Genetic Diversity in Cytokines Associated with Immune Variation and Resistance to Multiple Pathogens in a Natural Rodent Population

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Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex (MHC); the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations. Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles (Microtus agrestis) to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species. By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes (Interleukin 1 beta (Il1b), Il2, and Il12b), rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci. The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations. Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans.

Vyšlo v časopise: Genetic Diversity in Cytokines Associated with Immune Variation and Resistance to Multiple Pathogens in a Natural Rodent Population. PLoS Genet 7(10): e32767. doi:10.1371/journal.pgen.1002343
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002343

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Zdroje

1. SommerS 2005 The importance of immune gene variability (MHC) in evolutionary ecology and conservation. Frontiers in Zoology 2 16

2. PiertneySBOliverMK 2006 The evolutionary ecology of the major histocompatibility complex. Heredity 96 7 21

3. JepsonABanyaWSisay-JoofFHassan-KingMNunesC 1997 Quantification of the relative contribution of major histocompatibility complex (MHC) and non-MHC genes to human immune responses to foreign antigens. Infection and Immunity 65 872 876

4. Acevedo-WhitehouseKCunninghamAA 2006 Is MHC enough for understanding wildlife immunogenetics? Trends in Ecology and Evolution 21 433 438

5. HillAVS 2001 The genomics and genetics of human infectious disease susceptibility. Annual Review of Genomics and Human Genetics 2 373 400

6. HollegaardMVBidwellJL 2006 Cytokine gene polymorphism in human disease: On-line databases, Supplement 3. Genes and Immunity 7 269 276

7. OllierWER 2004 Cytokine genes and disease susceptibility. Cytokine 28 174 178

8. de KoningD-JArchibaldAHaleyCS 2007 Livestock genomics: bridging the gap between mice and men. Trends in Biotechnology 25 483 489

9. GrenfellBTAmosWArnebergPBjørnstadONGreenmanJV 2002 Visions for future research in wildlife epidemiology. HudsonPJRizzoliAGrenfellBTHeesterbeekHDobsonAP The Ecology of Wildlife Diseases Oxford Oxford University Press 151 164

10. TelferSLambinXBirtlesRBeldomenicoPBurtheS 2010 Species interactions in a parasite community drive infection risk in a wildlife population. Science 330 243 246

11. CleavelandSHessGRDobsonAPLaurensonMKMcCallumHI 2002 The role of pathogens in biological conservation. HudsonPJRizzoliAGrenfellBTHeesterbeekHDobsonAP The Ecology of Wildlife Diseases Oxford Oxford University Press 139 150

12. GrahamALCattadoriIMLloyd-SmithJOFerrariMJBjørnstadON 2007 Transmission consequences of coinfection: cytokines writ large? Trends in Parasitology 23 284 291

13. KourilskyPTruffa-BachiP 2001 Cytokine fields and the polarization of the immune response. Trends in Immunology 22 502 509

14. GomezLMCamargoJFCastiblancoJRuiz-NarváezEACadenaJ 2006 Analysis of IL1B, TAP1, TAP2 and IKBL polymorphisms on susceptibility to tuberculosis. Tissue Antigens 67 290 296

15. Van DeventerSJH 2000 Cytokine and cytokine receptor polymorphisms in infectious disease. Intensive Care Medicine 26 Supplement 1 S98 S102

16. RomaniLPuccettiPBistoniF 1997 Interleukin-12 in infectious diseases. Clinical Microbiology Reviews 10 611 636

17. SmithAJPHumphriesSE 2009 Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine & Growth Factor Reviews 20 43 59

18. ReedSG 1999 TGF-β in infections and infectious diseases. Microbes and Infection 1 1313 1325

19. BayleyJPOttenhoffTHMVerweijCL 2004 Is there a future for TNF promoter polymorphisms? Genes and Immunity 5 315 329

20. KelsoA 1998 Cytokines: Principles and prospects. Immunology & Cell Biology 76 300 317

21. AllenJEMaizelsRM 2011 Diversity and dialogue in immunity to helminths. Nature Reviews Immunology 11 375 388

22. VineyMERileyEMBuchananKL 2005 Optimal immune responses: Immunocompetence revisited. Trends in Ecology and Evolution 20 665 669

23. CharbonnelNGoüy de BellocqJMorandS 2006 Immunogenetics of micromammalmacroparasite interactions Micromammals and Macroparasites 401 442

24. AbbasAKMurphyKMSherA 1996 Functional diversity of helper T lymphocytes. Nature 383 787 793

25. BradleyJEJacksonJA 2008 Measuring immune system variation to help understand host-pathogen community dynamics. Parasitology 135 807 823

