Abstract
Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism in the MTHFR gene (677C → T) results in reduced enzymatic activity, and is associated with an increased risk for neural tube defects and cardiovascular disease. The high prevalence of this polymorphism suggests that it may have experienced a selective advantage under environmental pressure, possibly an infectious agent. To test the hypothesis that methylenetetrahydrofolate reductase (MTHFR) genotype influences the outcome of infectious disease, we examined the response of Mthfr-deficient mice against mouse cytomegalovirus (MCMV) infection. Acute MCMV infection of Mthfr−/− mice resulted in early control of cytokine secretion, decreased viral titer and preservation of spleen immune cells, in contrast to Mthfr wild-type littermates. The phenotype was abolished in MTHFR transgenic mice carrying an extra copy of the gene. Infection of primary fibroblasts with MCMV showed a decrease in viral replication and in the number of productively infected cells in Mthfr+/− fibroblasts compared with wild-type cells. These results indicate that Mthfr deficiency protects against MCMV infection in vivo and in vitro, suggesting that human genetic variants may provide an advantage in the host response against certain pathogens.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Stanger O . Physiology of folic acid in health and disease. Curr Drug Metab 2002; 3: 211–223.
Goyette P, Christensen B, Rosenblatt DS, Rozen R . Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet 1996; 59: 1268–1275.
Goyette P, Frosst P, Rosenblatt DS, Rozen R . Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet 1995; 56: 1052–1059.
Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG et al. Human methylenetetrahydrofolate reductase: Isolation of cDNA, mapping and mutation identification. Nat Genet 1994; 7: 195–200.
Gueant-Rodriguez RM, Gueant JL, Debard R, Thirion S, Hong LX, Bronowicki JP et al. Prevalence of methylenetetrahydrofolate reductase 677 T and 1298C alleles and folate status: A comparative study in Mexican, West African, and European populations. Am J Clin Nutr 2006; 83: 701–707.
Schneider JA, Rees DC, Liu YT, Clegg JB . Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet 1998; 62: 1258–1260.
Weisberg I, Tran P, Christensen B, Sibani S, Rozen R . A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998; 64: 169–172.
Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML . The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol 1999; 6: 359–365.
van der Put NM, van den Heuvel LP, Steegers-Theunissen RP, Trijbels FJ, Eskes TK, Mariman EC et al. Decreased methylene tetrahydrofolate reductase activity due to the 677C-->T mutation in families with spina bifida offspring. J Mol Med 1996; 74: 691–694.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.
Pouniotis DS, Proudfoot O, Minigo G, Hanley JL, Plebanski M . Malaria parasite interactions with the human host. J Postgrad Med 2004; 50: 30–34.
Bronowicki JP, Abdelmouttaleb I, Peyrin-Biroulet L, Venard V, Khiri H, Chabi N et al. Methylenetetrahydrofolate reductase 677T allele protects against persistent HBV infection in West Africa. J Hepatol 2008; 48: 532–539.
Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-Cacan S et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 2001; 10: 433–443.
Celtikci B, Leclerc D, Lawrance AK, Deng L, Friedman HC, Krupenko NI et al. Altered expression of methylenetetrahydrofolate reductase modifies response to methotrexate in mice. Pharmacogenet Genomics 2008; 18: 577–589.
McGeoch DJ, Rixon FJ, Davison AJ . Topics in herpesvirus genomics and evolution. Virus Res 2006; 117: 90–104.
Vancikova Z, Dvorak P . Cytomegalovirus infection in immunocompetent and immunocompromised individuals--a review. Curr Drug Targets Immune Endocr Metabol Disord 2001; 1: 179–187.
Reddehase MJ, Podlech J, Grzimek NK . Mouse models of cytomegalovirus latency: Overview. J Clin Virol 2002; 25 (Suppl 2): S23–S36.
Lembo D, Gribaudo G, Cavallo R, Riera L, Angeretti A, Hertel L et al. Human cytomegalovirus stimulates cellular dihydrofolate reductase activity in quiescent cells. Intervirology 1999; 42: 30–36.
Gribaudo G, Riera L, Lembo D, De Andrea M, Gariglio M, Rudge TL et al. Murine cytomegalovirus stimulates cellular thymidylate synthase gene expression in quiescent cells and requires the enzyme for replication. J Virol 2000; 74: 4979–4987.
Krmpotic A, Bubic I, Polic B, Lucin P, Jonjic S . Pathogenesis of murine cytomegalovirus infection. Microbes Infect 2003; 5: 1263–1277.
Smith HR, Heusel JW, Mehta IK, Kim S, Dorner BG, Naidenko OV et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci USA 2002; 99: 8826–8831.
Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL . Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 2002; 296: 1323–1326.
Bekiaris V, Timoshenko O, Hou TZ, Toellner K, Shakib S, Gaspal F et al. Ly49H+ NK cells migrate to and protect splenic white pulp stroma from murine cytomegalovirus infection. J Immunol 2008; 180: 6768–6776.
Fodil-Cornu N, Lee SH, Belanger S, Makrigiannis AP, Biron CA, Buller RM et al. Ly49h-deficient C57BL/6 mice: A new mouse cytomegalovirus-susceptible model remains resistant to unrelated pathogens controlled by the NK gene complex. J Immunol 2008; 181: 6394–6405.
Hahm B, Trifilo MJ, Zuniga EI, Oldstone MB . Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling. Immunity 2005; 22: 247–257.
McNally JM, Zarozinski CC, Lin MY, Brehm MA, Chen HD, Welsh RM . Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses. J Virol 2001; 75: 5965–5976.
Robbins SH, Bessou G, Cornillon A, Zucchini N, Rupp B, Ruzsics Z et al. Natural killer cells promote early CD8 T cell responses against cytomegalovirus. PLoS Pathog 2007; 3: e123.
Wheat RL, Clark PY, Brown MG . Quantitative measurement of infectious murine cytomegalovirus genomes in real-time PCR. J Virol Methods 2003; 112: 107–113.
Pinto AK, Hill AB . Viral interference with antigen presentation to CD8+ T cells: Lessons from cytomegalovirus. Viral Immunol 2005; 18: 434–444.
Depatie C, Lee SH, Stafford A, Avner P, Belouchi A, Gros P et al. Sequence-ready BAC contig, physical, and transcriptional map of a 2-Mb region overlapping the mouse chromosome 6 host-resistance locus Cmv1. Genomics 2000; 66: 161–174.
Ishikawa R, Biron CA . IFN induction and associated changes in splenic leukocyte distribution. J Immunol 1993; 150: 3713–3727.
Acknowledgements
We are grateful to Nadia Prud’homme for technical assistance and Gregory Boivin for critical review of the text. This work was supported by the Canadian Institutes of Health Research MOP-7781 (SMV) and MOP-4232 (RR).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)
Supplementary information
Rights and permissions
About this article
Cite this article
Fodil-Cornu, N., Kozij, N., Wu, Q. et al. Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection. Genes Immun 10, 662–666 (2009). https://doi.org/10.1038/gene.2009.50
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gene.2009.50
Keywords
This article is cited by
-
Infection risk in Rheumatoid Arthritis and Spondyloarthropathy patients under treatment with DMARDs, Corticosteroids and TNF-α antagonists
Journal of Translational Medicine (2014)
-
The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D)
Molecular Psychiatry (2013)