Genetic Analysis of Tropism Using a Naturally Attenuated Cutaneous Strain

English version České info

Visceral leishmaniasis is one of the most lethal parasitic diseases, and the mechanisms that govern its survival in visceral organs are not understood. Here, we obtained an atypical cutaneous Leishmania donovani clinical isolate from Sri Lanka and compared it to a typical visceral disease causing clinical isolate. Through whole genome sequencing, bioinformatics analysis, experimental infection in mice and functional genomic analysis, this study provides novel information on what differentiates a deadly visceral strain from a benign cutaneous strain. Results indicate that the ability of Leishmania parasites to cause visceral or cutaneous leishmaniasis may be determined by mutations or amplification of a few genes, or combinations of these factors. Overall, this work contributes to the understanding of parasite virulence and may help guide disease control efforts.

Vyšlo v časopise: Genetic Analysis of Tropism Using a Naturally Attenuated Cutaneous Strain. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004244
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004244

Souhrn

Zdroje

1. AlvarJ, VelezID, BernC, HerreroM, DesjeuxP, et al. (2012) Leishmaniasis Worldwide and Global Estimates of Its Incidence. Plos One 7: e35671.

2. MurrayHW, BermanJD, DaviesCR, SaraviaNG (2005) Advances in leishmaniasis. Lancet 366 : 1561–1577.

3. McCallLI, ZhangWW, MatlashewskiG (2013) Determinants for the development of visceral leishmaniasis disease. PLoS Pathog 9: e1003053.

4. KarunaweeraND, PratlongF, SiriwardaneHVYD, IhalamullaRL, DedetJP (2003) Lankan cutaneous leishmaniasis is caused by Leishmania donovani zymodeme MON-37. Transactions of the Royal Society of Tropical Medicine and Hygiene 97 : 380–381.

5. RanasingheS, WickremasingheR, MunasingheA, HulangamuwaS, SivanantharajahS, et al. (2013) Cross-Sectional Study to Assess Risk Factors for Leishmaniasis in an Endemic Region in Sri Lanka. Am J Trop Med Hyg 89 : 742–749.

6. SiriwardanaHVYD, NoyesHA, BeechingNJ, ChanceML, KarunaweeraND, et al. (2007) Leishmania donovani and cutaneous leishmaniasis, Sri Lanka. Emerging Infectious Diseases 13 : 476–478.

7. AbeygunasekaraPH, CostaYJ, SeneviratneN, RatnatungaN, Wijesundera MdeS (2007) Locally acquired visceral leishmaniasis in Sri Lanka. Ceylon Med J 52 : 30–31.

8. RanasingheS, ZhangWW, WickremasingheR, AbeygunasekeraP, ChandrasekharanV, et al. (2012) Leishmania donovani zymodeme MON-37 isolated from an autochthonous visceral leishmaniasis patient in Sri Lanka. Pathogens and global health 106 : 421–424.

9. ZhangWW, MatlashewskiG (1997) Loss of virulence in Leishmania donovani deficient in an amastigote-specific protein, A2. Proc Natl Acad Sci U S A 94 : 8807–8811.

10. ZhangWW, MatlashewskiG (2010) Screening Leishmania donovani-specific genes required for visceral infection. Mol Microbiol 77 : 505–517.

11. DowningT, ImamuraH, DecuypereS, ClarkTG, CoombsGH, et al. (2011) Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance. Genome Research 21 : 2143–2156.

12. RogersMB, HilleyJD, DickensNJ, WilkesJ, BatesPA, et al. (2011) Chromosome and gene copy number variation allow major structural change between species and strains of Leishmania. Genome Research 21 : 2129–2142.

13. ZhangWW, MatlashewskiG (2001) Characterization of the A2-A2rel gene cluster in Leishmania donovani: involvement of A2 in visceralization during infection. Mol Microbiol 39 : 935–948.

14. AzzouniF, MohlerJ (2012) Role of 5alpha-reductase inhibitors in prostate cancer prevention and treatment. Urology 79 : 1197–1205.

15. QiuXB, ShaoYM, MiaoS, WangL (2006) The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cellular and molecular life sciences: CMLS 63 : 2560–2570.

16. DhirV, GouldingD, FieldMC (2004) TbRAB1 and TbRAB2 mediate trafficking through the early secretory pathway of Trypanosoma brucei. Molecular and Biochemical Parasitology 137 : 253–265.

17. SauveAA, YounDY (2012) Sirtuins: NAD(+)-dependent deacetylase mechanism and regulation. Current Opinion in Chemical Biology 16 : 535–543.

18. JewellJL, GuanKL (2013) Nutrient signaling to mTOR and cell growth. Trends in Biochemical Sciences 38 : 233–242.

19. ClaytonCE (2002) Life without transcriptional control? From fly to man and back again (vol 21, pg 1881, 2002). Embo Journal 21 : 3917–3917.

20. da SilvaLM, BeverleySM (2010) Expansion of the target of rapamycin (TOR) kinase family and function in Leishmania shows that TOR3 is required for acidocalcisome biogenesis and animal infectivity. Proc Natl Acad Sci U S A 107 : 11965–11970.

21. SterkersY, LachaudL, BourgeoisN, CrobuL, Bastien, PagesM (2012) Novel insights into genome plasticity in eukaryotes: mosaic aneuploidy in Leishmania. Mol Micro 86 : 15–23.

22. ZhangWW, MendezS, GhoshA, MylerP, IvensA, et al. (2003) Comparison of the A2 gene locus in Leishmania donovani and Leishmania major and its control over cutaneous infection. J Biol Chem 278 : 35508–35515.

23. McCallLI, MatlashewskiG (2010) Localization and induction of the A2 virulence factor in Leishmania: evidence that A2 is a stress response protein. Mol Microbiol 77 : 518–530.

24. McCallLI, MatlashewskiG (2012) Involvement of the Leishmania donovani virulence factor A2 in protection against heat and oxidative stress. Exp Parasitol 132 : 109–115.

25. GhedinE, ZhangWW, CharestH, SundarS, KenneyRT, et al. (1997) Antibody response against a Leishmania donovani amastigote-stage-specific protein in patients with visceral leishmaniasis. Clin Diagn Lab Immunol 4 : 530–535.

26. Diaz-GonzalezR, KuhlmannFM, Galan-RodriguezC, Madeira da SilvaL, SaldiviaM, et al. (2011) The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing. PLoS Negl Trop Dis 5: e1297.

27. BranquinhaMH, MarinhoFA, SangenitoLS, OliveiraSS, GoncalvesKC, et al. (2013) Calpains: potential targets for alternative chemotherapeutic intervention against human pathogenic trypanosomatids. Current medicinal chemistry 20 : 3174–3185.

28. DePristoMA, BanksE, PoplinR, GarimellaKV, MaguireJR, et al. (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43 : 491.

29. CingolaniP, PlattsA, WangLL, CoonM, NguyenT, et al. (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w(1118); iso-2; iso-3. Fly 6 : 80–92.

30. ArmourCD, CastleJC, ChenR, BabakT, LoerchP, et al. (2009) Digital transcriptome profiling using selective hexamer priming for cDNA synthesis. Nature methods 6 : 647–649.