW et al.(2005). Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas. Cancer Res 65: 9982–9990.
*Lun, XQ, Zhou, H, Alain, T, Sun, B, Wang, L, Barrett, JW et al.(2007). Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin. Cancer Res 67: 8818–8827.
*MacNeill AL, Turner PC, Moyer RW, (2006) Mutation of the Myxoma virus SERP2 P1-site to prevent proteinase inhibition causes apoptosis in cultured RK-13 cells and attenuates disease in rabbits, but mutation to alter specificity causes apoptosis without reducing virulence.  Virology. 2006 Dec 5-20;356(1-2):12-22. Epub 2006 Sep 7.
*Stanford, MM, Shaban, M, Barrett, J, Werden, SJ, Gilbert, PA, Bondy-Denomy, J, MacKenzie, L, Graham, K, Chambers, F, and McFadden, G, Myxoma Virus Oncolysis of Primary and Metastatic B16F10 Mouse Tumors In Vivo. Molecular Therapy (2007) 16 1, 52–59.
*Stanford, MM, Barrett, JW, Nazarian, SH, Werden, S and McFadden, G. (2007). Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells. Journal of Virology, 81: 1251–1260.
*Stanford, MM, Werden, SJ and McFadden, G. (2007). Myxoma virus in the European rabbit: interactions between the virus and its susceptible host. Vet Res 38: 299–318
*Stanford‌, MM, and McFadden, G. (2007) Myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer. Expert Opinion on Biological Therapy, Vol. 7, No. 9, Pages 1415-1425.
*Sypula, J, Wang, F, Ma, Y, Bell, JC and McFadden, G. (2004). Myxoma virus tropism in human tumor cells. Gene Ther Mol Biol 8: 108–114.
*Wang, G, Barrett, JW, Stanford, M, Werden, SJ, Johnston, JB, Gao, X et al.(2006). Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor. Proc Natl Acad Sci USA 103: 4640–4645.
*Wang G, Barrett JW, Stanford M, Werden SJ, Johnston JB, Gao X, Sun M, Cheng JQ, McFadden G. Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor. Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4640-5. Epub 2006 Mar 14.
*Yang, WQ, Lun, X, Palmer, CA, Wilcox, ME, Muzik, H, Shi, ZQ, Dyck, R, Coffey, M, Thompson, B, Hamilton, M, Nishikawa, S, Brasher, P, Fonseca, K, George, D, Rewcastle, NB, Johnston, R, Stewart, D, Lee, P, Senger, D, Forsyth, P, (2004) Efficacy and Safety Evaluation of Human Reovirus Type 3 in Immunocompetent Animals, Clinical Cancer Research Vol. 10, 8561-8576

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Lancet fluke/Small liver fluke
Dicrocoelium dendriticum3.jpg
Scientific classification
Kingdom: Animalia
Phylum: Platyhelminthes
Class: Trematoda
Order: Plagiorchiida
Family: Dicrocoeliidae
Genus: Dicrocoelium
Species: D. dendriticum
Binomial name
Dicrocoelium dendriticum
Rudolphi, 1819

Dicrocoelium dendriticum is a small liver fluke, that is, a parasitic organism. It benefits from its relationship to the host while contributing nothing to the survival of that host such that it in most cases may lower host fitness. Theory and mechanisms on parasite manipulation of host fitness is a current topic of much controversy (see ‘Small Liver Fluke Manipulation of Host Behavior’ section below).Dicrocoeliosis is a globally present parasitic infection caused by Dicroceolium, which infect the bile ducts and gall bladder of wild and domestic animals. Since it is not as pathogenic as other flukes very little is known about this parasite. Moreover, since it has two intermediate hosts Dicrocoeliosis is difficult to reproduce under experimental conditions.

Morphology

Dorso-ventrally flattned (lance shaped), adult lancet flukes are semi transparent ~8-14mm in length and ~2-3mm in width, oval shaped with the anterior slightly more narrow in shape compared to its posterior, both ends being slightly tapered [1]. At its tip the anterior contains an oral sucker. A hermaphrodite, the adult lancet fluke contains two lobed testes, in its anterior region, juxtaposed to its ovary, and the uterus lies below in its midsection. Vitellaria glands flank its reproductive organs, and are important in egg production. The digestive components (gut and bladder) lie in the posterior portion of its body[2]

Parasitic Reservoirs: inside and outside the Definitive HostZebrina Conchology A.jpgIntermediate hosts.jpg

Dicrocoelium dendriticum’s habitat includes lowland or mountain pastures, of dry and alkaline consistency, providing appropriate conditions for its definitive and intermediate hosts (shown above).[2] [3] The adult lancet fluke necessarily inhabits the liver of its definitive host, specifically the bile ducts and gall bladder of domesticated and wild ruminating animals (sheep, goat and cattle). Although, they can also be found in the liver of dogs, rabbits, horses, humans and some rodents [3]. Endogenous host and environmental conditions are critical for its survival, whereby each intermediate host must be favored in the collective biotope, making it difficult to model similar conditions in the laboratory. Since its continuance into the liver of its definitive host for sexual reproduction is dependent on prior passage through two other distinct host organisms, conditions must favor each part of this biological community. Once an adult, it uses its hermaphroditic body plan to propagate itself several orders of magnitude, but to get their the fluke must be ingested by specific intermediate hosts, which allow it to carry out the different stages of its life cycle [3].

