Linking the effects of helminth infection, diet and the gut microbiota with human whole-blood signatures


Autoři: Soo Ching Lee aff001;  Mei San Tang aff003;  Alice V. Easton aff003;  Joseph Cooper Devlin aff003;  Ling Ling Chua aff004;  Ilseung Cho aff006;  Foong Ming Moy aff007;  Tsung Fei Khang aff008;  Yvonne A. L. Lim aff001;  P’ng Loke aff003
Působiště autorů: Department of Parasitology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia aff001;  Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia aff002;  Department of Microbiology, New York University School of Medicine, New York, New York, United States of America aff003;  Department of Obstetrics and Gynecology, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia aff004;  Department of Paediatrics, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia aff005;  Department of Medicine, Division of Gastroenterology, New York University School of Medicine, New York, New York, United States of America aff006;  Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia aff007;  University of Malaya Centre for Data Analytics, University of Malaya, Kuala Lumpur, Malaysia aff008;  Institute of Mathematical Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia aff009
Vyšlo v časopise: Linking the effects of helminth infection, diet and the gut microbiota with human whole-blood signatures. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008066
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008066

Souhrn

Helminth infection and dietary intake can affect the intestinal microbiota, as well as the immune system. Here we analyzed the relationship between fecal microbiota and blood profiles of indigenous Malaysians, referred to locally as Orang Asli, in comparison to urban participants from the capital city of Malaysia, Kuala Lumpur. We found that helminth infections had a larger effect on gut microbial composition than did dietary intake or blood profiles. Trichuris trichiura infection intensity also had the strongest association with blood transcriptional profiles. By characterizing paired longitudinal samples collected before and after deworming treatment, we determined that changes in serum zinc and iron levels among the Orang Asli were driven by changes in helminth infection status, independent of dietary metal intake. Serum zinc and iron levels were associated with changes in the abundance of several microbial taxa. Hence, there is considerable interplay between helminths, micronutrients and the microbiota on the regulation of immune responses in humans.

Klíčová slova:

Blood – Gene regulation – Gut bacteria – Helminth infections – Helminths – Microbiome – principal component analysis – Zinc


Zdroje

1. Babayan SA, Allen JE, Bradley JE, Geuking MB, Graham AL, Grencis RK, et al. Wild immunology: converging on the real world. Ann N Y Acad Sci. 2011;1236:17–29. Epub 2011/10/29. doi: 10.1111/j.1749-6632.2011.06251.x 22032399.

2. Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol. 2013;13(8):607–14. Epub 2013/07/06. doi: 10.1038/nri3476 23827958; PubMed Central PMCID: PMC3789590.

3. Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nat Rev Immunol. 2011;11(6):375–88. Epub 2011/05/26. nri2992 [pii] doi: 10.1038/nri2992 21610741.

4. Bethony J, Brooker S, Albonico M, Geiger SM, Loukas A, Diemert D, et al. Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet. 2006;367(9521):1521–32. doi: 10.1016/S0140-6736(06)68653-4 16679166.

5. Hotez PJ, Brindley PJ, Bethony JM, King CH, Pearce EJ, Jacobson J. Helminth infections: the great neglected tropical diseases. J Clin Invest. 2008;118(4):1311–21. Epub 2008/04/03. doi: 10.1172/JCI34261 18382743; PubMed Central PMCID: PMC2276811.

6. Hotez PJ, Mistry N, Rubinstein J, Sachs JD. Integrating neglected tropical diseases into AIDS, tuberculosis, and malaria control. N Engl J Med. 2011;364(22):2086–9. doi: 10.1056/NEJMp1014637 21631320.

7. Bancroft AJ, Hayes KS, Grencis RK. Life on the edge: the balance between macrofauna, microflora and host immunity. Trends Parasitol. 2012;28(3):93–8. Epub 2012/01/20. S1471-4922(11)00210-8 [pii] doi: 10.1016/j.pt.2011.12.001 22257556.

8. Leung JM, Loke P. A role for IL-22 in the relationship between intestinal helminths, gut microbiota and mucosal immunity. Int J Parasitol. 2013;43(3–4):253–7. Epub 2012/11/28. S0020-7519(12)00295-0 [pii] doi: 10.1016/j.ijpara.2012.10.015 23178750.

