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Mediators of Inflammation
Volume 2015, Article ID 791847, 22 pages
http://dx.doi.org/10.1155/2015/791847
Review Article

Trachoma and Ocular Chlamydial Infection in the Era of Genomics

Department of Clinical Research, Faculty of Infectious Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK

Received 17 April 2015; Accepted 5 August 2015

Academic Editor: Amedeo Amedei

Copyright © 2015 Tamsyn Derrick et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Sightsavers, “Sightsavers Annual Review: 24,” MISC12, 2012.
  2. WHO Alliance, “Weekly epidemiological record,” Relevé épidémiologique Hebdomadaire, vol. 96, pp. 421–428, 2014. View at Google Scholar
  3. J. D. Keenan, B. Ayele, T. Gebre et al., “Childhood mortality in a cohort treated with mass azithromycin for trachoma,” Clinical Infectious Diseases, vol. 52, no. 7, pp. 883–888, 2011. View at Publisher · View at Google Scholar
  4. E. J. Giamarellos-Bourboulis, “Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators,” International Journal of Antimicrobial Agents, vol. 31, no. 1, pp. 12–20, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. V. Jimenez, H. C. Gelderblom, R. Mann Flueckiger, P. M. Emerson, D. Haddad, and T. M. Lietman, “Mass drug administration for trachoma: how long is not long enough?” PLoS Neglected Tropical Diseases, vol. 9, no. 3, Article ID e0003610, 2015. View at Publisher · View at Google Scholar
  6. C. L. Coles, K. Mabula, J. C. Seidman et al., “Mass distribution of azithromycin for trachoma control is associated with increased risk of azithromycin-resistant Streptococcus pneumoniae carriage in young children 6 months after treatment,” Clinical Infectious Diseases, vol. 56, no. 11, pp. 1519–1526, 2013. View at Publisher · View at Google Scholar · View at Scopus
  7. M. J. Burton, S. N. Rajak, V. H. Hu et al., “Pathogenesis of progressive scarring trachoma in Ethiopia and Tanzania and its implications for disease control: two cohort studies,” PLoS Neglected Tropical Diseases, vol. 9, no. 5, Article ID e0003763, 2015. View at Publisher · View at Google Scholar
  8. R. G. Rank and L. Yeruva, “Hidden in plain sight: chlamydial gastrointestinal infection and its relevance to persistence in human genital infection,” Infection and Immunity, vol. 82, no. 4, pp. 1362–1371, 2014. View at Publisher · View at Google Scholar · View at Scopus
  9. A. P. Craig, F. Y. S. Kong, L. Yeruva et al., “Is it time to switch to doxycycline from azithromycin for treating genital chlamydial infections in women? Modelling the impact of autoinoculation from the gastrointestinal tract to the genital tract,” BMC Infectious Diseases, vol. 15, article 200, 2015. View at Publisher · View at Google Scholar
  10. A. R. Last, S. E. Burr, H. A. Weiss et al., “Risk factors for active trachoma and ocular Chlamydia trachomatis infection in treatment-naïve trachoma-hyperendemic communities of the Bijagós Archipelago, Guinea Bissau,” PLoS Neglected Tropical Diseases, vol. 8, no. 6, Article ID e2900, 2014. View at Publisher · View at Google Scholar · View at Scopus
  11. V. H. Hu, P. Massae, H. A. Weiss et al., “In vivo confocal microscopy of trachoma in relation to normal tarsal conjunctiva,” Ophthalmology, vol. 118, no. 4, pp. 747–754, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. V. H. Hu, M. J. Holland, I. A. Cree et al., “In vivo confocal microscopy and histopathology of the conjunctiva in trachomatous scarring and normal tissue: a systematic comparison,” British Journal of Ophthalmology, vol. 97, no. 10, pp. 1333–1337, 2013. View at Publisher · View at Google Scholar · View at Scopus
  13. D. C. W. Mabey, V. Hu, R. L. Bailey, M. J. Burton, and M. J. Holland, “Towards a safe and effective chlamydial vaccine: lessons from the eye,” Vaccine, vol. 32, no. 14, pp. 1572–1578, 2014. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Sowa, J. Sowa, L. H. Collier, and W. A. Blyth, “Trachoma vaccine field trials in The Gambia,” Journal of Hygiene, vol. 67, no. 4, pp. 699–717, 1969. View at Publisher · View at Google Scholar · View at Scopus
  15. R. L. Bailey, M. J. Burton, and D. C. W. Mabey, “Trachoma vaccine trials in the Gambia,” in Chlamydial Infections. Proceedings of the Thirteenth International Symposium on Human Chlamydial Infections, J. Schachter, G. Byrne, and M. A. Chernesky, Eds., pp. 485–488, Asilomar Conference Grounds, Pacific Grove, Calif, USA, 2014. View at Google Scholar
  16. D. C. W. Mabey, V. H. Hu, R. L. Bailey et al., “Towards a safe and effective chlamydial vaccine: lessons from the eye,” in Proceedings of the 13th International Symposium on Human Chlamydial Infections, J. Schachter, G. Byrne, M. A. Chernesky, and etal, Eds., pp. 489–492, Asilomar Conference Grounds, Pacific Grove, Calif, USA, June 2014.
  17. V. H. Hu, M. J. Holland, and M. J. Burton, “Trachoma: protective and pathogenic ocular immune responses to Chlamydia trachomatis,” PLoS Neglected Tropical Diseases, vol. 7, no. 2, Article ID e2020, 2013. View at Publisher · View at Google Scholar
  18. R. G. Rank, C. Dascher, A. K. Bowlin, and P. M. Bavoil, “Systemic immunization with Hsp60 alters the development of chlamydial ocular disease,” Investigative Ophthalmology and Visual Science, vol. 36, no. 7, pp. 1344–1351, 1995. View at Google Scholar · View at Scopus
  19. E. A. Wagar, J. Schachter, P. Bavoil, and R. S. Stephens, “Differential human serologic response to two 60,000 molecular weight Chlamydia trachomatis antigens,” Journal of Infectious Diseases, vol. 162, no. 4, pp. 922–927, 1990. View at Publisher · View at Google Scholar · View at Scopus
  20. T. Skwor, R. P. Kandel, S. Basravi, A. Khan, B. Sharma, and D. Dean, “Characterization of humoral immune responses to chlamydial HSP60, CPAF, and CT795 in inflammatory and severe trachoma,” Investigative Ophthalmology & Visual Science, vol. 51, no. 10, pp. 5128–5136, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. N. M. Budrys, S. Gong, A. K. Rodgers et al., “Chlamydia trachomatis antigens recognized in women with tubal factor infertility, normal fertility, and acute infection,” Obstetrics and Gynecology, vol. 119, no. 5, pp. 1009–1016, 2012. View at Publisher · View at Google Scholar · View at Scopus
  22. C. Lu, M. J. Holland, S. Gong et al., “Genome-wide identification of Chlamydia trachomatis antigens associated with trachomatous trichiasis,” Investigative Ophthalmology & Visual Science, vol. 53, no. 6, pp. 2551–2559, 2012. View at Publisher · View at Google Scholar · View at Scopus
  23. M. J. Holland, R. L. Bailey, L. J. Hayes, H. C. Whittle, and D. C. W. Mabey, “Conjunctival scarring in trachoma is associated with depressed cell-mediated immune responses to chlamydial antigens,” Journal of Infectious Diseases, vol. 168, no. 6, pp. 1528–1531, 1993. View at Publisher · View at Google Scholar · View at Scopus
  24. M. J. Holland, R. L. Bailey, D. J. Conway et al., “T helper type-1 (Th1)/Th2 profiles of peripheral blood mononuclear cells (PBMC); responses to antigens of Chlamydia trachomatis in subjects with severe trachomatous scarring,” Clinical & Experimental Immunology, vol. 105, pp. 429–435, 1996. View at Google Scholar
  25. A. M. Abu El-Asrar, K. Geboes, K. F. Tabbara, S. A. Al-Kharashi, L. Missotten, and V. Desmet, “Immunopathogenesis of conjunctival scarring in trachoma,” Eye, vol. 12, no. 3, pp. 453–460, 1998. View at Publisher · View at Google Scholar · View at Scopus
  26. A. Gall, A. Horowitz, H. Joof et al., “Systemic effector and regulatory immune responses to chlamydial antigens in trachomatous trichiasis,” Frontiers in Microbiology, vol. 2, article 10, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. R. C. Brunham and J. Rey-Ladino, “Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine,” Nature Reviews Immunology, vol. 5, no. 2, pp. 149–161, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. N. Olivares-Zavaleta, W. M. Whitmire, L. Kari, G. L. Sturdevant, and H. D. Caldwell, “CD8+ T cells define an unexpected role in live-attenuated vaccine protective immunity against Chlamydia trachomatis infection in macaques,” The Journal of Immunology, vol. 192, no. 10, pp. 4648–4654, 2014. View at Publisher · View at Google Scholar · View at Scopus
  29. R. S. Stephens, “The cellular paradigm of chlamydial pathogenesis,” Trends in Microbiology, vol. 11, no. 1, pp. 44–51, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. S. J. Rasmussen, L. Eckmann, A. J. Quayle et al., “Secretion of proinflammatory cytokines by epithelial cells in response to Chlamydia infection suggests a central role for epithelial cells in chlamydial pathogenesis,” The Journal of Clinical Investigation, vol. 99, no. 1, pp. 77–87, 1997. View at Publisher · View at Google Scholar · View at Scopus
  31. S. Dessus-Babus, T. L. Darville, F. P. Cuozzo, K. Ferguson, and P. B. Wyrick, “Differences in innate immune responses (in vitro) to HeLa cells infected with nondisseminating serovar E and disseminating serovar L2 of Chlamydia trachomatis,” Infection and Immunity, vol. 70, no. 6, pp. 3234–3248, 2002. View at Publisher · View at Google Scholar · View at Scopus
  32. Z. Zhu, C. G. Lee, T. Zheng et al., “Airway inflammation and remodeling in asthma. Lessons from interleukin 11 and interleukin 13 transgenic mice,” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 10, pp. S67–S70, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. L. R. Buckner, M. E. Lewis, S. J. Greene, T. P. Foster, and A. J. Quayle, “Chlamydia trachomatis infection results in a modest pro-inflammatory cytokine response and a decrease in T cell chemokine secretion in human polarized endocervical epithelial cells,” Cytokine, vol. 63, no. 2, pp. 151–165, 2013. View at Publisher · View at Google Scholar · View at Scopus
  34. A. Natividad, T. C. Freeman, D. Jeffries et al., “Human conjunctival transcriptome analysis reveals the prominence of innate defense in Chlamydia trachomatis infection,” Infection and Immunity, vol. 78, no. 11, pp. 4895–4911, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. A. L. Barron, Microbiology of Chlamydia, edited by: A. L. Barron, CRC Press, 1988.
