Transcriptome of Sphaerospora molnari (Cnidaria, Myxosporea) blood stages provides proteolytic arsenal as potential therapeutic targets against sphaerosporosis in common carp.

Publisher: BioMed Central Country of Publication: England NLM ID: 100965258 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2164 (Electronic) Linking ISSN: 14712164 NLM ISO Abbreviation: BMC Genomics Subsets: MEDLINE

Original Publication: London : BioMed Central, [2000-

Carps/*microbiology ; Fish Diseases/*parasitology ; Myxozoa/*genetics ; Parasitic Diseases, Animal/*parasitology ; Peptide Hydrolases/*genetics; Animals ; Antiparasitic Agents/pharmacology ; Antiparasitic Agents/therapeutic use ; Drug Discovery ; Fish Diseases/therapy ; Myxozoa/growth & development ; Parasitic Diseases, Animal/therapy ; Phylogeny ; Transcriptome ; Virulence Factors

Background: Parasites employ proteases to evade host immune systems, feed and replicate and are often the target of anti-parasite strategies to disrupt these interactions. Myxozoans are obligate cnidarian parasites, alternating between invertebrate and fish hosts. Their genes are highly divergent from other metazoans, and available genomic and transcriptomic datasets are limited. Some myxozoans are important aquaculture pathogens such as Sphaerospora molnari replicating in the blood of farmed carp before reaching the gills for sporogenesis and transmission. Proliferative stages cause a massive systemic lymphocyte response and the disruption of the gill epithelia by spore-forming stages leads to respiratory problems and mortalities. In the absence of a S. molnari genome, we utilized a de novo approach to assemble the first transcriptome of proliferative myxozoan stages to identify S. molnari proteases that are upregulated during the first stages of infection when the parasite multiplies massively, rather than in late spore-forming plasmodia. Furthermore, a subset of orthologs was used to characterize 3D structures and putative druggable targets.
Results: An assembled and host filtered transcriptome containing 9436 proteins, mapping to 29,560 contigs was mined for protease virulence factors and revealed that cysteine proteases were most common (38%), at a higher percentage than other myxozoans or cnidarians (25-30%). Two cathepsin Ls that were found upregulated in spore-forming stages with a presenilin like aspartic protease and a dipeptidyl peptidase. We also identified downregulated proteases in the spore-forming development when compared with proliferative stages including an astacin metallopeptidase and lipases (qPCR). In total, 235 transcripts were identified as putative proteases using a MEROPS database. In silico analysis of highly transcribed cathepsins revealed potential drug targets within this data set that should be prioritised for development.
Conclusions: In silico surveys for proteins are essential in drug discovery and understanding host-parasite interactions in non-model systems. The present study of S. molnari's protease arsenal reveals previously unknown proteases potentially used for host exploitation and immune evasion. The pioneering dataset serves as a model for myxozoan virulence research, which is of particular importance as myxozoan diseases have recently been shown to emerge and expand geographically, due to climate change.