9. Plieskatt JL, Deenonpoe R, Mulvenna JP, Krause L, Sripa B, Bethony JM, et al. Infection with the carcinogenic liver fluke Opisthorchis viverrini modifies intestinal and biliary microbiome. FASEB J. 2013;27(11):4572–84. doi: 10.1096/fj.13-232751 23925654; PubMed Central PMCID: PMC3804743.

10. Walk ST, Blum AM, Ewing SA, Weinstock JV, Young VB. Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus. Inflamm Bowel Dis. 2010;16(11):1841–9. Epub 2010/09/18. doi: 10.1002/ibd.21299 20848461; PubMed Central PMCID: PMC2959136.

11. Wu S, Li RW, Li W, Beshah E, Dawson HD, Urban JF Jr. Worm burden-dependent disruption of the porcine colon microbiota by Trichuris suis infection. PLoS One. 2012;7(4):e35470. Epub 2012/04/26. doi: 10.1371/journal.pone.0035470 [pii]. 22532855; PubMed Central PMCID: PMC3332011.

12. Broadhurst MJ, Ardeshir A, Kanwar B, Mirpuri J, Gundra UM, Leung JM, et al. Therapeutic helminth infection of macaques with idiopathic chronic diarrhea alters the inflammatory signature and mucosal microbiota of the colon. PLoS Pathog. 2012;8(11):e1003000. Epub 2012/11/21. doi: 10.1371/journal.ppat.1003000 [pii]. 23166490.

13. Lee SC, Tang MS, Lim YA, Choy SH, Kurtz ZD, Cox LM, et al. Helminth colonization is associated with increased diversity of the gut microbiota. PLoS Negl Trop Dis. 2014;8(5):e2880. doi: 10.1371/journal.pntd.0002880 24851867; PubMed Central PMCID: PMC4031128.

14. Hayes KS, Bancroft AJ, Goldrick M, Portsmouth C, Roberts IS, Grencis RK. Exploitation of the intestinal microflora by the parasitic nematode Trichuris muris. Science. 2010;328(5984):1391–4. Epub 2010/06/12. 328/5984/1391 [pii] doi: 10.1126/science.1187703 20538949.

15. Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016;14(5):273–87. doi: 10.1038/nrmicro.2016.17 26972811; PubMed Central PMCID: PMC5243131.

16. Cohen ML. Changing patterns of infectious disease. Nature. 2000;406(6797):762–7. doi: 10.1038/35021206 10963605.

17. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet. 1997;349(9064):1498–504. doi: 10.1016/S0140-6736(96)07492-2 9167458.

18. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222–7. Epub 2012/06/16. doi: 10.1038/nature11053 22699611; PubMed Central PMCID: PMC3376388.

19. Elliott DE, Weinstock JV. Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Annals of the New York Academy of Sciences. 2011;1247:83–96. Epub 2012/01/14. doi: 10.1111/j.1749-6632.2011.06292.x 22239614.

20. Blaser MJ, Falkow S. What are the consequences of the disappearing human microbiota? Nat Rev Microbiol. 2009;7(12):887–94. Epub 2009/11/10. nrmicro2245 [pii] doi: 10.1038/nrmicro2245 19898491.

21. Rook GA. Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health. Proc Natl Acad Sci U S A. 2013;110(46):18360–7. doi: 10.1073/pnas.1313731110 24154724; PubMed Central PMCID: PMC3831972.

22. McSorley HJ, Maizels RM. Helminth infections and host immune regulation. Clin Microbiol Rev. 2012;25(4):585–608. Epub 2012/10/05. 25/4/585 [pii] doi: 10.1128/CMR.05040-11 23034321; PubMed Central PMCID: PMC3485755.

23. Harnett W, Harnett MM. Helminth-derived immunomodulators: can understanding the worm produce the pill? Nat Rev Immunol. 2010;10(4):278–84. Epub 2010/03/13. nri2730 [pii] doi: 10.1038/nri2730 20224568.

24. Brindley PJ, Mitreva M, Ghedin E, Lustigman S. Helminth genomics: The implications for human health. PLoS Negl Trop Dis. 2009;3(10):e538. doi: 10.1371/journal.pntd.0000538 19855829; PubMed Central PMCID: PMC2757907.

25. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489(7415):220–30. Epub 2012/09/14. nature11550 [pii] doi: 10.1038/nature11550 22972295; PubMed Central PMCID: PMC3577372.

26. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268–73. Epub 2012/06/08. science.1223490 [pii] doi: 10.1126/science.1223490 22674334.