  36. M. J. Burton, S. N. Rajak, J. Bauer et al., “Conjunctival transcriptome in scarring trachoma,” Infection and Immunity, vol. 79, no. 1, pp. 499–511, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. M. J. Burton, A. Ramadhani, H. A. Weiss et al., “Active trachoma is associated with increased conjunctival expression of IL17A and profibrotic cytokines,” Infection and Immunity, vol. 79, no. 12, pp. 4977–4983, 2011. View at Publisher · View at Google Scholar · View at Scopus
  38. V. H. Hu, H. A. Weiss, A. M. Ramadhani et al., “Innate immune responses and modified extracellular matrix regulation characterize bacterial infection and cellular/connective tissue changes in scarring trachoma,” Infection and Immunity, vol. 80, no. 1, pp. 121–130, 2012. View at Publisher · View at Google Scholar · View at Scopus
  39. D. J. Conway, M. J. Holland, A. E. Campbell et al., “HLA class I and II polymorphisms and trachomatous scarring in a Chlamydia trachomatis—endemic population,” The Journal of Infectious Diseases, vol. 174, no. 3, pp. 643–646, 1996. View at Publisher · View at Google Scholar · View at Scopus
  40. R. W. Peeling, R. L. Bailey, D. J. Comvay et al., “Antibody response to the 60-kDa chlamydial heat-shock protein is associated with scarring trachoma,” The Journal of Infectious Diseases, vol. 177, no. 1, pp. 256–259, 1998. View at Publisher · View at Google Scholar · View at Scopus
  41. L. K. Gaur, R. W. Peeling, M. Cheang et al., “Association of Chlamydia trachomatis heat-shock protein 60 antibody and HLA class II DQ alleles,” Journal of Infectious Diseases, vol. 180, no. 1, pp. 234–237, 1999. View at Publisher · View at Google Scholar · View at Scopus
  42. C. R. Cohen, S. S. Sinei, E. A. Bukusi, J. J. Bwayo, K. K. Holmes, and R. C. Brunham, “Human leukocyte antigen class II DQ alleles associated with Chlamydia trachomatis tubal infertility,” Obstetrics and Gynecology, vol. 95, no. 1, pp. 72–77, 2000. View at Publisher · View at Google Scholar · View at Scopus
  43. M. J. Holland, D. J. Conway, T. J. Blanchard et al., “Synthetic peptides based on Chlamydia trachomatis antigens identify cytotoxic T lymphocyte responses in subjects from a trachoma-endemic population,” Clinical & Experimental Immunology, vol. 107, no. 1, pp. 44–49, 1997. View at Publisher · View at Google Scholar · View at Scopus
  44. O. S. M. Mahdi, H. C. Whittle, H. Joof, D. C. W. Mabey, and R. L. Bailey, “Failure to detect HLA-A6802-restricted CD8+ T cells specific for Chlamydia trachomatis antigens in subjects from trachoma-endemic communities,” Clinical and Experimental Immunology, vol. 123, no. 1, pp. 68–72, 2001. View at Publisher · View at Google Scholar · View at Scopus
  45. M. J. Holland, N. Faal, I. Sarr et al., “The frequency of Chlamydia trachomatis major outer membrane protein-specific CD8+ T lymphocytes in active trachoma is associated with current ocular infection,” Infection and Immunity, vol. 74, no. 3, pp. 1565–1572, 2006. View at Publisher · View at Google Scholar
  46. M. N. Starnbach, M. J. Bevan, and M. F. Lampe, “Protective cytotoxic T lymphocytes are induced during murine infection with Chlamydia trachomatis,” The Journal of Immunology, vol. 153, no. 11, pp. 5183–5189, 1994. View at Google Scholar · View at Scopus
  47. S.-K. Kim, L. Devine, M. Angevine, R. DeMars, and P. B. Kavathas, “Direct detection and magnetic isolation of Chlamydia trachomatis major outer membrane protein-specific CD8+ CTLs with HLA class I tetramers,” Journal of Immunology, vol. 165, no. 12, pp. 7285–7292, 2000. View at Publisher · View at Google Scholar · View at Scopus
  48. S. C. Fankhauser and M. N. Starnbach, “PD-L1 limits the mucosal CD8+ T cell response to Chlamydia trachomatis,” The Journal of Immunology, vol. 192, no. 3, pp. 1079–1090, 2014. View at Publisher · View at Google Scholar · View at Scopus
  49. L. Kari, W. M. Whitmire, N. Olivares-Zavaleta et al., “A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primates,” The Journal of Experimental Medicine, vol. 208, no. 11, pp. 2217–2223, 2011. View at Publisher · View at Google Scholar · View at Scopus
  50. K. P. Karunakaran, H. Yu, X. Jiang et al., “Outer membrane proteins preferentially load MHC class II peptides: implications for a Chlamydia trachomatis T cell vaccine,” Vaccine, vol. 33, no. 18, pp. 2159–2166, 2015. View at Publisher · View at Google Scholar
  51. A. G. White, J. Bogh, W. Leheny et al., “HLA antigens in Omanis with blinding trachoma: markers for disease susceptibility and resistance,” British Journal of Ophthalmology, vol. 81, no. 6, pp. 431–434, 1997. View at Publisher · View at Google Scholar · View at Scopus
  52. M. Abbas, L. D. Bobo, Y.-H. Hsieh et al., “Human leukocyte antigen (HLA)-B, DRB1, and DQB1 allotypes associated with disease and protection of trachoma endemic villagers,” Investigative Ophthalmology and Visual Science, vol. 50, no. 4, pp. 1734–1738, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. C. H. Roberts, S. Molina, P. Makalo et al., “Conjunctival scarring in trachoma is associated with the HLA-C Ligand of KIR and is exacerbated by heterozygosity at KIR2DL2/KIR2DL3,” PLoS Neglected Tropical Diseases, vol. 8, no. 3, Article ID e2744, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. C. C. Winter, J. E. Gumperz, P. Parham, E. O. Long, and N. Wagtmann, “Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition,” The Journal of Immunology, vol. 161, no. 2, pp. 571–577, 1998. View at Google Scholar · View at Scopus
  55. E. Ciccone, D. Pende, M. Vitale et al., “Self class I molecules protect normal cells from lysis mediated by autologous natural killer cells,” European Journal of Immunology, vol. 24, no. 4, pp. 1003–1006, 1994. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Colonna, E. G. Brooks, M. Falco, G. B. Ferrara, and J. L. Strominger, “Generation of allospecffic natural killer cells by stimulation across a polymorphism of HLA-C,” Science, vol. 260, no. 5111, pp. 1121–1124, 1993. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Colonna, G. Borsellino, M. Falco, G. B. Ferrara, and J. L. Strominger, “HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 24, pp. 12000–12004, 1993. View at Publisher · View at Google Scholar · View at Scopus
  58. R. Biassoni, C. Cantoni, M. Falco et al., “The human leukocyte antigen (HLA)-C-specific ‘activatory’ or ‘inhibitory’ natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions,” The Journal of Experimental Medicine, vol. 183, no. 2, pp. 645–650, 1996. View at Publisher · View at Google Scholar · View at Scopus
