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Genome-wide screening identifies Plasmodium chabaudi-induced modifications of DNA methylation status of Tlr1 and Tlr6 gene promoters in liver, but not spleen, of female C57BL/6 mice

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Abstract

Epigenetic reprogramming of host genes via DNA methylation is increasingly recognized as critical for the outcome of diverse infectious diseases, but information for malaria is not yet available. Here, we investigate the effect of blood-stage malaria of Plasmodium chabaudi on the DNA methylation status of host gene promoters on a genome-wide scale using methylated DNA immunoprecipitation and Nimblegen microarrays containing 2,000 bp oligonucleotide features that were split into −1,500 to −500 bp Ups promoters and −500 to +500 bp Cor promoters, relative to the transcription site, for evaluation of differential DNA methylation. Gene expression was analyzed by Agilent and Affymetrix microarray technology. Challenging of female C57BL/6 mice with 106 P. chabaudi-infected erythrocytes resulted in a self-healing outcome of infections with peak parasitemia on day 8 p.i. These infections induced organ-specific modifications of DNA methylation of gene promoters. Among the 17,354 features on Nimblegen arrays, only seven gene promoters were identified to be hypermethylated in the spleen, whereas the liver exhibited 109 hyper- and 67 hypomethylated promoters at peak parasitemia in comparison with non-infected mice. Among the identified genes with differentially methylated Cor-promoters, only the 7 genes Pigr, Ncf1, Klkb1, Emr1, Ndufb11, and Tlr6 in the liver and Apol6 in the spleen were detected to have significantly changed their expression. Remarkably, the Cor promoter of the toll-like receptor Tlr6 became hypomethylated and Tlr6 expression increased by 3.4-fold during infection. Concomitantly, the Ups promoter of the Tlr1 was hypermethylated, but Tlr1 expression also increased by 11.3-fold. TLR6 and TLR1 are known as auxillary receptors to form heterodimers with TLR2 in plasma membranes of macrophages, which recognize different pathogen-associated molecular patterns (PAMPs), as, e.g., intact 3-acyl and sn-2-lyso-acyl glycosylphosphatidylinositols of P. falciparum, respectively. Our data suggest therefore that malaria-induced epigenetic fine-tuning of Tlr6 and Tlr1 through DNA methylation of their gene promoters in the liver is critically important for initial recognition of PAMPs and, thus, for the final self-healing outcome of blood-stage infections with P. chabaudi malaria.

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References

  • Akira S, Takeda K (2004) Toll-like receptors signalling. Nature Rev Imunol 4:499–511

    Article  CAS  Google Scholar 

  • Al-Quraishy S, Delic D, Sies H, Wunderlich F, Abdel-Baki AA, Dkhil MA (2011) Differential miRNA expression in the mouse jejunum during garlic treatment of Eimeria papillata infections. Parasitol Res 109:387–394

    Article  PubMed  Google Scholar 

  • Al-Quraishy S, Dkhil M, Delic D, Abdel-Baki AA, Wunderlich F (2012) Organ-specific testosterone-insensitive response of miRNA expression of C57BL/6 mice to Plasmodium chabaudi malaria. Parasitol Res 111:1093–1101

    Article  PubMed  Google Scholar 

  • Benten WPM, Ulrich P, Kühn-Velten WN, Vohr HW, Wunderlich F (1997) Testosterone-induced susceptibility to Plasmodium chabaudi malaria: persistence after withdrawal of testosterone. Parasite Immunol 13:357–367

    Google Scholar 

  • Bierne H, Hamon M, Cossart P (2013) Epigenetics and bacterial infections. Cold Spring Harbor Perspect Med 2(12):a010272

    Article  Google Scholar 

  • Bilzer M, Roggel F, Gerbes AL (2006) Role of Kupffer cells in host defense and liver disease. Liver Int 26:1175–1186

    Article  PubMed  CAS  Google Scholar 

  • Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21

    Article  PubMed  CAS  Google Scholar 

  • Bosman GJ, Willekens FL, Werre JM (2005) Erythrocyte aging: a more than superficial resemblance to apoptosis? Cell Physiol Biochem 16:1–8

    Article  PubMed  CAS  Google Scholar 

  • Cedar H, Bergman Y (2012) Programming of DNA methylation patterns. Annu Rev Biochem 81:97–117

    Article  PubMed  CAS  Google Scholar 

  • Chotivanich K, Udomsangpetch R, McGready R, Proux S, Newton P, Pukrittayakamee S, Looareesuwan S, White NJ (2002) Central role of the spleen in malaria parasite clearence. J Inf Dis 185:1538–1541