Life Cycle: A Definitive Host and Two Intermediate Hosts

A trifecta of successful host:parasite adaptation, the small liver flukes’ life cycle and mode of transmission have been well described by the work of Krull and Mapes. Collectively their work showed that infection of the definitive host is initiated by ingestion of infected ants and cannot be bypassed by eating the slimeballs of infected snails, the first intermediate host.[2][3][1]Adult flukes in the bile ducts, lay dark brown eggs each containing a miracidium, which are expelled with the bile into the intestine and later incorporated into the feces. These eggs are viable embryos, which are only hatched upon ingestion by the appropriate species of snail, Cionella lubrica in North America (There are many other possible host snail species depending on geographical location i.e. In France, Cochlicella acuta) [3]. The hatching mericidia penetrate the glandular intestinal epithelium and then undergo several rounds of asexual replication into daughter sporocysts [2][3]. These daughter sporocysts mature into motile larva, called mature cercariae and travel to the snails’ respiratory chambers, a process that can take 5 months depending on season or age of the snail.[2] [3] The cercariae contain glands which are speculated to be involved in the formation of slimeballs. Several ~500-5000 cercariae are collected in these slime accumulations but little is known about the mechanism of their formation.[2][3] Slimeballs stick to nearby plants and debris, each snail usually produces one but can produce more.[2] These slimeballs are ingested by a specific species of ant, in North America Formica fusca (Again, several species are capable of being intermediate host, differences being dependent on location). The larva then transform into metacercariae which grow in the abdomen of the ant. After a period of about a month [1], at the expense of its own survival, a single metacercariae will become localized in the subesophageal ganglion, which results in changes in normal behavior of the ant, when temperatures are low [2]. In this parasite adaptive state the infected ant climbs to the tips on blades of grass where they are exposed to grazing mammals such as sheep, goats and cows[2] [3][1]. Finally, the metacercariae have arrived at their destination in the definitive host, where they are encysted in the duodenum [3]. The larva excyst and migrate to the bile ducts and then the gall bladder. In the bile ducts they develop into cross fertilizing and hermaphroditic adult flukes, capable of releasing new eggs into the environment, in the host excrement.[2][3] [1] Dicrocoelium LifeCycle.gif

Epidemiology

D. Dendriticum transmission depends on the presence of its intermediate hosts and the conditions that favor their survival. These conditions and thus the occurrence of D. dendriticum are dependent on; dry and alkaline soils [3]. Overall dicrocoeliosis is present sporadically in Europe, China, Japan, North Africa, South America, and some parts of North America, Australia and Africa. Although, it is endemic in parts of Spain, Brazil and a few Mediterranean countries.[4] These small liver flukes are found in dry lowland or mountain pastures, which provide sufficient conditions for the survival of snails and ants[3]. The prevalence of infection varies with season and the snail which is parasitized [3].

Pathology

D dendriticum egg wtmt JCG C.jpg Disease occurrence in humans is rare, but infection by eating plants covered with infected ants (image of larval metacecariae egg, found in infected ant abdomen, is shown above or parasite manipulated ant on blade of grass shown below) or through ingestion of uncooked infected liver is possible. Although, in general livestock are at higher risk for infection. The small liver fluke has little identifiable clinical manifestations in infected hosts, compared other liver flukes i.e. Fasciola. Even in heavily infected hosts they are asymptomatic, often suffering from anaemia, oedema or emaciation [3]. Also, the pathogenic effects of D. dendriticum can become confounded by simultaneous infections with other nematodes. Still some have been able to detect its effect on the liver [3]. In this case sheep liver was examined post mortum which appeared to have heavy scarring on its surface, hardening due to calcification and fibrosis, and displayed disruption of the bile ducts as a result of irritation caused by the presence of the small liver flukes [3].