  59. E. O. Long, M. Colonna, and L. L. Lanier, “Inhibitory MHC class I receptors on NK and T cells: a standard nomenclature,” Immunology Today, vol. 17, no. 2, article 100, 1996. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Colonna and J. Samaridis, “Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells,” Science, vol. 268, no. 5209, pp. 405–408, 1995. View at Publisher · View at Google Scholar · View at Scopus
  61. S. Kim, J. Poursine-Laurent, S. M. Truscott et al., “Licensing of natural killer cells by host major histocompatibility complex class I molecules,” Nature, vol. 436, no. 7051, pp. 709–713, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Moretta, C. Bottino, D. Pende et al., “Identification of four subsets of human CD3−CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition,” Journal of Experimental Medicine, vol. 172, no. 6, pp. 1589–1598, 1990. View at Publisher · View at Google Scholar · View at Scopus
  63. A. Moretta, G. Tambussi, C. Bottino et al., “A novel surface antigen expressed by a subset of human CD3-CD16+ natural killer cells. Role in cell activation and regulation of cytolytic function,” The Journal of Experimental Medicine, vol. 171, no. 3, pp. 695–714, 1990. View at Publisher · View at Google Scholar · View at Scopus
  64. B. Huard and L. Karlsson, “A subpopulation of CD8+ T cells specific for melanocyte differentiation antigens expresses killer inhibitory receptors (KIR) in healthy donors: evidence for a role of KIR in the control of peripheral tolerance,” European Journal of Immunology, vol. 30, no. 6, pp. 1665–1675, 2000. View at Google Scholar · View at Scopus
  65. S. Ferrini, A. Cambiaggi, R. Meazza et al., “T cell clones expressing the natural killer cell-related p58 receptor molecule display heterogeneity in phenotypic properties and p58 function,” European Journal of Immunology, vol. 24, no. 10, pp. 2294–2298, 1994. View at Publisher · View at Google Scholar · View at Scopus
  66. N.-K. S. Al Basatena, A. MacNamara, A. M. Vine et al., “KIR2DL2 enhances protective and detrimental HLA class I-mediated immunity in chronic viral infection,” PLoS Pathogens, vol. 7, no. 10, Article ID e1002270, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. W. K. Chan, P. Rujkijyanont, G. Neale et al., “Multiplex and genome-wide analyses reveal distinctive properties of KIR+ and CD56+ T cells in human blood,” The Journal of Immunology, vol. 191, no. 4, pp. 1625–1636, 2013. View at Publisher · View at Google Scholar · View at Scopus
  68. D. J. Conway, M. J. Holland, R. L. Bailey et al., “Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-α) gene promoter and with elevated TNF-α levels in tear fluid,” Infection and Immunity, vol. 65, no. 3, pp. 1003–1006, 1997. View at Google Scholar
  69. A. Natividad, N. Hanchard, M. J. Holland et al., “Genetic variation at the TNF locus and the risk of severe sequelae of ocular Chlamydia trachomatis infection in Gambians,” Genes & Immunity, vol. 8, no. 4, pp. 288–295, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. B. Atik, T. A. Skwor, R. P. Kandel et al., “Identification of novel single nucleotide polymorphisms in inflammatory genes as risk factors associated with trachomatous trichiasis,” PLoS ONE, vol. 3, no. 10, Article ID e3600, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. A. Natividad, J. Wilson, O. Koch et al., “Risk of trachomatous scarring and trichiasis in Gambians varies with SNP haplotypes at the interferon-gamma and interleukin-10 loci,” Genes and Immunity, vol. 6, no. 4, pp. 332–340, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. A. Natividad, J. Hull, G. Luoni et al., “Innate immunity in ocular Chlamydia trachomatis infection: contribution of IL8 and CSF2 gene variants to risk of trachomatous scarring in Gambians,” BMC Medical Genetics, vol. 10, article 138, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Natividad, M. J. Holland, K. A. Rockett et al., “Susceptibility to sequelae of human ocular chlamydial infection associated with allelic variation in IL10 cis-regulation,” Human Molecular Genetics, vol. 17, no. 2, pp. 323–329, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Savy, B. J. Hennig, C. P. Doherty et al., “Haptoglobin and sickle cell polymorphisms and risk of active trachoma in gambian children,” PLoS ONE, vol. 5, no. 6, Article ID e11075, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. Y.-Y. Teo, K. S. Small, and D. P. Kwiatkowski, “Methodological challenges of genome-wide association analysis in Africa,” Nature Reviews Genetics, vol. 11, no. 2, pp. 149–160, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. M. J. Newport and C. Finan, “Genome-wide association studies and susceptibility to infectious diseases,” Briefings in Functional Genomics, vol. 10, no. 2, pp. 98–107, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. M. Jallow, Y. Y. Teo, K. S. Small et al., “Genome-wide and fine-resolution association analysis of malaria in West Africa,” Nature Genetics, vol. 41, pp. 657–665, 2009. View at Publisher · View at Google Scholar
  78. B. Howie, C. Fuchsberger, M. Stephens, J. Marchini, and G. R. Abecasis, “Fast and accurate genotype imputation in genome-wide association studies through pre-phasing,” Nature Genetics, vol. 44, no. 8, pp. 955–959, 2012. View at Publisher · View at Google Scholar · View at Scopus
  79. SA. Morré, S. Ouburg, V.-D. Margreet, S. Ioana, and F. Fabrizio, “EpiGenChlamydia Consortium,” 2015, http://www.epigenchlamydia.eu/cms/.
  80. C. H. Roberts, C. Franklin, S. Molina-Gonzalez et al., “A genome wide association scan reveals pathway—wide genomic differences between cases of scarring trachoma and controls,” in Proceedings of the 13th International Symposium on Human Chlamydial Infections, J. Schachter, G. Byrne, M. A. Chernesky, and etal, Eds., pp. 501–504, Asilomar Conference Grounds, Pacific Grove, Calif, USA, June 2014.
  81. Y. Su, X. Wang, J. Enitra et al., “Host genetics and upper genital tract disease in Chlamydia muridarum infected mice: a forward genetic approach with translational implications,” in Proceedings of the 13th International Symposium on Human Chlamydial Infections, J. Schachter, G. Byrne, M. A. Chernesky, and etal, Eds., pp. 261–264, Asilomar Conference Grounds, Pacific Grove, Calif, USA, June 2014.