    Article  Google Scholar 

  • Cohen S, Lambert PH (1982) In: Cohen S, Warren KS (eds) Imunology of parasitic infections, 2nd edn. Blackwell, Oxford, pp 422–474

    Google Scholar 

  • Crispe IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27:147–163

    Article  PubMed  CAS  Google Scholar 

  • Delic D, Gailus N, Vohr HW, Dkhil M, Al-Quraishy S, Wunderlich F (2010a) Testosterone-induced permanent changes of hepatic gene expression in female mice sustained during Plasmodium chabaudi malaria infection. J Mol Endocrinol 45:379–390

    Article  PubMed  CAS  Google Scholar 

  • Delic D, Warskulat U, Borsch E, Al-Qahtani A-GS, Häussinger D, Wunderlich F (2010b) Loss of ability to self-heal malaria upon taurine transporter deletion. Infect Immun 78:1642–1649

    Article  PubMed  CAS  Google Scholar 

  • Delic D, Dkhil M, Al-Quraishy S, Wunderlich F (2011a) Hepatic miRNA expression reprogrammed by Plasmodium chabaudi malaria. Parsitol Res 108:1111–1121

    Article  Google Scholar 

  • Delic D, Ellinger-Ziegelbauer H, Vohr HW, Dkhil M, Al-Quraishy S, Wunderlich F (2011b) Testosterone response of hepatic gene expression in female mice having acquired testosterone-unresponsive immunity to Plasmodium chabaudi malaria. Steroids 76:1204–1212

    Article  PubMed  CAS  Google Scholar 

  • Dkhil MA, Al-Quraishy S, Delic D, Abdel-Baki AA, Wunderlich F (2013) Testosterone-induced persistent susceptibility to Plasmodium chabaudi malaria: long-term changes of lincRNA and mRNA expression in the spleen. Steroids 78:220–227

    Article  PubMed  CAS  Google Scholar 

  • Doolan DL, Dobafio C, Baird JK (2009) Acquired immunity to malaria. Clin Microbiol Rev 22:13–36

    Article  PubMed  CAS  Google Scholar 

  • Garcia LS (2010) Malaria. Clin Lab Med 30(1):93–129

    Article  PubMed  Google Scholar 

  • Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 20:261–282

    Article  Google Scholar 

  • Häussinger D, Kubitz R, Reinehr R, Bode JG, Schliess F (2004) Molecular aspects of medicine: from experimental to clinical hepatology. Mol Aspects Med 25:221–360

    Article  PubMed  Google Scholar 

  • Jarra W, Brown KN (1989) Protective immunity to malaria: studies with cloned lines of rodent malaria in CBA/Ca mice. IV. The specificity of mechanisms resulting in crisis and resolution of the primary acute phase parasitaemia of Plasmodium chabaudi chabaudi and P. yoelii yoelii. Parasite Immunol 11:1–13

    Article  PubMed  CAS  Google Scholar 

  • Jensen M, Mehlhorn H (2009) Seventy-five years of resorchin in the fight against malaria. Parasitol Res 105:609–627

    Article  PubMed  Google Scholar 

  • Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 29:484–492

    Article  Google Scholar 

  • Junpee A, Tencomnao T, Sanprasert V, Nuchprayoon S (2010) Association between toll-like receptor 2 (TLR2) polymorphisms and asymptomatic bancroftian filariasis. Parasitol Res 107:807–816

    Article  PubMed  Google Scholar 

  • Krishnegowa G, Hajjar AM, Zhu J, Douglass EJ, Uematsu S, Akira S, Woods AS, Gowda DC (2005) Induction of proinflammatory responses in macrophages by the glycosylphsophatidylinositols of Plasmodium falciparum. J Biol Chem 9:8606–8616

    Google Scholar 

  • Kruecken J, Dkhil MA, Braun JV, Schroetel RM, El-Khadragy M, Carmeliet P, Mossmann H, Wunderlich F (2005a) Testosterone suppresses protective responses of the liver to blood-stage malaria. Infect Immun 73:436–443

    Article  CAS  Google Scholar 

  • Kruecken J, Mehnert LI, Dkhil M, El-Khadragy M, Benten WPM, Mossman H, Wunderlich F (2005b) Massive destruction of malaria-parasitized red blood cells despite spleen closure. Infect Immun 73:6390–6398

    Article  CAS  Google Scholar 

  • Kruecken J, Delic D, Pauen H, Wojtalla A, El-Khadragy M, Dkhil MA, Mossmann H, Wunderlich F (2009) Augmented partcle trapping and attenuated inflammation in the liver by protective vaccination against Plasmodium chabaudi malaria. Malar J 8:54–64