Small Liver Fluke Manipulation of Host Behavior

Out on the open plains, in the evening or just before sunrise a keen observer might see something quite remarkable. Several ants with their mandibles attached firmly to blades of grass. If their timing is right, they will later find themselves in a fatal journey culminating with their special hitchhikers (metacercariae) being transmitted successfully into the definitive hosts liver. If no livestock graze on these particular grasses then the ant will return to its normal duties in its colony[2]. This manipulation of the second intermediate host is carried out when a mature cercaria in the ant abdomen matures into a metacercariae which is now motile and able to travel to the ant's subesophageal ganglion. As a result, the ant and the parasite (localized in the brain) are sacrificed[2][3]. Clearly, there is a conflict of interest between host and parasite which only makes sense to the parasite. But, while the eggs of the parasite are passed on to the terminal host, the parasite which traveled to the ant brain had to sacrifice itself in the process. Thus this single motile parasite does not have the ability to pass on its genes. There is no model to explain this behavior but some have proposed that kin selection may be taking place and that the altruistic ant may share genes with other larva in the ant which will survive[5]. This behavior has gotten the attention of many biologist and those with scientific interest. Some have seen this as an example of how some adaptations while perfectly natural are clearly not beneficial to the intermediate host (the ant). This example of parasite manipulation of host behavior has been used by Biologist, Richard Dawkins and Philosopher, Dan Dennett, to explain how some adaptations while harmful, still propagate themselves quite readily from individual to individual. The latter conceptual example was used by these authors, in connection with how memes, units of cultural inheritance may transmit themselves, throughout the human population. 800px-Ant on leaf.jpg

Controversy: Cultural Diversity an Evolutionary Fluke?

The above mentioned example of parasite manipulation of host behavior has been cited by Richard Dawkins and Dan Dennett,In Dawkin's book The Extended Phenotype to explain how some adaptations while harmful, still propagate themselves quite readily from individual to individual [6]. The concept of host manipulation was used, in connection with how memes, units of cultural inheritance (first mentioned in Dawkins' the Self Gene), might transmit themselves amongst humans. Still this particular case of behavioral manipulation in ants is difficult to extrapolate to parasitic manipulation in humans. Especially, since this effect on ant behavior is only characterized in terms of physiological changes that take place in the ant once infected by the parasite and behavior and cognitive function in humans is highly complex. In any case, the field of Memetics is developing quickly and while still highly controversial it appears ideas and cultural practices, like religions, may also evolve by the process of natural selection (see Dan Dennetts TED talks [1]and [2].

Current Research

Experimental ELISA for diagnosis of ovine dicrocoeliosis and application in a field survey A. Broglia et al. 2009

This group demonstrated that it was more efficient to serotype infected livestock versus waiting for a coprological sample. The latter being almost a month less sensitive post infection compared to the ELISA assay. The antigen, a small liver specific antigen, derived from an infected sheep's bile ducts, was previously isolated by another group and used for this study.

Dicrocoeliosis of ruminants: a little known fluke disease D. Otranto et al. 2003

This review mentions the lack of overall current study on D. dendriticum and review general information about the parasite. Briefly, it reviews the life cycle of D. Dendriticum which has two intermediate hosts, its epidemiology, a worldwide disease endemic in only some parts of Spain, South America a few Mediterranean countries. Also, the article mentions that the more practical forms of disease control would be better husbandry practices, pretreatment of free grazing animals likely to be infected and even introduce other animals to prey on the intermediate hosts.

Post parasitic infection

The paper Hepatic marker enzymes, biochemical parameters and pathological effects in lambs experimentally infected with Dicroceolium dendriticum (Dignea) M.Y. Manga-Gonzalez et al. 200 studied several qualitative and quantitative parameters post experimental parasitic infection. The authors quantified the levels of, key hepatic enzymes, number of worms post necropsy, and qualitatively examined histological slides of the infected lamb post mortum. The authors found significant increases in hepatic enzyme activity ( ALT & AST), which the authors suspected was a pathogenic response to parasite invasion which produces host-toxic metabolites.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Desmond, James introduction to animal parisitology p. 214 Figure 14.14
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 Krull, W. H., and C. R. Mapes. "Studies on the biology of Dicrocoelium dendriticum (Rudolphi, 1819) Looss, 1899 (Trematoda: Dicrocoeliidae), including its relation to the intermediate host, Cionella lubrica II. Collection of the snail, Cionella lubrica, and its maintenance in the laboratory." Cornell Vet 41 (1951): 433-44.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 Otranto, Domenic Dicrocoeliosis of ruminants: a little known fluke disease Trends in Parasitology 2003
  4. ↑ Broglia, A. Experimental ELISA for diagnosis of ovine dicrocoeliosis and application in a field survey Parasitology Research 2009
  5. ↑ Gandon, Sylvain Parasitic manipulation: a theoretical framework may help
  6. ↑ Dawkins, Richard The Extended Phenotype 1982, 1999 With a new afterword by Daniel Dennett

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