  82. D. C. Ko, K. P. Shukla, C. Fong et al., “A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease,” The American Journal of Human Genetics, vol. 85, no. 2, pp. 214–227, 2009. View at Publisher · View at Google Scholar · View at Scopus
  83. D. C. Ko and T. J. Urban, “Understanding human variation in infectious disease susceptibility through clinical and cellular GWAS,” PLoS Pathogens, vol. 9, no. 8, Article ID e1003424, 2013. View at Publisher · View at Google Scholar
  84. R. S. Stephens, S. Kalman, C. Lammel et al., “Genome sequence of an obligate intracellular pathogen of humans: Chlamydia trachomatis,” Science, vol. 282, no. 5389, pp. 754–759, 1998. View at Publisher · View at Google Scholar · View at Scopus
  85. L. Kari, W. M. Whitmire, J. H. Carlson et al., “Pathogenic diversity among Chlamydia trachomatis ocular strains in nonhuman primates is affected by subtle genomic variations,” Journal of Infectious Diseases, vol. 197, no. 3, pp. 449–456, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. H. M. B. Seth-Smith, S. R. Harris, K. Persson et al., “Co-evolution of genomes and plasmids within Chlamydia trachomatis and the emergence in Sweden of a new variant strain,” BMC Genomics, vol. 10, article 239, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. S. Kalman, W. Mitchell, R. Marathe et al., “Comparative genomes of Chlamydia pneumoniae and C. trachomatis,” Nature Genetics, vol. 21, no. 4, pp. 385–389, 1999. View at Publisher · View at Google Scholar · View at Scopus
  88. T. D. Read, R. C. Brunham, C. Shen et al., “Genome sequences of Chlamydia trachomatis MoPn and Chlamydia pneumoniae AR39,” Nucleic Acids Research, vol. 28, no. 6, pp. 1397–1406, 2000. View at Publisher · View at Google Scholar · View at Scopus
  89. M. Shirai, H. Hirakawa, M. Kimoto et al., “Comparison of whole genome sequences of Chlamydia pneumoniae J138 from Japan and CWL029 from USA,” Nucleic Acids Research, vol. 28, no. 12, pp. 2311–2314, 2000. View at Publisher · View at Google Scholar · View at Scopus
  90. T. D. Read, G. S. A. Myers, R. C. Brunham et al., “Genome sequence of Chlamydophila caviae (Chlamydia psittaci GPIC): examining the role of niche-specific genes in the evolution of the Chlamydiaceae,” Nucleic Acids Research, vol. 31, no. 8, pp. 2134–2147, 2003. View at Publisher · View at Google Scholar · View at Scopus
  91. S. R. Harris, I. N. Clarke, H. M. B. Seth-Smith et al., “Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing,” Nature Genetics, vol. 44, no. 4, pp. 413–419, 2012. View at Publisher · View at Google Scholar · View at Scopus
  92. J. P. Gomes, W. J. Bruno, A. Nunes et al., “Evolution of Chlamydia trachomatis diversity occurs by widespread interstrain recombination involving hotspots,” Genome Research, vol. 17, no. 1, pp. 50–60, 2007. View at Publisher · View at Google Scholar · View at Scopus
  93. B. M. Jeffrey, R. J. Suchland, K. L. Quinn, J. R. Davidson, W. E. Stamm, and D. D. Rockey, “Genome sequencing of recent clinical Chlamydia trachomatis strains identifies loci associated with tissue tropism and regions of apparent recombination,” Infection and Immunity, vol. 78, no. 6, pp. 2544–2553, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. Y. Wang, S. Kahane, L. T. Cutcliffe, R. J. Skilton, P. R. Lambden, and I. N. Clarke, “Development of a transformation system for chlamydia trachomatis: restoration of glycogen biosynthesis by acquisition of a plasmid shuttle vector,” PLoS Pathogens, vol. 7, no. 9, Article ID e1002258, 2011. View at Publisher · View at Google Scholar · View at Scopus
  95. Y. Wang, S. Kahane, L. T. Cutcliffe et al., “Genetic transformation of a clinical (genital tract), plasmid-free isolate of Chlamydia trachomatis: engineering the plasmid as a cloning vector,” PLoS ONE, vol. 8, no. 3, Article ID e59195, 2013. View at Publisher · View at Google Scholar · View at Scopus
  96. Y. Wang, L. T. Cutcliffe, R. J. Skilton, K. Persson, C. Bjartling, and I. N. Clarke, “Transformation of a plasmid-free, genital tract isolate of Chlamydia trachomatis with a plasmid vector carrying a deletion in CDS6 revealed that this gene regulates inclusion phenotype,” Pathogens and Disease, vol. 67, no. 2, pp. 100–103, 2013. View at Publisher · View at Google Scholar · View at Scopus
  97. L. Song, J. H. Carlson, W. M. Whitmire et al., “Chlamydia trachomatis plasmid-encoded pgp4 is a transcriptional regulator of virulence-associated genes,” Infection and Immunity, vol. 81, no. 3, pp. 636–644, 2013. View at Publisher · View at Google Scholar · View at Scopus
  98. L. Kari, M. M. Goheen, L. B. Randall et al., “Generation of targeted Chlamydia trachomatis null mutants,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 17, pp. 7189–7193, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. A. Omsland, J. Sager, V. Nair, D. E. Sturdevant, and T. Hackstadt, “Developmental stage-specific metabolic and transcriptional activity of Chlamydia trachomatis in an axenic medium,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 48, pp. 19781–19785, 2012. View at Publisher · View at Google Scholar · View at Scopus
  100. H. M. B. Seth-Smith, S. R. Harris, R. J. Skilton et al., “Whole-genome sequences of Chlamydia trachomatis directly from clinical samples without culture,” Genome Research, vol. 23, no. 5, pp. 855–866, 2013. View at Publisher · View at Google Scholar · View at Scopus
  101. M. T. Christiansen, A. C. Brown, S. Kundu et al., “Whole-genome enrichment and sequencing of Chlamydia trachomatis directly from clinical samples,” BMC Infectious Diseases, vol. 14, article 591, 2014. View at Publisher · View at Google Scholar · View at Scopus
  102. V. Borges, R. Ferreira, A. Nunes et al., “Effect of long-term laboratory propagation on Chlamydia trachomatis genome dynamics,” Infection, Genetics and Evolution, vol. 17, pp. 23–32, 2013. View at Publisher · View at Google Scholar · View at Scopus
  103. P. M. Bavoil, G. Myers, B. Ma et al., “Eco-pathogenomics of chlamydial reproductive tract infection (EPCRTI),” in Proceedings of the 13th International Symposium on Human Chlamydial Infections, J. Schachter, G. Byrne, M. A. Chernesky et al., Eds., pp. 63–66, Asilomar Conference Grounds, Pacific Grove, Calif, USA, June 2014.
  104. C. Bonner, H. D. Caldwell, J. H. Carlson et al., “Chlamydia trachomatis virulence factor CT135 is stable in vivo but highly polymorphic in vitro,” Pathogens and Disease, vol. 73, Article ID ftv043, 2015. View at Publisher · View at Google Scholar
  105. S. D. Tyler, G. A. Peters, C. Grose et al., “Genomic cartography of varicella-zoster virus: a complete genome-based analysis of strain variability with implications for attenuation and phenotypic differences,” Virology, vol. 359, no. 2, pp. 447–458, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. D. J. Dargan, E. Douglas, C. Cunningham et al., “Sequential mutations associated with adaptation of human cytomegalovirus to growth in cell culture,” Journal of General Virology, vol. 91, pp. 1535–1546, 2010. View at Publisher · View at Google Scholar
  107. N. L. Bachmann, M. J. Sullivan, M. Jelocnik, G. S. A. Myers, P. Timms, and A. Polkinghorne, “Culture-independent genome sequencing of clinical samples reveals an unexpected heterogeneity of infections by Chlamydia pecorum,” Journal of Clinical Microbiology, vol. 53, no. 5, pp. 1573–1581, 2015. View at Publisher · View at Google Scholar
  108. D. Longbottom, M. Russell, S. M. Dunbar, G. E. Jones, and A. J. Herring, “Molecular cloning and characterization of the genes coding for the highly immunogenic cluster of 90-kilodalton envelope proteins from the Chlamydia psittaci subtype that causes abortion in sheep,” Infection & Immunity, vol. 66, no. 4, pp. 1317–1324, 1998. View at Google Scholar · View at Scopus