    Article  Google Scholar 

  • Langhorne J, Ndungu FM, Sponaas AM, Marsk K (2008) Immunity to malaria: more questions than answers. Nat Immunol 7:725–732

    Article  Google Scholar 

  • Lempiäinen H, Müller A, Brasa S, Teo SS, Roloff TC, Morawiec L, Zamurovic N, Vicart A, Funhoff E, Couttet P, Schübeler D, Grenet O, Marlowe J, Moggs J, Terranova R (2011) Phenobarbital mediates an epigenetic switch at the constitutive androstan receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice. Plos One 6(3):e18216

    Article  PubMed  Google Scholar 

  • Liang P, Song F, Ghosh S, Morien E, Qin M, Mahmood S, Fujiwara K, Igarashi J, Nagase H, Held WA (2011) Genome-wide survey reveals dynamic widespread tissue-specific changes in DNA methylation during development. BMC Genomics 12:231–247

    Article  PubMed  CAS  Google Scholar 

  • Liu Q, Tuo W, Gao H, Zhu XQ (2010) MicroRNAs of parasites: current status and future perspectives. Parasitol Res 107:501–507

    Article  PubMed  Google Scholar 

  • MacKinnon MJ, Read AF (2003) Virulence in malaria: an evolutionary viewpoint. Phil Trans R Soc Lond B Biol Sci 359:965–986

    Google Scholar 

  • Mannoor MK, Halder RC, Morshed SR, Ariyasinghe A, Bakir HY, Kawamura H, Watanabe H, Sekikawa H, Abo T (2002) Essential role of extrathymic T cells in protection against malaria. J Immunol 169:301–306

    PubMed  CAS  Google Scholar 

  • McCall CE, Yoza B, Liu T, El-gazzar M (2010) Gene-specific epigenetic regulation in serious infections with systemic inflammation. J Innate Immun 2:395–405

    Article  PubMed  Google Scholar 

  • Mehlhorn H (ed) (2008) Enzyclopedic reference of parasitology, vol 1, 3rd edn. Berlin, Springer

    Google Scholar 

  • Mertens I, ClinckspoorI JT, Nachman R, Schoofs L (2006) FMRFamide related peptide ligands activate the Caenorhabditis elegans orphan GPCR Y59H11AL.1. Peptides 27:1291–1296

    Article  PubMed  CAS  Google Scholar 

  • Mohn F, Weber M, Schübeler D, Roloff TC (2009) Methylated DNA immunoprecipitation (MeDIP). Meth Mol Biol 507:55–64

    Article  CAS  Google Scholar 

  • Moore LD, Le T, Fan G (2012) DNA methylation and its basic function. Neuropsychopharmacol 38:23–38

    Article  Google Scholar 

  • Muehlfeld S, Schmitt-Wrede HP, Harder A, Wunderlich F (2009) FMRFamide-like neuropeptides as putative ligands of the latrophilin-like HC110-R from Haemonchus contortus. Mol Biochem Parasitol 164(2):162–164

    Article  CAS  Google Scholar 

  • Murthi P, Kalionis B, Ghabrial H, Dunlop NE, Smallwood RA, Sewell RB (2006) Kupffer cell function during the erythrocytic stages of malaria. J Gastroenterol Hepatol 21:313–318

    Article  PubMed  CAS  Google Scholar 

  • Ndlovu MN, Denis H, Fuks F (2011) Exposing the DNA methylome iceberg. Trends Biochem Sci 36:381–387

    PubMed  CAS  Google Scholar 

  • Oliveira-Nascimento L, Massari P, Wetzler LM (2012) The role of TLR2 in infection and immunity. Front Immunol 3:1–17

    Article  Google Scholar 

  • Paschos K, Allday MJ (2010) Epigenetic reprogrammimg of host genes in viral and microbial pathogenesis. Trends Microbiol 18:439–447

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra K, Barik TK, Reddy BP, Sharma P, Dash AP (2011) Malaria vector control: from past to future. Parasitol Res 108:757–779

    Article  PubMed  Google Scholar 

  • Santourlidis S, Trompeter HI, Weinhold S, Eisermann B, Meyer KL, Wernet P, Uhrberg M (2002) Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells. J Immunol 15:4253–4261

