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Reduced interferon (IFN)-α conditioned by IFNA2 (−173) and IFNA8 (−884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality

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Abstract

Severe malarial anemia (SMA) is a leading cause of pediatric morbidity and mortality in holoendemic Plasmodium falciparum transmission areas. Although dysregulation in cytokine production is an important etiology of SMA, the role of IFN-α in SMA has not been reported. As such, we investigated the relationship between IFN-α promoter polymorphisms [i.e., IFNA2 (A-173T) and IFNA8 (T-884A)], SMA, and functional changes in IFN-α production in children (n = 663; <36 months) residing in a holoendemic P. falciparum transmission region of Kenya. Children with SMA had lower circulating IFN-α than malaria-infected children without severe anemia (P = 0.025). Multivariate logistic regression analyses revealed that heterozygosity at −884 (TA) was associated with an increased risk of SMA [OR 2.80 (95 % CI 1.22–6.43); P = 0.015] and reduced IFN-α relative to wild type (TT; P = 0.038). Additional analyses demonstrated that carriage of the −173T/−884A (TA) haplotype was associated with increased susceptibility to SMA [OR 3.98 (95 % CI 1.17–13.52); P = 0.026] and lower IFN-α (P = 0.031). Follow-up of these children for 36 months revealed that carriers of TA haplotype had greater all-cause mortality than non-carriers (P < 0.001). Generation of reporter constructs showed that the IFNA8 wild-type −884TT exhibited higher levels of luciferase expression than the variant alleles (P < 0.001). Analyses of malaria-associated inflammatory mediators demonstrated that carriers of TA haplotype had altered production of IL-1β, MIG, and IL-13 compared to non-carriers (P < 0.050). Thus, variation at IFNA2 −173 and IFNA8 −884 conditions reduced IFN-α production, and increased susceptibility to SMA and mortality.

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References

  • Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V (2002) Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359:1311–1312

    Article  PubMed  CAS  Google Scholar 

  • Anstey NM, Boutlis CS, Saunders JR (2002) Systemic nitric oxide production in human malaria. I. Analysis of NO metabolites in biological fluids. Methods Mol Med 72:461–467

    PubMed  CAS  Google Scholar 

  • Anyona SB, Kempaiah P, Raballah E, Ouma C, Were T, Davenport GC, Konah SN, Vulule JM, Hittner JB, Gichuki CW, Ong’echa JM, Perkins DJ (2011) Functional promoter haplotypes of interleukin-18 condition susceptibility to severe malarial anemia and childhood mortality. Infect Immun 79:4923–4932

    Article  PubMed  CAS  Google Scholar 

  • Awandare GA, Kempaiah P, Ochiel DO, Piazza P, Keller CC, Perkins DJ (2011) Mechanisms of erythropoiesis inhibition by malarial pigment and malaria-induced proinflammatory mediators in an in vitro model. Am J Hematol 86:155–162

    Article  PubMed  CAS  Google Scholar 

  • Beier JC, Oster CN, Onyango FK, Bales JD, Sherwood JA, Perkins PV, Chumo DK, Koech DV, Whitmire RE, Roberts CR et al (1994) Plasmodium falciparum incidence relative to entomologic inoculation rates at a site proposed for testing malaria vaccines in western Kenya. Am J Trop Med Hyg 50:529–536

    PubMed  CAS  Google Scholar 

  • Beilharz MW, McDonald W, Watson MW, Heng J, McGeachie J, Lawson CM (1997) Low-dose oral type I interferons reduce early virus replication of murine cytomegalovirus in vivo. J Interf Cytokine Res 17:625–630

    Article  CAS  Google Scholar 

  • Bekisz J, Schmeisser H, Hernandez J, Goldman ND, Zoon KC (2004) Human interferons alpha, beta and omega. Growth Factors 22:243–251

    Article  PubMed  CAS  Google Scholar 

  • Biron CA (1999) Initial and innate responses to viral infections—pattern setting in immunity or disease. Curr Opin Microbiol 2:374–381

    Article  PubMed  CAS  Google Scholar 

  • Biron CA (2001) Interferons alpha and beta as immune regulators: a new look. Immunity 14:661–664

    Article  PubMed  CAS  Google Scholar 

  • Bloland PB, Ruebush TK, McCormick JB, Ayisi J, Boriga DA, Oloo AJ, Beach R, Hawley W, Lal A, Nahlen B, Udhayakumar V, Campbell CC (1999) Longitudinal cohort study of the epidemiology of malaria infections in an area of intense malaria transmission I. Description of study site, general methodology, and study population. Am J Trop Med Hyg 60:635–640