27. Ivanov II, Littman DR. Modulation of immune homeostasis by commensal bacteria. Curr Opin Microbiol. 2011;14(1):106–14. Epub 2011/01/11. S1369-5274(10)00190-6 [pii] doi: 10.1016/j.mib.2010.12.003 21215684; PubMed Central PMCID: PMC3123735.

28. Honda K, Littman DR. The microbiome in infectious disease and inflammation. Annu Rev Immunol. 2012;30:759–95. Epub 2012/01/10. doi: 10.1146/annurev-immunol-020711-074937 22224764; PubMed Central PMCID: PMC4426968.

29. Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet. 2012;13(4):260–70. Epub 2012/03/14. nrg3182 [pii] doi: 10.1038/nrg3182 22411464.

30. Reynolds LA, Smith KA, Filbey KJ, Harcus Y, Hewitson JP, Redpath SA, et al. Commensal-pathogen interactions in the intestinal tract: lactobacilli promote infection with, and are promoted by, helminth parasites. Gut Microbes. 2014;5(4):522–32. doi: 10.4161/gmic.32155 25144609; PubMed Central PMCID: PMC4822684.

31. Ramanan D, Bowcutt R, Lee SC, Tang MS, Kurtz ZD, Ding Y, et al. Helminth infection promotes colonization resistance via type 2 immunity. Science. 2016;352(6285):608–12. Epub 2016/04/16. doi: 10.1126/science.aaf3229 27080105; PubMed Central PMCID: PMC4905769.

32. Ramanan D, Tang MS, Bowcutt R, Loke P, Cadwell K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity. 2014;41(2):311–24. Epub 2014/08/05. doi: 10.1016/j.immuni.2014.06.015 25088769; PubMed Central PMCID: PMC4238935.

33. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A. 2010;107(33):14691–6. Epub 2010/08/04. 1005963107 [pii] doi: 10.1073/pnas.1005963107 20679230; PubMed Central PMCID: PMC2930426.

34. Zackular JP, Skaar EP. The role of zinc and nutritional immunity in Clostridium difficile infection. Gut Microbes. 2018:00-. doi: 10.1080/19490976.2018.1448354 29533126

35. Palmer LD, Skaar EP. Transition Metals and Virulence in Bacteria. Annual review of genetics. 2016;50:67–91. doi: 10.1146/annurev-genet-120215-035146 PMC5125913. 27617971

36. Nairn BL, Lonergan ZR, Wang J, Braymer JJ, Zhang Y, Calcutt MW, et al. The response of Acinetobacter baumannii to Zinc starvation. Cell Host Microbe. 2016;19(6):826–36. doi: 10.1016/j.chom.2016.05.007 27281572; PubMed Central PMCID: PMC4901392.

37. Aitchison J. The statistical analysis of compositional data. London; New York: Chapman and Hall; 1986. xv, 416 p. p.

38. Blanchet FG, Legendre P, Borcard D. Forward selection of explanatory variables. Ecology. 2008;89(9):2623–32. Epub 2008/10/04. doi: 10.1890/07-0986.1 18831183.

39. Falony G, Joossens M, Vieira-Silva S, Wang J, Darzi Y, Faust K, et al. Population-level analysis of gut microbiome variation. Science. 2016;352(6285):560–4. Epub 2016/04/30. doi: 10.1126/science.aad3503 27126039.

40. Huang L, Appleton JA. Eosinophils in Helminth Infection: Defenders and Dupes. Trends Parasitol. 2016;32(10):798–807. Epub 2016/06/06. doi: 10.1016/j.pt.2016.05.004 27262918; PubMed Central PMCID: PMC5048491.

41. Shrestha N, Bahnan W, Wiley DJ, Barber G, Fields KA, Schesser K. eIF2 signaling regulates pro-inflammatory cytokine expression and bacterial invasion. Journal of Biological Chemistry. 2012. doi: 10.1074/jbc.M112.375915 22761422

42. Korten S, Volkmann L, Saeftel M, Fischer K, Taniguchi M, Fleischer B, et al. Expansion of NK cells with reduction of their inhibitory Ly-49A, Ly-49C, and Ly-49G2 receptor-expressing subsets in a murine helminth infection: contribution to parasite control. J Immunol. 2002;168(10):5199–206. doi: 10.4049/jimmunol.168.10.5199 11994476

43. Hsieh GC, Loukas A, Wahl AM, Bhatia M, Wang Y, Williamson AL, et al. A secreted protein from the human hookworm necator americanus binds selectively to NK cells and induces IFN-gamma production. J Immunol. 2004;173(4):2699–704. doi: 10.4049/jimmunol.173.4.2699 15294988.