Sci Rep. 2016 Dec 16;6:39093. (PMID: 27982057)
Proc Natl Acad Sci U S A. 2015 Dec 1;112(48):14912-7. (PMID: 26627241)
Science. 1984 Sep 28;225(4669):1449-52. (PMID: 17770061)
Am Nat. 2017 Aug;190(2):244-265. (PMID: 28731797)
Bioinformatics. 2015 Oct 1;31(19):3210-2. (PMID: 26059717)
G3 (Bethesda). 2017 Mar 10;7(3):871-880. (PMID: 28122948)
Mol Immunol. 2015 Dec;68(2 Pt A):72-6. (PMID: 26006050)
PLoS Biol. 2018 Jul 31;16(7):e2005359. (PMID: 30063702)
Bioinformatics. 2006 Jul 1;22(13):1658-9. (PMID: 16731699)
Biochem J. 2002 Jun 15;364(Pt 3):703-10. (PMID: 12049634)
PLoS Negl Trop Dis. 2016 Jul 27;10(7):e0004834. (PMID: 27463369)
BMC Genomics. 2014 Jan 28;15:71. (PMID: 24467778)
Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21486-91. (PMID: 23236186)
Gigascience. 2018 Jul 1;7(7):. (PMID: 29917104)
Biochem J. 2010 Apr 14;427(3):523-34. (PMID: 20196774)
J Biol Chem. 2008 Apr 11;283(15):9896-908. (PMID: 18160404)
DNA Res. 2018 Oct 1;25(5):499-510. (PMID: 29947776)
Biochem Biophys Res Commun. 2009 Mar 13;380(3):454-9. (PMID: 19174148)
Nat Protoc. 2015 Jun;10(6):845-58. (PMID: 25950237)
FEBS J. 2008 Apr;275(7):1485-99. (PMID: 18279375)
J Parasitol Res. 2012;2012:748206. (PMID: 22792442)
Nucleic Acids Res. 2014 Jan;42(Database issue):D503-9. (PMID: 24157837)
Parasit Vectors. 2014 Aug 28;7:398. (PMID: 25167920)
Philos Trans R Soc Lond B Biol Sci. 2009 Jan 12;364(1513):85-98. (PMID: 18930879)
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W677-80. (PMID: 15980561)
Biochim Biophys Acta. 2013 Dec;1828(12):2828-39. (PMID: 24099004)
J Immunol. 2000 Dec 1;165(11):6447-53. (PMID: 11086084)
Annu Rev Pathol. 2006;1:497-536. (PMID: 18039124)
J Clin Invest. 1994 Apr;93(4):1602-8. (PMID: 8163662)
J Biol Chem. 1999 Nov 5;274(45):32411-7. (PMID: 10542284)
Infect Immun. 2006 Feb;74(2):961-7. (PMID: 16428741)
Parasit Vectors. 2018 Jun 15;11(1):347. (PMID: 29903034)
Mol Cell Biochem. 2010 Aug;341(1-2):17-31. (PMID: 20349119)
Comp Biochem Physiol C Toxicol Pharmacol. 2006 Mar-Apr;142(3-4):328-46. (PMID: 16434235)
Front Cell Infect Microbiol. 2012 May 16;2:72. (PMID: 22919663)
Front Pharmacol. 2016 Apr 25;7:107. (PMID: 27199750)
Science. 2002 Jun 21;296(5576):2215-8. (PMID: 12077416)
Comp Biochem Physiol B Biochem Mol Biol. 2008 Mar;149(3):477-89. (PMID: 18187354)
Dis Aquat Organ. 2012 Oct 10;101(1):33-42. (PMID: 23047189)
Int J Parasitol. 2012 May 1;42(5):481-8. (PMID: 22549023)
Infect Immun. 2003 Feb;71(2):1008-10. (PMID: 12540585)
Pharmacogenomics. 2007 Sep;8(9):1267-72. (PMID: 17924840)
Parasitology. 2007 Nov;134(Pt 12):1727-39. (PMID: 17651531)
PLoS Negl Trop Dis. 2018 Aug 23;12(8):e0005639. (PMID: 30138311)
BMC Genomics. 2010 Apr 03;11:222. (PMID: 20361874)
Nat Genet. 2019 Jan;51(1):163-174. (PMID: 30397333)
Genome Biol Evol. 2018 Mar 1;10(3):909-917. (PMID: 29608715)
Mol Phylogenet Evol. 2013 Jul;68(1):93-105. (PMID: 23500334)
Vet Res. 2009 Jul-Aug;40(4):41. (PMID: 19401141)
Front Cell Infect Microbiol. 2018 Mar 13;8:67. (PMID: 29594064)
Nucleic Acids Res. 2001 May 1;29(9):e45. (PMID: 11328886)
PLoS Genet. 2013 Apr;9(4):e1003457. (PMID: 23593039)
PLoS One. 2013 Aug 19;8(8):e71597. (PMID: 23977083)
Mar Genomics. 2018 Feb;37:135-147. (PMID: 29198427)
Expert Rev Vaccines. 2005 Feb;4(1):89-101. (PMID: 15757476)
Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11992-11997. (PMID: 29078391)
PLoS One. 2009;4(4):e5078. (PMID: 19337374)
Pathogens. 2013 Feb 19;2(1):105-29. (PMID: 25436884)
Genome Biol Evol. 2014 Nov 08;6(12):3182-98. (PMID: 25381665)
Pharmacol Ther. 2012 Mar;133(3):257-79. (PMID: 22138604)
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11015-22. (PMID: 10500116)
Parasit Vectors. 2019 May 6;12(1):208. (PMID: 31060624)
Nat Rev Genet. 2011 Sep 07;12(10):671-82. (PMID: 21897427)
Expert Opin Drug Discov. 2016 Aug;11(8):815-24. (PMID: 27238605)
Clin Exp Immunol. 2016 Jun;184(3):265-83. (PMID: 26671446)
Sci Rep. 2017 Aug 3;7(1):7214. (PMID: 28775251)
PLoS Negl Trop Dis. 2018 Aug 23;12(8):e0005840. (PMID: 30138310)
PLoS Negl Trop Dis. 2018 Aug 23;12(8):e0006512. (PMID: 30138453)
Int J Parasitol. 2008 Nov;38(13):1579-88. (PMID: 18599060)
Mol Ecol. 2018 Apr;27(7):1651-1666. (PMID: 29575260)

634429 European Commission Horizon 2020 Research and Innovation Action; 19-28399X Grantová Agentura České Republiky; NN124220 Hungarian National Research, Development and Innovation Office

Keywords: Aquaculture; Drug targets; In silico screening; Myxozoa; Parasite; Proteases

0 (Antiparasitic Agents)
0 (Virulence Factors)
EC 3.4.- (Peptide Hydrolases)

Date Created: 20200618 Date Completed: 20210308 Latest Revision: 20210308

20231215

PMC7296530

10.1186/s12864-020-6705-y

32546190