    Google Scholar 

  • Santourlidis S, Wernet P, Ghanjati F, Graffmann N, Springer J, Kriegs C, Zhao X, Brands J, Arauzo-Bravo MJ, Neves R, Koegler G, Uhrberg M (2011) Unrestricted somatic stemm cells (USSC) from human umbilical cord blood display uncommitted epigenetic signatures of the major stem cell pluripotency genes. Stem Cell Res 6:60–69

    Article  PubMed  CAS  Google Scholar 

  • Shames DS, Minna JD, Gazdar AF (2007) DNA methylation in health, disease, and cancer. Curr Mol Med 7:85–102

    Article  PubMed  CAS  Google Scholar 

  • Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204–220

    Article  PubMed  CAS  Google Scholar 

  • Stein RA (2012) Epigenetics and environmental exposures. J Epidemiol Community Health 66:8–134

    Article  PubMed  Google Scholar 

  • Stephens R, Culleton RL, Lamb TJ (2011) The contribution of Plasmodium chabaudi to our understanding of malaria. Trends Parasitol 28:73–82

    Article  PubMed  Google Scholar 

  • Suarez-Alvarez B, Rodriguez RM, Fraga MF, Lopez-larrea C (2012) DNA methylation: a promising landscape for immune system-related diseases. Trens Genet 28:506–514

    Article  CAS  Google Scholar 

  • WHO (2010) World malaria report. World Health Organization, Geneva

    Google Scholar 

  • Wunderlich CM, Delic D, Behnke K, Ströhle P, Chaurasia B, Al-Quraishy S, Wunderlich F, Brüning JC, Wunderlich FT (2012) Cutting edge: inhibition of IL-6 trans-signalling protects from malaria-induced lethality in mice. J Immunol 188:4141–4144

    Article  PubMed  CAS  Google Scholar 

  • Wunderlich F, Dkhil M, Mehnert LI, Braun JV, El-Khadragy M, Borsch E, Hermsen D, Benten WPM, Pfeffer K, Mossmann H, Kruecken J (2005) Testosterone responsiveness of spleen and liver in female lymphotoxin b receptor-deficient mice resitant to blood-stage malaria. Microbes Infect 7:399–409

    Article  PubMed  CAS  Google Scholar 

  • Wunderlich F, Mossmann H, Helwig M, Schillinger G (1988) Resistance to Plasmodium chabaudi in B10 mice. Infect Immun 56:2400–2406

    PubMed  CAS  Google Scholar 

  • Wunderlich F, Stübig H, Königk E (1982) Dvelopment of Plasmodium chabaudi in mice red blood cells: Structural properties of the host and parasite membranes. J Protozool 29:60–66

    Article  PubMed  CAS  Google Scholar 

  • Yazdani SS, Mukherjee P, Chauhan VS, Chitnis CE (2006) Immune responses to asexual blood-stages of malaria parasites. Curr Mol Med 6:187–203

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Ho SM (2011) Epigenetics meets endocrinology. J Mol Endocrinol 46:R11–R32

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, Tang H, Wang Z, Zhang B, Liu W, Lu H, Xiao L, Liu X, Wnag R, Li X, Wu M, Li G (2011) MiR-185 targets the DNA methyltransferases 1 and regulates global DNA methylation in human glioma. Mol Cancer 10:124–140

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. MJ Arauzo-Bravo for expert advice in bioinformatic evaluation of differential DNA methylation. This research was supported by King Saud University, National Program for Science and Technology, through grant no. 10-BIO1212-02.

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Authors and Affiliations

  1. Department of Zoology, College of Science, King Saud University, P.O. Box: 2455, Riyadh, 11451, Saudi Arabia

    Saleh Al-Quraishy, Mohamed A. Dkhil & Abdel Azeem S. Abdel-Baki

  2. Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt

    Mohamed A. Dkhil

  3. Zoology, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt

    Abdel Azeem S. Abdel-Baki

  4. Molecular Parasitology, Heinrich-Heine-University, Duesseldorf, Germany

    Denis Delic & Frank Wunderlich

  5. Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-University, Duesseldorf, Germany

    Simeon Santourlidis

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  1. Saleh Al-Quraishy
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  2. Mohamed A. Dkhil
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  3. Abdel Azeem S. Abdel-Baki
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  6. Frank Wunderlich
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Correspondence to Saleh Al-Quraishy.

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Al-Quraishy, S., Dkhil, M.A., Abdel-Baki, A.A.S. et al. Genome-wide screening identifies Plasmodium chabaudi-induced modifications of DNA methylation status of Tlr1 and Tlr6 gene promoters in liver, but not spleen, of female C57BL/6 mice. Parasitol Res 112, 3757–3770 (2013). https://doi.org/10.1007/s00436-013-3565-2

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