  109. D. R. Stothard, G. A. Toth, and B. E. Batteiger, “Polymorphic membrane protein H has evolved in parallel with the three disease-causing groups of Chlamydia trachomatis,” Infection and Immunity, vol. 71, no. 3, pp. 1200–1208, 2003. View at Publisher · View at Google Scholar · View at Scopus
  110. J. P. Gomes, A. Nunes, W. J. Bruno, M. J. Borrego, C. Florindo, and D. Dean, “Polymorphisms in the nine polymorphic membrane proteins of Chlamydia trachomatis across all serovars: evidence for serovar da recombination and correlation with tissue tropism,” Journal of Bacteriology, vol. 188, no. 1, pp. 275–286, 2006. View at Publisher · View at Google Scholar · View at Scopus
  111. D. D. Rockey, R. A. Heinzen, and T. Hackstadt, “Cloning and characterization of a Chlamydia psittaci gene coding for a protein localized in the inclusion membrane of infected cells,” Molecular Microbiology, vol. 15, no. 4, pp. 617–626, 1995. View at Publisher · View at Google Scholar · View at Scopus
  112. R.-C. Hsia, Y. Pannekoek, E. Ingerowski, and P. M. Bavoil, “Type III secretion genes identify a putative virulence locus of Chlamydia,” Molecular Microbiology, vol. 25, no. 2, pp. 351–359, 1997. View at Publisher · View at Google Scholar · View at Scopus
  113. P. S. Hefty and R. S. Stephens, “Chlamydial type III secretion system is encoded on ten operons preceded by Sigma 70-like promoter elements,” Journal of Bacteriology, vol. 189, no. 1, pp. 198–206, 2006. View at Publisher · View at Google Scholar · View at Scopus
  114. H. D. Caldwell, H. Wood, D. Crane et al., “Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates,” The Journal of Clinical Investigation, vol. 111, no. 11, pp. 1757–1769, 2003. View at Publisher · View at Google Scholar · View at Scopus
  115. H. Wood, C. Fehlner-Gardner, J. Berry et al., “Regulation of tryptophan synthase gene expression in Chlamydia trachomatis,” Molecular Microbiology, vol. 49, no. 5, pp. 1347–1359, 2003. View at Publisher · View at Google Scholar · View at Scopus
  116. J. H. Carlson, H. Wood, C. Roshick, H. D. Caldwell, and G. McClarty, “In vivo and in vitro studies of Chlamydia trachomatis TrpR:DNA interactions,” Molecular Microbiology, vol. 59, no. 6, pp. 1678–1691, 2006. View at Publisher · View at Google Scholar · View at Scopus
  117. C. M. O'Connell, Y. M. AbdelRahman, E. Green et al., “Toll-like receptor 2 activation by Chlamydia trachomatis is plasmid dependent, and plasmid-responsive chromosomal loci are coordinately regulated in response to glucose limitation by C. trachomatis but not by C. muridarum,” Infection and Immunity, vol. 79, no. 3, pp. 1044–1056, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. T. Hackstadt, M. A. Scidmore-Carlson, E. I. Shaw, and E. R. Fischer, “The Chlamydia trachomatis IncA protein is required for homotypic vesicle fusion,” Cellular Microbiology, vol. 1, no. 2, pp. 119–130, 1999. View at Publisher · View at Google Scholar · View at Scopus
  119. R. J. Suchland, D. D. Rockey, J. P. Bannantine, and W. E. Stamm, “Isolates of Chlamydia trachomatis that occupy nonfusogenic inclusions lack IncA, a protein localized to the inclusion membrane,” Infection and Immunity, vol. 68, no. 1, pp. 360–367, 2000. View at Publisher · View at Google Scholar · View at Scopus
  120. D. E. Nelson, D. D. Crane, L. D. Taylor, D. W. Dorward, M. M. Goheen, and H. D. Caldwell, “Inhibition of chlamydiae by primary alcohols correlates with the strain-specific complement of plasticity zone phospholipase D genes,” Infection and Immunity, vol. 74, no. 1, pp. 73–80, 2006. View at Publisher · View at Google Scholar · View at Scopus
  121. L. D. Taylor, D. E. Nelson, D. W. Dorward, W. M. Whitmire, and H. D. Caldwell, “Biological characterization of Chlamydia trachomatis plasticity zone MACPF domain family protein CT153,” Infection and Immunity, vol. 78, no. 6, pp. 2691–2699, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. D. LaVerda, L. N. Albanese, P. E. Ruther et al., “Seroreactivity to Chlamydia trachomatis Hsp10 correlates with severity of human genital tract disease,” Infection & Immunity, vol. 68, no. 1, pp. 303–309, 2000. View at Publisher · View at Google Scholar · View at Scopus
  123. A. Kol, A. H. Lichtman, R. W. Finberg, P. Libby, and E. A. Kurt-Jones, “Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells,” Journal of Immunology, vol. 164, no. 1, pp. 13–17, 2000. View at Publisher · View at Google Scholar · View at Scopus
  124. J. H. Carlson, S. Hughes, D. Hogan et al., “Polymorphisms in the Chlamydia trachomatis cytotoxin locus associated with ocular and genital isolates,” Infection and Immunity, vol. 72, no. 12, pp. 7063–7072, 2004. View at Publisher · View at Google Scholar · View at Scopus
  125. J. H. Carlson, W. M. Whitmire, D. D. Crane et al., “The Chlamydia trachomatis plasmid is a transcriptional regulator of chromosomal genes and a virulence factor,” Infection and Immunity, vol. 76, no. 6, pp. 2273–2283, 2008. View at Publisher · View at Google Scholar · View at Scopus
  126. L. C. Frazer, T. Darville, K. Chandra-Kuntal et al., “Plasmid-cured Chlamydia caviae activates TLR2-dependent signaling and retains virulence in the guinea pig model of genital tract infection,” PLoS ONE, vol. 7, no. 1, Article ID e30747, 2012. View at Publisher · View at Google Scholar · View at Scopus
  127. C. Tan, J. K. Spitznagel, H.-Z. Shou et al., “The polymorphic membrane protein gene family of the Chlamydiaciae,” in Chlamydia: Genomics and Pathogenesis, P. M. Bavoil and P. B. Wyrick, Eds., pp. 195–218, Horizon Bioscience, Norfolk, UK, 2006. View at Google Scholar
  128. K. A. Swanson, L. D. Taylor, S. D. Frank et al., “Chlamydia trachomatis polymorphic membrane protein D is an oligomeric autotransporter with a higher-order structure,” Infection and Immunity, vol. 77, no. 1, pp. 508–516, 2009. View at Publisher · View at Google Scholar · View at Scopus
  129. W. Wehrl, V. Brinkmann, P. R. Jungblut, T. F. Meyer, and A. J. Szczepek, “From the inside out—processing of the Chlamydial autotransporter PmpD and its role in bacterial adhesion and activation of human host cells,” Molecular Microbiology, vol. 51, no. 2, pp. 319–334, 2004. View at Publisher · View at Google Scholar · View at Scopus
  130. R. J. Belland, M. A. Scidmore, D. D. Crane et al., “Chlamydia trachomatis cytotoxicity associated with complete and partial cytotoxin genes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13984–13989, 2001. View at Publisher · View at Google Scholar · View at Scopus
  131. I. Tietzel, C. El-Haibi, and R. A. Carabeo, “Human guanylate binding proteins potentiate the anti-chlamydia effects of interferon-gamma,” PLoS ONE, vol. 4, no. 8, Article ID e6499, 2009. View at Publisher · View at Google Scholar · View at Scopus
  132. N. R. Thomson, M. T. G. Holden, C. Carder et al., “Chlamydia trachomatis: genome sequence analysis of lymphogranuloma venereum isolates,” Genome Research, vol. 18, no. 1, pp. 161–171, 2008. View at Publisher · View at Google Scholar · View at Scopus
  133. B. Fan, B. van der Pol, and D. Nelson, “Do chlamydial cytotoxins mediate IFN-γ immune evasion,” in Proceedings of the European Society for Chlamydia Research, vol. 6, pp. 165–171, 2008. View at Google Scholar
  134. M. Sait, M. Livingstone, E. M. Clark et al., “Genome sequencing and comparative analysis of three Chlamydia pecorum strains associated with different pathogenic outcomes,” BMC Genomics, vol. 15, article 23, 2014. View at Publisher · View at Google Scholar · View at Scopus
  135. A. Ciervo, F. Mancini, and A. Cassone, “Transcription, expression, localization and immunoreactivity of Chlamydophila pneumoniae Phospholipase D protein,” Microbial Pathogenesis, vol. 43, no. 2, pp. 96–105, 2007. View at Publisher · View at Google Scholar · View at Scopus