26. ColtmanDWWilsonKPilkingtonJGStearMJPembertonJM 2001 A microsatellite polymorphism in the gamma interferon gene is associated with resistance to gastrointestinal nematodes in a naturally-parasitized population of Soay sheep. Parasitology 122 571 582

27. EzenwaVOEtienneRSLuikartGBeja-PereiraAJollesAE 2010 Hidden consequences of living in a wormy world: Nematode-induced immune suppression facilitates tuberculosis invasion in African buffalo. American Naturalist 176 613 624

28. JacksonJABegonMBirtlesRPatersonSFribergIM 2011 The analysis of immunological profiles in wild animals: a case study on immunodynamics in the field vole, Microtus agrestis. Molecular Ecology 20 893 909

29. MarquetSDoumboOCabantousSPoudiougouBArgiroL 2008 A functional promoter variant in IL12B predisposes to cerebral malaria. Human Molecular Genetics 17 2190 2195

30. ComingsDEMacMurrayJP 2000 Molecular heterosis: A review. Molecular Genetics and Metabolism 71 19 31

31. RidruechaiCMahasirimongkolSPhromjaiJYanaiHNishidaN 2010 Association analysis of susceptibility candidate region on chromosome 5q31 for tuberculosis. Genes and Immunity 11 416 422

32. BorishLCSteinkeJW 2003 2. Cytokines and chemokines. Journal of Allergy and Clinical Immunology 111 S460 S475

33. SteinkeJWBorishL 2006 3. Cytokines and chemokines. Journal of Allergy and Clinical Immunology 117 S441 S445

34. TurnerAK 2010 Immunogenetics and polymorphism in a natural population of field voles. PhD Thesis: University of Liverpool, UK. Accessible at http://research-archive.liv.ac.uk/1468/

35. KasteleinRAHunterCACuaDJ 2007 Discovery and Biology of IL-23 and IL-27: Related but Functionally Distinct Regulators of Inflammation. Annual Review of Immunology 25 221 242

36. WeaverCTHarringtonLEManganPRGavrieliMMurphyKM 2006 Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties. Immunity 24 677 688

37. BlackWCBaerCFAntolinMFDuTeauNM 2001 Population genomics: Genome-wide sampling of insect populations Annual Review of Entomology 441 469

38. RoffDABenediktHBrianKH 2005 Variation and Life-History Evolution. Variation Burlington Academic Press 333 357

39. RoseMR 1982 Antagonistic pleiotropy, dominance, and genetic variation1. Heredity 48 63 78

40. CorwinEJ 2000 Understanding cytokines. Part I: Physiology and mechanism of action. Biological research for nursing 2 30 40

41. DowningTLloydATO'FarrellyCBradleyDG 2010 The Differential Evolutionary Dynamics of Avian Cytokine and TLR Gene Classes. Journal of Immunology 184 6993 7000

42. DeanMCarringtonMO'BrienSJ 2002 Balanced polymorphism selected by genetic versus infectious human disease. Annual Review of Genomics and Human Genetics 3 263 292

43. GrahamALAllenJEReadAF 2005 Evolutionary causes and consequences of immunopathology Annual Review of Ecology, Evolution, and Systematics 373 397

44. CouperKNBlountDGRileyEM 2008 IL-10: The master regulator of immunity to infection. Journal of Immunology 180 5771 5777

45. HamiltonWDZukM 1982 Heritable true fitness and bright birds: A role for parasites? Science 218 384 387

46. FolstadIKarterAJ 1992 Parasites, bright males, and the immunocompetence handicap. American Naturalist 139 603 622

47. PedersenABBabayanSA 2011 Wild immunology. Molecular Ecology 20 872 880

48. AbolinsSRPocockMJOHafallaJCRRileyEMVineyME 2011 Measures of immune function of wild mice, Mus musculus. Molecular Ecology 20 881 892

49. HawleyDMAltizerSM 2011 Disease ecology meets ecological immunology: understanding the links between organismal immunity and infection dynamics in natural populations. Functional Ecology 25 48 60

50. DemasGEZyslingDABeechlerBRMuehlenbeinMPFrenchSS 2011 Beyond phytohaemagglutinin: Assessing vertebrate immune function across ecological contexts. Journal of Animal Ecology DOI:10.1111/j.1365-2656.2011.01813.x. Epub March 14 2011

51. MackeyKSteinkampAChomczynskiP 1998 DNA extraction from small blood volumes and the processing of cellulose blood cards for use in polymerase chain reaction. Applied Biochemistry and Biotechnology - Part B Molecular Biotechnology 9 1 5

52. RaymondMRoussetF 1995 GENEPOP (Version 1.2): Population Genetics Software for Exact Tests and Ecumenicism. Journal of Heredity 86 248 249