44. Hepworth MR, Grencis RK. Disruption of Th2 immunity results in a gender-specific expansion of IL-13 producing accessory NK cells during helminth infection. J Immunol. 2009;183(6):3906–14. doi: 10.4049/jimmunol.0900577 19692641; PubMed Central PMCID: PMC2738657.

45. Schirmer M, Smeekens SP, Vlamakis H, Jaeger M, Oosting M, Franzosa EA, et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell. 2016;167(4):1125–36.e8. Epub 2016/11/05. doi: 10.1016/j.cell.2016.10.020 27814509; PubMed Central PMCID: PMC5131922.

46. Zackular JP, Moore JL, Jordan AT, Juttukonda LJ, Noto MJ, Nicholson MR, et al. Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection. Nat Med. 2016;22(11):1330–4. Epub 2016/11/01. doi: 10.1038/nm.4174 27668938; PubMed Central PMCID: PMC5101143.

47. Lahiri A, Abraham C. Activation of pattern recognition receptors up-regulates metallothioneins, thereby increasing intracellular accumulation of zinc, autophagy, and bacterial clearance by macrophages. Gastroenterology. 2014;147(4):835–46. Epub 2014/06/25. doi: 10.1053/j.gastro.2014.06.024 24960189; PubMed Central PMCID: PMC4170054.

48. Khuroo MS, Khuroo MS, Khuroo NS. Trichuris dysentery syndrome: a common cause of chronic iron deficiency anemia in adults in an endemic area (with videos). Gastrointest Endosc. 2010;71(1):200–4. doi: 10.1016/j.gie.2009.08.002 19879568.

49. George MM, Subramanian Vignesh K, Landero Figueroa JA, Caruso JA, Deepe GS. Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell–Th17 Balance. The Journal of Immunology. 2016;197(5):1864–76. doi: 10.4049/jimmunol.1600410 27465530

50. Read SA, O’Connor KS, Suppiah V, Ahlenstiel CLE, Obeid S, Cook KM, et al. Zinc is a potent and specific inhibitor of IFN-λ3 signalling. Nature Communications. 2017;8:15245. doi: 10.1038/ncomms15245 https://www.nature.com/articles/ncomms15245#supplementary-information. 28513591

51. Kongsbak K, Wahed MA, Friis H, Thilsted SH. Acute Phase Protein Levels, T. trichiura, and Maternal Education Are Predictors of Serum Zinc in a Cross-Sectional Study in Bangladeshi Children. The Journal of Nutrition. 2006;136(8):2262–8. doi: 10.1093/jn/136.8.2262 16857851

52. Akinwande KS, Morenikeji OA, Arinola OG. Anthropometric Indices and Serum Micronutrient Status of Helminth—Infected School Children from Semi-Urban Communities in Southwestern Nigeria. Niger J Physiol Sci. 2017;32(2):195–200. Epub 2018/02/28. 29485641.

53. Arinola GO, Morenikeji OA, Akinwande KS, Alade AO, Olateru-Olagbegi O, Alabi PE, et al. Serum Micronutrients in Helminth-infected Pregnant Women and Children: Suggestions for Differential Supplementation During Anti-helminthic Treatment. Annals of Global Health. 2015;81(5):705–10. doi: 10.1016/j.aogh.2015.10.001 27036729

54. de Gier B, Nga TT, Winichagoon P, Dijkhuizen MA, Khan NC, van de Bor M, et al. Species-Specific Associations between Soil-Transmitted Helminths and Micronutrients in Vietnamese Schoolchildren. Am J Trop Med Hyg. 2016;95(1):77–82. doi: 10.4269/ajtmh.15-0533 27246448; PubMed Central PMCID: PMC4944714.

55. de Gier B, Mpabanzi L, Vereecken K, van der Werff SD, D'Haese PC, Fiorentino M, et al. Height, zinc and soil-transmitted helminth infections in schoolchildren: a study in Cuba and Cambodia. Nutrients. 2015;7(4):3000–10. Epub 2015/04/24. doi: 10.3390/nu7043000 25903454; PubMed Central PMCID: PMC4425185.