    PubMed  CAS  Google Scholar 

  • Bogdan C (2000) The function of type I interferons in antimicrobial immunity. Curr Opin Immunol 12:419–424

    Article  PubMed  CAS  Google Scholar 

  • Brabin BJ, Hakimi M, Pelletier D (2001) An analysis of anemia and pregnancy-related maternal mortality. J Nutr 131:604S–614S discussion 614S-615S

    PubMed  CAS  Google Scholar 

  • Brinkmann V, Geiger T, Alkan S, Heusser CH (1993) Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells. J Exp Med 178:1655–1663

    Article  PubMed  CAS  Google Scholar 

  • CHIP_bioinformatics. http://snpper.chip.org/bio/snpper-enter

  • Court M (2008) http://www.tufts.edu/~mcourt01/Documents/Court%20lab%20-%20HW%20calculator.xls

  • Ferbas JJ, Toso JF, Logar AJ, Navratil JS, Rinaldo CR Jr (1994) CD4+ blood dendritic cells are potent producers of IFN-alpha in response to in vitro HIV-1 infection. J Immunol 152:4649–4662

    PubMed  CAS  Google Scholar 

  • Foster GR, Rodrigues O, Ghouze F, Schulte-Frohlinde E, Testa D, Liao MJ, Stark GR, Leadbeater L, Thomas HC (1996) Different relative activities of human cell-derived interferon-alpha subtypes: IFN-alpha 8 has very high antiviral potency. J Interf Cytokine Res 16:1027–1033

    CAS  Google Scholar 

  • Francis ML, Fan XS, Meltzer MS (1996) Loss ability to produce IFN-alpha in response to HIV-1 as monocytes differentiate into macrophages. Induction through a mechanism independent of double-stranded RNA. J Immunol 156:2481–2487

    PubMed  CAS  Google Scholar 

  • Garcia JC, Ariza AM, Lasa AM, Gonzalez LJ, Perez VB (2007) Increased antiviral activity of microscale-purified HuIFN alpha 8 (human interferon alpha 8) over HuIFN alpha 2b in Hep-2 cells challenged with Mengo virus. Biotechnol Appl Biochem 48:159–165

    Article  PubMed  CAS  Google Scholar 

  • Gaunt TRRS, Zapata C, Day IN (2006) MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers. BMC Bioinf 7:227

    Article  Google Scholar 

  • Hamel MJ, Adazu K, Obor D, Sewe M, Vulule J, Williamson JM, Slutsker L, Feikin DR, Laserson KF (2011) A reversal in reductions of child mortality in western Kenya, 2003–2009. Am J Trop Med Hyg 85:597–605

    Article  PubMed  Google Scholar 

  • Havell EA, Hayes TG, Vilcek J (1978) Synthesis of two distinct interferons by human fibroblasts. Virology 89:330–334

    Article  PubMed  CAS  Google Scholar 

  • Izaguirre A, Barnes BJ, Amrute S, Yeow WS, Megjugorac N, Dai J, Feng D, Chung E, Pitha PM, Fitzgerald-Bocarsly P (2003) Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells. J Leukoc Biol 74:1125–1138

    Article  PubMed  CAS  Google Scholar 

  • Keller CC, Kremsner PG, Hittner JB, Misukonis MA, Weinberg JB, Perkins DJ (2004) Elevated nitric oxide production in children with malarial anemia: hemozoin-induced nitric oxide synthase type 2 transcripts and nitric oxide in blood mononuclear cells. Infect Immun 72:4868–4873

    Article  PubMed  CAS  Google Scholar 

  • Keller CCOC, Ouma Y, Awandare GA, Davenport GC, Were T, Hittner JB, Vulule JM, Ong’echa JM, Perkins DJ (2009a) Suppression of a novel hematopoietic mediator in children with severe malarial anemia. Infect Immun 77(9):3864–3871

    Article  PubMed  CAS  Google Scholar 

  • Keller CC, Ouma C, Ouma Y, Awandare GA, Davenport GC, Were T, Hittner JB, Vulule JM, Ong’echa JM, Perkins DJ (2009b) Suppression of a novel hematopoietic mediator in children with severe malarial anemia. Infect Immun 77(9):3864–3871