53. RoussetF 2008 GENEPOP'007: a complete re-implementation of the genepop software for Windows and Linux. Molecular Ecology Resources 8 103 106

54. GuoSWThompsonEA 1992 Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 48 361 372

55. Garnier-GerePDillmannC 1992 A computer program for testing pairwise linkage disequilibria in subdivided populations. Journal of Heredity 83 239

56. WeirBS 1996 Genetic Data Analysis II Sunderland, MA Sinaur Associates, Inc

57. BlackWCKrafsurES 1985 A FORTRAN program for the calculation and analysis of two-locus linkage disequilibrium coefficients. TAG Theoretical and Applied Genetics 70 491 496

58. WeirBS 1979 Inferences about Linkage Disequilibrium. Biometrics 35 235 254

59. RiceWR 1989 Analyzing tables of statistical tests. Evolution 43 223 225

60. HolmS 1979 A Simple Sequentially Rejective Multiple Test Procedure. Scandinavian Journal of Statistics 6 65 70

61. StephensMScheetP 2005 Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. American Journal of Human Genetics 76 449 462

62. StephensMSmithNJDonnellyP 2001 A new statistical method for haplotype reconstruction from population data. American Journal of Human Genetics 68 978 989

63. LibradoPRozasJ 2009 DnaSP v5: A software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25 1451 1452

64. PaunAReinertJTJiangZMedinCBalkhiMY 2008 Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response. Journal of Biological Chemistry 283 14295 14308

65. MullenACHighFAHutchinsASLeeHWVillarinoAV 2001 Role of T-bet in commitment of Th1 cells before IL-12-dependent selection. Science 292 1907 1910

66. ZhuJYamaneHCote-SierraJGuoLPaulWE 2006 GATA-3 promotes Th2 responses through three different mechanisms: Induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Research 16 3 10

67. HoriSNomuraTSakaguchiS 2003 Control of regulatory T cell development by the transcription factor Foxp3. Science 299 1057 1061

68. O'DonovanMRJohnsSWilcoxP 1995 The effect of PHA stimulation on lymphocyte sub-populations in whole-blood cultures. Mutagenesis 10 371 374

69. LivakKJSchmittgenTD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25 402 408

70. BownKJLambinXTelfordGROgdenNHTelferS 2008 Relative importance of Ixodes ricinus and Ixodes trianguliceps as vectors of Anaplasma phagocytophilum and Babesia microti in field vole (Microtus agrestis) populations. Applied and Environmental Microbiology 74 7118 7125

71. TelferSBownKJSekulesRBegonMHaydenT 2005 Disruption of a host-parasite system following the introduction of an exotic host species. Parasitology 130 661 668

72. TelferSBegonMBennettMBownKJBurtheS 2007 Contrasting dynamics of Bartonella spp. in cyclic field vole populations: The impact of vector and host dynamics. Parasitology 134 413 425

73. TelferSCloughHEBirtlesRJBennettMCarslakeD 2007 Ecological differences and coexistence in a guild of microparasites: Bartonella in wild rodents. Ecology 88 1841 1849

74. BirtlesRJHazelSMBennettMBownKRaoultD 2001 Longitudinal monitoring of the dynamics of infections due to Bartonella species in UK woodland rodents. Epidemiology and Infection 126 323 329

75. OliverMKTelferSPiertneySB 2009 Major histocompatibility complex (MHC) heterozygote superiority to natural multi-parasite infections in the water vole (Arvicola terrestris). Proceedings of the Royal Society B: Biological Sciences 276 1119 1128

76. R Development Core Team 2009 R: A language and environment for statistical computing Vienna, Austria R Foundation for Statistical Computing

77. ClarkAG 2004 The role of haplotypes in candidate gene studies. Genetic Epidemiology 27 321 333

78. YangYLiSSChienJWAndriesenJZhaoLP 2008 A systematic search for SNPs/haplotypes associated with disease phenotypes using a haplotype-based stepwise procedure. BMC Genetics 9

79. VasemägiAPrimmerCR 2005 Challenges for identifying functionally important genetic variation: the promise of combining complementary research strategies. Molecular Ecology 14 3623 3642

80. BoxGEPCoxDR 1964 An analysis of transformations (with discussion). Journal of the Royal Statistical Society B 26 211 252

81. TelferSBirtlesRBennettMLambinXPatersonS 2008 Parasite interactions in natural populations: insights from longitudinal data. Parasitology 135 767 781

82. AkaikeH 1973 Information theory and an extension of the maximum likelihood principle. PetranBNCsakiF International Symposium on Information Theory Budapest Akademiai Kiadi 267 281

83. JohnsonJBOmlandKS 2004 Model selection in ecology and evolution. Trends in Ecology and Evolution 19 101 108