56. Martin I, Djuardi Y, Sartono E, Rosa BA, Supali T, Mitreva M, et al. Dynamic changes in human-gut microbiome in relation to a placebo-controlled anthelminthic trial in Indonesia. PLoS Negl Trop Dis. 2018;12(8):e0006620. Epub 2018/08/10. doi: 10.1371/journal.pntd.0006620 30091979; PubMed Central PMCID: PMC6084808.

57. Easton AV, Quinones M, Vujkovic-Cvijin I, Oliveira RG, Kepha S, Odiere MR, et al. The Impact of Anthelmintic Treatment on Human Gut Microbiota Based on Cross-Sectional and Pre- and Postdeworming Comparisons in Western Kenya. MBio. 2019;10(2). Epub 2019/04/25. doi: 10.1128/mBio.00519-19 31015324; PubMed Central PMCID: PMC6479000.

58. Tee ES, Noor MI, Azudin MN, Idris K. Nutrient Composition of Malaysian Foods. 4th ed. Kuala Lumpur, Malaysia: Malaysian Food Composition Database Programme c/o Institute for Medical Research; 1997.

59. Kuhn M. Building Predictive Models in R Using the caret Package. Journal of Statistical Software. 2008;28(1548–7660):1–26. doi: 10.18637/jss.v028.i05

60. Lee SC, Tang MS, Lim YAL, Choy SH, Kurtz ZD, Cox LM, et al. Helminth Colonization Is Associated with Increased Diversity of the Gut Microbiota. PLOS Neglected Tropical Diseases. 2014;8(5):e2880. doi: 10.1371/journal.pntd.0002880 24851867

61. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, et al. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J. 2012;6(8):1621–4. Epub 2012/03/10. doi: 10.1038/ismej.2012.8 22402401; PubMed Central PMCID: PMC3400413.

62. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Lozupone CA, Turnbaugh PJ, et al. Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4516–22. Epub 2010/06/11. doi: 10.1073/pnas.1000080107 20534432; PubMed Central PMCID: PMC3063599.

63. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335–6. Epub 2010/04/13. doi: 10.1038/nmeth.f.303 20383131; PubMed Central PMCID: PMC3156573.

64. Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13(7):581–3. Epub 2016/05/24. doi: 10.1038/nmeth.3869 27214047; PubMed Central PMCID: PMC4927377.

65. Oksanen J, Blanchet FG, Friendly M, Kindt R, Legendre P, McGlinn D, et al. vegan: Community Ecology Package. 2018.

66. Chun H, Keleş S. Sparse partial least squares regression for simultaneous dimension reduction and variable selection. J R Stat Soc: Series B (Statistical Methodology). 2010;72. doi: 10.1111/j.1467-9868.2009.00723.x 20107611

67. Liu H, Roeder K, Wasserman L. Stability Approach to Regularization Selection (StARS) for High Dimensional Graphical Models. Proceedings of Advances in Neural Information Processing Systems (NIPS). 2010;23.

68. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biology. 2013;14(4):R36. doi: 10.1186/gb-2013-14-4-r36 23618408

69. Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–9. doi: 10.1093/bioinformatics/btu638 25260700

70. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8 25516281

71. Gentleman R, Carey V, Huber W, Hahne F. Genefilter: Methods for filtering genes from high-throughput experiments. Genefilter: Methods for filtering genes from high-throughput experiments: R package version 1.64.0.; 2018.

72. Liquet B, Cao K-AL, Hocini H, Thiébaut R. A novel approach for biomarker selection and the integration of repeated measures experiments from two assays. BMC Bioinformatics. 2012;13(1):325. doi: 10.1186/1471-2105-13-325 23216942

73. Rohart F, Gautier B, Singh A, Le Cao KA. mixOmics: An R package for 'omics feature selection and multiple data integration. PLoS Comput Biol. 2017;13(11):e1005752. Epub 2017/11/04. doi: 10.1371/journal.pcbi.1005752 29099853; PubMed Central PMCID: PMC5687754.

74. Singhania A, Verma R, Graham CM, Lee J, Tran T, Richardson M, et al. A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection. Nat Commun. 2018;9(1):2308. Epub 2018/06/21. doi: 10.1038/s41467-018-04579-w 29921861; PubMed Central PMCID: PMC6008327.

75. Carlson M. GO.db: A set of annotation maps describing the entire Gene Ontology. R package version 3.7.0.2018.

Štítky
Hygiena a epidemiologie Infekční lékařství Laboratoř

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