    Article  PubMed  CAS  Google Scholar 

  • Kun JF, Mordmuller B, Perkins DJ, May J, Mercereau-Puijalon O, Alpers M, Weinberg JB, Kremsner PG (2001) Nitric oxide synthase 2(Lambarene) (G-954C), increased nitric oxide production, and protection against malaria. J Infect Dis 184:330–336

    Article  PubMed  CAS  Google Scholar 

  • Kurtzhals JA, Rodrigues O, Addae M, Commey JO, Nkrumah FK, Hviid L (1997) Reversible suppression of bone marrow response to erythropoietin in Plasmodium falciparum malaria. Br J Haematol 97:169–174

    Article  PubMed  CAS  Google Scholar 

  • Kwiatkowski DP (2005) How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77:171–192

    Article  PubMed  CAS  Google Scholar 

  • Luty AJ, Perkins DJ, Lell B, Schmidt-Ott R, Lehman LG, Luckner D, Greve B, Matousek P, Herbich K, Schmid D, Weinberg JB, Kremsner PG (2000) Low interleukin-12 activity in severe Plasmodium falciparum malaria. Infect Immun 68:3909–3915

    Article  PubMed  CAS  Google Scholar 

  • Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483

    Article  PubMed  CAS  Google Scholar 

  • McElroy PD, Lal AA, Hawley WA, Bloland PB, Kuile FO, Oloo AJ, Harlow SD, Lin X, Nahlen BL (1999) Analysis of repeated hemoglobin measures in full-term, normal birth weight Kenyan children between birth and four years of age. III. The Asemobo Bay Cohort Project. Am J Trop Med Hyg 61:932–940

    PubMed  CAS  Google Scholar 

  • McElroy PD, ter Kuile FO, Lal AA, Bloland PB, Hawley WA, Oloo AJ, Monto AS, Meshnick SR, Nahlen BL (2000) Effect of Plasmodium falciparum parasitemia density on hemoglobin concentrations among full-term, normal birth weight children in western Kenya, IV. The Asembo Bay Cohort Project. Am J Trop Med Hyg 62:504–512

    PubMed  CAS  Google Scholar 

  • Mori S, Jewett A, Cavalcanti M, Murakami-Mori K, Nakamura S, Bonavida B (1998) Differential regulation of human NK cell-associated gene expression following activation by IL-2, IFN-alpha and PMA/ionomycin. Int J Oncol 12:1165–1170

    PubMed  CAS  Google Scholar 

  • Muasya T, Lore W, Yano K, Yatsuhashi H, Owiti FR, Fukuda M, Tamada MY, Kulundu J, Tukei J, Okoth FA (2008) Prevalence of hepatitis C virus and its genotypes among a cohort of drug users in Kenya. East Afr Med J 85:318–325

    PubMed  CAS  Google Scholar 

  • Muller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M (1994) Functional role of type I and type II interferons in antiviral defense. Science 264:1918–1921

    Article  PubMed  CAS  Google Scholar 

  • Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, Fullman N, Naghavi M, Lozano R, Lopez AD (2012) Global malaria mortality between 1980 and 2010: a systematic analysis. The Lancet 379:413–431

    Article  Google Scholar 

  • NCBI_refSNP. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=16938369and1096498

  • Ndiritu M, Cowgill KD, Ismail A, Chiphatsi S, Kamau T, Fegan G, Feikin DR, Newton CR, Scott JA (2006) Immunization coverage and risk factors for failure to immunize within the expanded programme on immunization in Kenya after introduction of new Haemophilus influenzae type b and hepatitis b virus antigens. BMC Public Health 6:132

    Article  PubMed  Google Scholar 

  • Novelli EM, Hittner JB, Davenport GC, Ouma C, Were T, Obaro S, Kaplan S, Ong’echa JM, Perkins DJ (2010) Clinical predictors of severe malarial anaemia in a holoendemic Plasmodium falciparum transmission area. Br J Haematol 149:711–721

    Article  PubMed  Google Scholar 

  • Obonyo CO, Steyerberg EW, Oloo AJ, Habbema JD (1998) Blood transfusions for severe malaria-related anemia in Africa: a decision analysis. Am J Trop Med Hyg 59:808–812

    PubMed  CAS  Google Scholar 

  • Okwara FN, Obimbo EM, Wafula EM, Murila FV (2004) Bacteraemia, urinary tract infection and malaria in hospitalised febrile children in Nairobi: is there an association? East Afr Med J 81:47–51