  136. D. R. Clifton, K. A. Fields, S. S. Grieshaber et al., “A chlamydial type III translocated protein is tyrosine-phosphorylated at the site of entry and associated with recruitment of actin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 27, pp. 10166–10171, 2004. View at Publisher · View at Google Scholar · View at Scopus
  137. W. M. Geisler, R. J. Suchland, D. D. Rockey, and W. E. Stamm, “Epidemiology and clinical manifestations of unique Chlamydia trachomatis isolates that occupy nonfusogenic inclusions,” Journal of Infectious Diseases, vol. 184, no. 7, pp. 879–884, 2001. View at Publisher · View at Google Scholar · View at Scopus
  138. K. M. Mirrashidi, C. A. Elwell, E. Verschueren et al., “Global mapping of the inc-human interactome reveals that retromer restricts Chlamydia infection,” Cell Host & Microbe, vol. 18, no. 1, pp. 109–121, 2015. View at Publisher · View at Google Scholar
  139. C. J. Hueck, “Type III protein secretion systems in bacterial pathogens of animals and plants,” Microbiology and Molecular Biology Reviews, vol. 62, no. 2, pp. 379–433, 1998. View at Google Scholar · View at Scopus
  140. J. J. Mecsas and E. J. Strauss, “Molecular mechanisms of bacterial virulence: type III secretion and pathogenicity islands,” Emerging Infectious Diseases, vol. 2, no. 4, pp. 270–288, 1996. View at Publisher · View at Google Scholar
  141. I. M. Sigar, J. H. Schripsema, Y. Wang et al., “Plasmid deficiency in urogenital isolates of Chlamydia trachomatis reduces infectivity and virulence in a mouse model,” Pathogens and Disease, vol. 70, no. 1, pp. 61–69, 2014. View at Publisher · View at Google Scholar · View at Scopus
  142. M. Russell, T. Darville, K. Chandra-Kuntal, B. Smith, C. W. Andrews Jr., and C. M. O'Connell, “Infectivity acts as in vivo selection for maintenance of the chlamydial cryptic plasmid,” Infection and Immunity, vol. 79, no. 1, pp. 98–107, 2011. View at Publisher · View at Google Scholar · View at Scopus
  143. A. R. Last, C. H. Roberts, E. Cassama et al., “Plasmid copy number and disease severity in naturally occurring ocular Chlamydia trachomatis infection,” Journal of Clinical Microbiology, vol. 52, no. 1, pp. 324–327, 2014. View at Publisher · View at Google Scholar · View at Scopus
  144. A. J. Twigg and D. Sherratt, “Trans-complementable copy-number mutants of plasmid ColE1,” Nature, vol. 283, no. 5743, pp. 216–218, 1980. View at Publisher · View at Google Scholar · View at Scopus
  145. N. S. Thomas, M. Lusher, C. C. Storey, and I. N. Clarke, “Plasmid diversity in Chlamydia,” Microbiology, vol. 143, no. 6, pp. 1847–1854, 1997. View at Publisher · View at Google Scholar · View at Scopus
  146. Q. An, G. Radcliffe, R. Vassallo et al., “Infection with a plasmid-free variant chlamydia related to Chlamydia trachomatis identified by using multiple assays for nucleic acid detection,” Journal of Clinical Microbiology, vol. 30, no. 11, pp. 2814–2821, 1992. View at Google Scholar · View at Scopus
  147. E. M. Peterson, B. A. Markoff, J. Schachter, and L. M. de la Maza, “The 7.5-kb plasmid present in Chlamydia trachomatis is not essential for the growth of this microorganism,” Plasmid, vol. 23, no. 2, pp. 144–148, 1990. View at Publisher · View at Google Scholar · View at Scopus
  148. S. F. Porcella, J. H. Carlson, D. E. Sturdevant et al., “Transcriptional profiling of human epithelial cells infected with plasmid-bearing and plasmid-deficient Chlamydia trachomatis,” Infection and Immunity, vol. 83, no. 2, pp. 534–543, 2015. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Laabei, M. Recker, J. K. Rudkin et al., “Predicting the virulence of MRSA from its genome sequence,” Genome Research, vol. 24, no. 5, pp. 839–849, 2014. View at Publisher · View at Google Scholar · View at Scopus
  150. T. D. Read and R. C. Massey, “Characterizing the genetic basis of bacterial phenotypes using genome-wide association studies: a new direction for bacteriology,” Genome Medicine, vol. 6, no. 11, article 109, 2014. View at Publisher · View at Google Scholar
  151. S. K. Sheppard, X. Didelot, G. Meric et al., “Genome-wide association study identifies vitamin B5 biosynthesis as a host specificity factor in Campylobacter,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 29, pp. 11923–11927, 2013. View at Publisher · View at Google Scholar · View at Scopus
  152. M. R. Farhat, B. J. Shapiro, K. J. Kieser et al., “Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis,” Nature Genetics, vol. 45, no. 10, pp. 1183–1189, 2013. View at Publisher · View at Google Scholar · View at Scopus
  153. M. T. Alam, R. A. Petit, E. K. Crispell et al., “Dissecting vancomycin-intermediate resistance in Staphylococcus aureus using genome-wide association,” Genome Biology and Evolution, vol. 6, no. 5, pp. 1174–1185, 2014. View at Publisher · View at Google Scholar · View at Scopus
  154. C. Chewapreecha, P. Marttinen, N. J. Croucher et al., “Comprehensive identification of single nucleotide polymorphisms associated with beta-lactam resistance within pneumococcal mosaic genes,” PLoS Genetics, vol. 10, no. 8, Article ID e1004547, 2014. View at Publisher · View at Google Scholar
  155. V. H. Hu, P. Massae, H. A. Weiss et al., “Bacterial infection in scarring trachoma,” Investigative Ophthalmology & Visual Science, vol. 52, pp. 2181–2186, 2011. View at Publisher · View at Google Scholar
  156. M. J. Burton, R. A. Adegbola, F. Kinteh et al., “Bacterial infection and trachoma in the Gambia: a case-control study,” Investigative Ophthalmology and Visual Science, vol. 48, no. 10, pp. 4440–4444, 2007. View at Publisher · View at Google Scholar · View at Scopus
  157. V. Cevallos, J. P. Whitcher, M. Melese et al., “Association of conjunctival bacterial infection and female sex in cicatricial trachoma,” Investigative Ophthalmology & Visual Science, vol. 53, no. 9, pp. 5208–5212, 2012. View at Publisher · View at Google Scholar · View at Scopus
  158. M. J. Burton, V. H. Hu, P. Massae et al., “What Is causing active trachoma? The role of nonchlamydial bacterial pathogens in a low prevalence setting,” Investigative Ophthalmology and Visual Science, vol. 52, no. 8, pp. 6012–6017, 2011. View at Publisher · View at Google Scholar · View at Scopus
  159. S. E. Burr, J. D. Hart, T. Edwards et al., “Association between ocular bacterial carriage and follicular trachoma following mass azithromycin distribution in The Gambia,” PLoS Neglected Tropical Diseases, vol. 7, no. 7, Article ID e2347, 2013. View at Publisher · View at Google Scholar · View at Scopus
  160. M. J. Burton, R. J. C. Bowman, H. Faal et al., “Long term outcome of trichiasis surgery in the Gambia,” British Journal of Ophthalmology, vol. 89, no. 5, pp. 575–579, 2005. View at Publisher · View at Google Scholar · View at Scopus
  161. M. J. Burton, R. L. Bailey, D. Jeffries et al., “Conjunctival expression of matrix metalloproteinase and proinflammatory cytokine genes after trichiasis surgery,” Investigative Ophthalmology and Visual Science, vol. 51, no. 7, pp. 3583–3590, 2010. View at Publisher · View at Google Scholar · View at Scopus
  162. D. N. Frank, A. L. St Amand, R. A. Feldman, E. C. Boedeker, N. Harpaz, and N. R. Pace, “Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 34, pp. 13780–13785, 2007. View at Publisher · View at Google Scholar · View at Scopus
  163. B. Willing, J. Halfvarson, J. Dicksved et al., “Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease,” Inflammatory Bowel Diseases, vol. 15, no. 5, pp. 653–660, 2009. View at Publisher · View at Google Scholar · View at Scopus
  164. A. W. Walker, J. D. Sanderson, C. Churcher et al., “High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease,” BMC Microbiology, vol. 11, article 7, 2011. View at Publisher · View at Google Scholar · View at Scopus
  165. A. J. McDermott and G. B. Huffnagle, “The microbiome and regulation of mucosal immunity,” Immunology, vol. 142, no. 1, pp. 24–31, 2014. View at Publisher · View at Google Scholar · View at Scopus
  166. M. Valentini, A. Piermattei, G. Di Sante, G. Migliara, G. Delogu, and F. Ria, “Immunomodulation by gut microbiota: role of Toll-like receptor expressed by T cells,” Journal of Immunology Research, vol. 2014, Article ID 586939, 8 pages, 2014. View at Publisher · View at Google Scholar
  167. M. M. Kosiewicz, A. L. Zirnheld, and P. Alard, “Gut microbiota, immunity, and disease: a complex relationship,” Frontiers in Microbiology, vol. 2, article 180, 2011. View at Publisher · View at Google Scholar · View at Scopus
  168. N. Van Oostrum, P. De Sutter, J. Meys, and H. Verstraelen, “Risks associated with bacterial vaginosis in infertility patients: a systematic review and meta-analysis,” Human Reproduction, vol. 28, no. 7, pp. 1809–1815, 2013. View at Publisher · View at Google Scholar · View at Scopus
  169. S. D. Spandorfer, A. Neuer, P. C. Giraldo, Z. Rosenwaks, and S. S. Witkin, “Relationship of abnormal vaginal flora, proinflammatory cytokines and idiopathic infertility in women undergoing IVF,” Journal of Reproductive Medicine for the Obstetrician and Gynecologist, vol. 46, no. 9, pp. 806–810, 2001. View at Google Scholar · View at Scopus
  170. Q. Dong, J. M. Brulc, A. Iovieno et al., “Diversity of bacteria at healthy human conjunctiva,” Investigative Ophthalmology and Visual Science, vol. 52, no. 8, pp. 5408–5413, 2011. View at Publisher · View at Google Scholar · View at Scopus
  171. Y. Zhou, H. Gao, K. A. Mihindukulasuriya et al., “Biogeography of the ecosystems of the healthy human body,” Genome Biology, vol. 14, article R1, 2013. View at Publisher · View at Google Scholar
  172. Y. Zhou, M. J. Holland, P. Makalo et al., “The conjunctival microbiome in health and trachomatous disease: a case control study,” Genome Medicine, vol. 6, article 99, 2014. View at Publisher · View at Google Scholar
  173. R. P. Dickson, J. R. Erb-Downward, and G. B. Huffnagle, “The role of the bacterial microbiome in lung disease,” Expert Review of Respiratory Medicine, vol. 7, no. 3, pp. 245–257, 2013. View at Publisher · View at Google Scholar · View at Scopus
  174. D.-P. Mao, Q. Zhou, C.-Y. Chen, and Z.-X. Quan, “Coverage evaluation of universal bacterial primers using the metagenomic datasets,” BMC Microbiology, vol. 12, article 66, 2012. View at Publisher · View at Google Scholar · View at Scopus
  175. G. Dubourg, J. C. Lagier, F. Armougom et al., “The gut microbiota of a patient with resistant tuberculosis is more comprehensively studied by culturomics than by metagenomics,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 32, no. 5, pp. 637–645, 2013. View at Publisher · View at Google Scholar · View at Scopus
  176. A. A. Pezzulo, P. H. Kelly, B. S. Nassar et al., “Abundant dnase I-sensitive bacterial DNA in healthy porcine lungs and its implications for the lung microbiome,” Applied and Environmental Microbiology, vol. 79, no. 19, pp. 5936–5941, 2013. View at Publisher · View at Google Scholar · View at Scopus
  177. J.-C. Lagier, F. Armougom, M. Million et al., “Microbial culturomics: paradigm shift in the human gut microbiome study,” Clinical Microbiology and Infection, vol. 18, no. 12, pp. 1185–1193, 2012. View at Publisher · View at Google Scholar · View at Scopus
  178. J.-C. Lagier, M. Million, P. Hugon, F. Armougom, and D. Raoult, “Human gut microbiota: repertoire and variations,” Frontiers in Cellular and Infection Microbiology, vol. 2, article 136, 2012. View at Publisher · View at Google Scholar
  179. A. Omsland, T. Hackstadt, and R. A. Heinzen, “Bringing culture to the uncultured: Coxiella burnetii and lessons for obligate intracellular bacterial pathogens,” PLoS Pathogens, vol. 9, no. 9, Article ID e1003540, 2013. View at Publisher · View at Google Scholar · View at Scopus
  180. N. W. Palm, M. R. de Zoete, T. W. Cullen et al., “Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease,” Cell, vol. 158, no. 5, pp. 1000–1010, 2014. View at Publisher · View at Google Scholar · View at Scopus
  181. A. L. Kau, J. D. Planer, J. Liu et al., “Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy,” Science Translational Medicine, vol. 7, no. 276, Article ID 276ra24, 2015. View at Publisher · View at Google Scholar
  182. H. Bierne, M. Hamon, and P. Cossart, “Epigenetics and bacterial infections,” Cold Spring Harbor Perspectives in Medicine, 2012. View at Publisher · View at Google Scholar
  183. S.-H. Shin, S.-Y. Park, J.-S. Ko, N. Kim, and G. H. Kang, “Aberrant CpG island hypermethylation in pediatric gastric mucosa in association with helicobacter pylori infection,” Archives of Pathology & Laboratory Medicine, vol. 135, no. 6, pp. 759–765, 2011. View at Google Scholar · View at Scopus
  184. F.-Y. Huang, A. O.-O. Chan, A. Rashid, D. K.-H. Wong, C.-H. Cho, and M.-F. Yuen, “Helicobacter pylori induces promoter methylation of E-cadherin via interleukin-1β activation of nitric oxide production in gastric cancer cells,” Cancer, vol. 118, no. 20, pp. 4969–4980, 2012. View at Publisher · View at Google Scholar · View at Scopus
  185. J. Kleinnijenhuis, J. Quintin, F. Preijers et al., “Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 43, pp. 17537–17542, 2012. View at Publisher · View at Google Scholar · View at Scopus
  186. M. Murata, Y. Azuma, K. Miura et al., “Chlamydial SET domain protein functions as a histone methyltransferase,” Microbiology, vol. 153, no. 2, pp. 585–592, 2007. View at Publisher · View at Google Scholar · View at Scopus
  187. M. E. Pennini, S. Perrinet, A. Dautry-Varsat, and A. Subtil, “Histone methylation by NUE, a novel nuclear effector of the intracellular pathogen Chlamydia trachomatis,” PLoS Pathogens, vol. 6, no. 7, Article ID e1000995, pp. 1–12, 2010. View at Publisher · View at Google Scholar · View at Scopus
  188. M. S. Humphrys, T. Creasy, Y. Sun et al., “Simultaneous transcriptional profiling of bacteria and their host cells,” PLoS ONE, vol. 8, no. 12, Article ID e80597, 2013. View at Publisher · View at Google Scholar · View at Scopus
  189. P. Kapranov, J. Cheng, S. Dike et al., “RNA maps reveal new RNA classes and a possible function for pervasive transcription,” Science, vol. 316, no. 5830, pp. 1484–1488, 2007. View at Publisher · View at Google Scholar · View at Scopus
  190. R. C. Friedman, K. K.-H. Farh, C. B. Burge, and D. P. Bartel, “Most mammalian mRNAs are conserved targets of microRNAs,” Genome Research, vol. 19, no. 1, pp. 92–105, 2009. View at Publisher · View at Google Scholar · View at Scopus
  191. J. Martinez, A. Patkaniowska, H. Urlaub, R. Lührmann, and T. Tuschl, “Single-stranded antisense siRNAs guide target RNA cleavage in RNAi,” Cell, vol. 110, no. 5, pp. 563–574, 2002. View at Publisher · View at Google Scholar · View at Scopus
  192. C. E. Vejnar and E. M. Zdobnov, “11673,” Nucleic Acids Research, vol. 40, no. 22, pp. 11673–11683, 2012. View at Publisher · View at Google Scholar · View at Scopus
  193. D. P. Bartel, “MicroRNAs: genomics, biogenesis, mechanism, and function,” Cell, vol. 116, no. 2, pp. 281–297, 2004. View at Publisher · View at Google Scholar · View at Scopus
  194. V. Ambros, “The functions of animal microRNAs,” Nature, vol. 431, no. 7006, pp. 350–355, 2004. View at Publisher · View at Google Scholar · View at Scopus
  195. S. Memczak, M. Jens, A. Elefsinioti et al., “Circular RNAs are a large class of animal RNAs with regulatory potency,” Nature, vol. 495, no. 7441, pp. 333–338, 2013. View at Publisher · View at Google Scholar · View at Scopus