    PubMed  CAS  Google Scholar 

  • Ong’echa JM, Davenport G, Vulule JM, Hittner JB, Perkins DJ (2011) Identification of inflammatory biomarkers for pediatric malarial anemia severity using novel statistical methods. Infect Immun (Epub ahead of print)

  • Ong’echa JM, Keller CC, Were T, Ouma C, Otieno RO, Landis-Lewis Z, Ochiel D, Slingluff JL, Mogere S, Ogonji GA, Orago AS, Vulule JM, Kaplan SS, Day RD, Perkins DJ (2006) Parasitemia, anemia, and malarial anemia in infants and young children in a rural holoendemic Plasmodium falciparum transmission area. Am J Trop Med Hyg 74:376–385

    PubMed  Google Scholar 

  • Ong’echa JM, Davenport GC, Vulule JM, Hittner JB, Perkins DJ (2011) Identification of inflammatory biomarkers for pediatric malarial anemia severity using novel statistical methods. Infect Immun (Epub ahead of print)

  • Othoro C, Lal AA, Nahlen B, Koech D, Orago AS, Udhayakumar V (1999) A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. J Infect Dis 179:279–282

    Article  PubMed  CAS  Google Scholar 

  • Otieno RO, Ouma C, Ong’echa JM, Keller CC, Were T, Waindi EN, Michaels MG, Day RD, Vulule JM, Perkins DJ (2006) Increased severe anemia in HIV-1-exposed and HIV-1-positive infants and children during acute malaria. AIDS 20:275–280

    Article  PubMed  Google Scholar 

  • Ouma C, Keller CC, Opondo DA, Were T, Otieno RO, Otieno MF, Orago AS, Ong’Echa JM, Vulule JM, Ferrell RE, Perkins DJ (2006) Association of FCgamma receptor IIA (CD32) polymorphism with malarial anemia and high-density parasitemia in infants and young children. Am J Trop Med Hyg 74:573–577

    PubMed  CAS  Google Scholar 

  • Ouma C, Davenport GC, Awandare GA, Keller CC, Were T, Otieno MF, Vulule JM, Martinson J, Ong’echa JM, Ferrell RE, Perkins DJ (2008) Polymorphic variability in the interleukin (IL)-1beta promoter conditions susceptibility to severe malarial anemia and functional changes in IL-1beta production. J Infect Dis 198:1219–1226

    Article  PubMed  CAS  Google Scholar 

  • Ouma C, Keller CC, Davenport GC, Were T, Konah S, Otieno MF, Hittner JB, Vulule JM, Martinson J, Ong’echa JM, Ferrell RE, Perkins DJ (2010) A novel functional variant in the stem cell growth factor promoter protects against severe malarial anemia. Infect Immun 78:453–460

    Article  PubMed  CAS  Google Scholar 

  • Perkins DJ, Kremsner PG, Schmid D, Misukonis MA, Kelly MA, Weinberg JB (1999) Blood mononuclear cell nitric oxide production and plasma cytokine levels in healthy Gabonese children with prior mild or severe malaria. Infect Immun 67:4977–4981

    PubMed  CAS  Google Scholar 

  • Perkins DJ, Were T, Davenport GC, Kempaiah P, Hittner JB, Ong’echa JM (2011) Severe malarial anemia: innate immunity and pathogenesis. Int J Biol Sci 7:1427–1442

    Article  PubMed  CAS  Google Scholar 

  • Sakamoto O, Hashiyama M, Minty A, Ando M, Suda T (1995) Interleukin-13 selectively suppresses the growth of human macrophage progenitors at the late stage. Blood 85:3487–3493

    PubMed  CAS  Google Scholar 

  • Samuel CE (2001) Antiviral actions of interferons. Clin Microbiol Rev 14:778–809

    Article  PubMed  CAS  Google Scholar 

  • Seto MH, Harkins RN, Adler M, Whitlow M, Church WB, Croze E (1995) Homology model of human interferon-alpha 8 and its receptor complex. Protein Sci 4:655–670

    Article  PubMed  CAS  Google Scholar 

  • Song IH, Toan NL, Xuan NT, Uhlemann AC, Boldt AB, Duy DN, Binh VQ, Kremsner PG, Kun JF (2006) A promoter polymorphism in the interferon alpha-2 gene is associated with the clinical presentation of hepatitis B. Mutat Res 601:137–143

    Article  CAS  Google Scholar 

  • Taylor JL, Grossberg SE (1998) The effects of interferon-alpha on the production and action of other cytokines. Semin Oncol 25:23–29

    PubMed  CAS  Google Scholar 

  • Tena-Tomas C, de Messias-Reason I, le Song H, Tomiuk J, Kemsner PG, Kun JF (2008) A globally occurring indel polymorphism in the promoter of the IFNA2 gene is not associated with severity of malaria but with the positivity rate of HCV. BMC Genet 9:80

    Article  PubMed  Google Scholar 

  • Vigario AM, Belnoue E, Cumano A, Marussig M, Miltgen F, Landau I, Mazier D, Gresser I, Renia L (2001) Inhibition of Plasmodium yoelii blood-stage malaria by interferon alpha through the inhibition of the production of its target cell, the reticulocyte. Blood 97:3966–3971

    Article  PubMed  CAS  Google Scholar 

  • Vigario AM, Belnoue E, Gruner AC, Mauduit M, Kayibanda M, Deschemin JC, Marussig M, Snounou G, Mazier D, Gresser I, Renia L (2007) Recombinant human IFN-alpha inhibits cerebral malaria and reduces parasite burden in mice. J Immunol 178:6416–6425

    PubMed  CAS  Google Scholar 

  • Vilcek J (2006) Fifty years of interferon research: aiming at a moving target. Immunity 25:343–348

    Article  PubMed  CAS  Google Scholar 

  • Were T, Hittner JB, Ouma C, Otieno RO, Orago AS, Ong’echa JM, Vulule JM, Keller CC, Perkins DJ (2006) Suppression of RANTES in children with Plasmodium falciparum malaria. Haematologica 91:1396–1399

    PubMed  CAS  Google Scholar 

  • Were T, Davenport GC, Yamo EO, Hittner JB, Awandare GA, Otieno MF, Ouma C, Orago AS, Vulule JM, Ong’echa JM, Perkins DJ (2009) Naturally acquired hemozoin by monocytes promotes suppression of RANTES in children with malarial anemia through an IL-10-dependent mechanism. Microbes Infect 11:811–819

    Article  PubMed  CAS  Google Scholar 

  • Were T, Davenport GC, Hittner JB, Ouma C, Vulule JM, Ong’echa JM, Perkins DJ (2011) Bacteremia in Kenyan children presenting with malaria. J Clin Microbiol 49:671–676

    Article  PubMed  CAS  Google Scholar 

  • WHO (2000) Centers for Disease Control and Prevention. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94:S1–S90

    Google Scholar 

  • Wickramasinghe SN, Abdalla SH (2000) Blood and bone marrow changes in malaria. Baillieres Best Pract Res Clin Haematol 13:277–299

    Article  PubMed  CAS  Google Scholar 

  • Xi X, Schlegel N, Caen JP, Minty A, Fournier S, Caput D, Ferrara P, Han ZC (1995) Differential effects of recombinant human interleukin-13 on the in vitro growth of human haemopoietic progenitor cells. Br J Haematol 90:921–927

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Institutes of Health Research Grants R01AI51305 and D43TW05884 (DJP). The authors gratefully acknowledge the assistance of the Siaya District Hospital team and the University of New Mexico/KEMRI staff for all the clinical support. We are very grateful to all the parents, guardians, and children who participated in the study. The authors sincerely thank the Director of Kenya Medical Research Institute for approving the data to be published in the study.

Conflict of interest

The authors have declared that no competing interests exist.

Ethical standard

The study was approved by the ethical and scientific review committees at the University of Pittsburgh and University of New Mexico and the Kenya Medical Research Institute.

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Authors and Affiliations

  1. Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, MSC10-5550, Albuquerque, NM, 87131-0001, USA

    Prakasha Kempaiah, Gregory C. Davenport, John M. Ong’echa & Douglas J. Perkins

  2. University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Kisumu, Kenya

    Samuel B. Anyona, Evans Raballah, Tom Were, John M. Ong’echa & Douglas J. Perkins

  3. Department of Pathology, Kenyatta University, Nairobi, Kenya

    Tom Were

  4. Department of Psychology, College of Charleston, Charleston, SC, USA

    James B. Hittner

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  1. Prakasha Kempaiah
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  2. Samuel B. Anyona
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  3. Evans Raballah
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Kempaiah, P., Anyona, S.B., Raballah, E. et al. Reduced interferon (IFN)-α conditioned by IFNA2 (−173) and IFNA8 (−884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality. Hum Genet 131, 1375–1391 (2012). https://doi.org/10.1007/s00439-012-1175-1

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