  196. T. B. Hansen, T. I. Jensen, B. H. Clausen et al., “Natural RNA circles function as efficient microRNA sponges,” Nature, vol. 495, no. 7441, pp. 384–388, 2013. View at Publisher · View at Google Scholar · View at Scopus
  197. M. Van Kouwenhove, M. Kedde, and R. Agami, “MicroRNA regulation by RNA-binding proteins and its implications for cancer,” Nature Reviews Cancer, vol. 11, no. 9, pp. 644–656, 2011. View at Publisher · View at Google Scholar · View at Scopus
  198. S. R. Viswanathan, G. Q. Daley, and R. I. Gregory, “Selective blockade of microRNA processing by Lin28,” Science, vol. 320, no. 5872, pp. 97–100, 2008. View at Publisher · View at Google Scholar · View at Scopus
  199. C. Staedel and F. Darfeuille, “MicroRNAs and bacterial infection,” Cellular Microbiology, vol. 15, no. 9, pp. 1496–1507, 2013. View at Publisher · View at Google Scholar · View at Scopus
  200. A. Eulalio, L. N. Schulte, and J. Voge, “The mammalian microRNA response to bacterial infections,” RNA Biology, vol. 9, no. 6, pp. 742–750, 2012. View at Publisher · View at Google Scholar · View at Scopus
  201. C. Maudet, M. Mano, and A. Eulalio, “microRNAs in the interaction between host and bacterial pathogens,” FEBS Letters, vol. 588, no. 22, pp. 4140–4147, 2014. View at Publisher · View at Google Scholar · View at Scopus
  202. L. Yeruva, G. S. Myers, N. Spencer et al., “Early microRNA expression profile as a prognostic biomarker for the development of pelvic inflammatory disease in a mouse model of chlamydial genital infection,” mBio, vol. 5, no. 3, Article ID e01241-14, 2014. View at Publisher · View at Google Scholar
  203. R. Gupta, T. Arkatkar, J.-J. Yu et al., “Chlamydia muridarum infection associated host MicroRNAs in the murine genital tract and contribution to generation of host immune response,” The American Journal of Reproductive Immunology, vol. 73, no. 2, pp. 126–140, 2015. View at Publisher · View at Google Scholar · View at Scopus
  204. R. L. Rossi, G. Rossetti, L. Wenandy et al., “Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b,” Nature Immunology, vol. 12, no. 8, pp. 796–803, 2011. View at Publisher · View at Google Scholar · View at Scopus
  205. J. U. Igietseme, Y. Omosun, J. Partin et al., “Prevention of chlamydia-induced infertility by inhibition of local caspase activity,” The Journal of Infectious Diseases, vol. 207, no. 7, pp. 1095–1104, 2013. View at Publisher · View at Google Scholar · View at Scopus
  206. W. Zhang, X. Yi, S. Guo et al., “A single-nucleotide polymorphism of miR-146a and psoriasis: an association and functional study,” Journal of Cellular and Molecular Medicine, vol. 18, no. 11, pp. 2225–2234, 2014. View at Publisher · View at Google Scholar
  207. W. Wang, F. R. Stassen, H.-M. Surcel et al., “Analyses of polymorphisms in the inflammasome-associated NLRP3 and miRNA-146A genes in the susceptibility to and tubal pathology of Chlamydia trachomatis infection,” Drugs of Today, vol. 45, pp. 95–103, 2009. View at Google Scholar · View at Scopus
  208. T. Derrick, C. h. Roberts, M. Rajasekhar et al., “Conjunctival MicroRNA expression in inflammatory trachomatous scarring,” PLoS Neglected Tropical Diseases, vol. 7, no. 3, p. e2117, 2013. View at Publisher · View at Google Scholar
  209. G. Liu, A. Friggeri, Y. Yang, Y.-J. Park, Y. Tsuruta, and E. Abraham, “miR-147, a microRNA that is induced upon toll-like receptor stimulation, regulates murine macrophage inflammatory responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 37, pp. 15819–15824, 2009. View at Publisher · View at Google Scholar · View at Scopus
  210. T. Bertero, S. Grosso, K. Robbe-Sermesant et al., “‘Seed-milarity’ confers to hsa-miR-210 and hsa-miR-147b similar functional activity,” PLoS ONE, vol. 7, Article ID e44919, 2012. View at Publisher · View at Google Scholar
  211. S. Tian, S. Huang, S. Wu, W. Guo, J. Li, and X. He, “MicroRNA-1285 inhibits the expression of p53 by directly targeting its 3′ untranslated region,” Biochemical and Biophysical Research Communications, vol. 396, no. 2, pp. 435–439, 2010. View at Publisher · View at Google Scholar · View at Scopus
  212. H. Hidaka, N. Seki, H. Yoshino et al., “Tumor suppressive microRNA-1285 regulates novel molecular targets: aberrant expression and functional significance in renal cell carcinoma,” Oncotarget, vol. 3, no. 1, pp. 44–57, 2012. View at Google Scholar · View at Scopus
  213. B. R. Cullen, “Viruses and microRNAs: RISCy interactions with serious consequences,” Genes & Development, vol. 25, no. 18, pp. 1881–1894, 2011. View at Publisher · View at Google Scholar · View at Scopus
  214. W. de Vries and B. Berkhout, “RNAi suppressors encoded by pathogenic human viruses,” The International Journal of Biochemistry & Cell Biology, vol. 40, no. 10, pp. 2007–2012, 2008. View at Publisher · View at Google Scholar · View at Scopus
  215. M. Kumar, S. K. Sahu, R. Kumar et al., “microRNA let-7 modulates the immune response to Mycobacterium tuberculosis infection via control of A20, an inhibitor of the NF-κB pathway,” Cell Host & Microbe, vol. 17, no. 3, pp. 345–356, 2015. View at Publisher · View at Google Scholar · View at Scopus
  216. A. H. Buck, G. Coakley, F. Simbari et al., “Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity,” Nature Communications, vol. 5, article 5488, 2014. View at Publisher · View at Google Scholar
  217. Y. Furuse, R. Finethy, H. A. Saka et al., “Search for microRNAs expressed by intracellular bacterial pathogens in infected mammalian cells,” PLoS ONE, vol. 9, no. 9, Article ID e106434, 2014. View at Publisher · View at Google Scholar · View at Scopus
  218. Y. M. Abdelrahman, L. A. Rose, and R. J. Belland, “Developmental expression of non-coding RNAs in Chlamydia trachomatis during normal and persistent growth,” Nucleic Acids Research, vol. 39, no. 5, pp. 1843–1854, 2011. View at Publisher · View at Google Scholar · View at Scopus
  219. M. Albrecht, C. M. Sharma, R. Reinhardt, J. Vogel, and T. Rudel, “Deep sequencing-based discovery of the Chlamydia trachomatis transcriptome,” Nucleic Acids Research, vol. 38, no. 3, Article ID gkp1032, pp. 868–877, 2009. View at Publisher · View at Google Scholar · View at Scopus
  220. S. Ricci, R. Cevenini, E. Cosco, M. Comanducci, G. Ratti, and V. Scarlato, “Transcriptional analysis of the Chlamydia trachomatis plasmid pCT identifies temporally regulated transcripts, anti-sense RNA and σ70-selected promoters,” Molecular & General Genetics, vol. 237, no. 3, pp. 318–326, 1993. View at Publisher · View at Google Scholar · View at Scopus
  221. R. Kalluri and R. A. Weinberg, “The basics of epithelial-mesenchymal transition,” The Journal of Clinical Investigation, vol. 119, no. 6, pp. 1420–1428, 2009. View at Publisher · View at Google Scholar
  222. M. Zeisberg and E. G. Neilson, “Biomarkers for epithelial-mesenchymal transitions,” Journal of Clinical Investigation, vol. 119, no. 6, pp. 1429–1437, 2009. View at Publisher · View at Google Scholar · View at Scopus
  223. E. M. Zeisberg, O. Tarnavski, M. Zeisberg et al., “Endothelial-to-mesenchymal transition contributes to cardiac fibrosis,” Nature Medicine, vol. 13, no. 8, pp. 952–961, 2007. View at Google Scholar · View at Scopus
  224. H. Okada, F. Strutz, T. M. Danoff, R. Kalluri, and E. G. Neilson, “Possible mechanisms of renal fibrosis,” Contributions to Nephrology, vol. 118, pp. 147–154, 1996. View at Publisher · View at Google Scholar · View at Scopus
  225. M. Iwano, D. Plieth, T. M. Danoff, C. Xue, H. Okada, and E. G. Neilson, “Evidence that fibroblasts derive from epithelium during tissue fibrosis,” The Journal of Clinical Investigation, vol. 110, no. 3, pp. 341–350, 2002. View at Publisher · View at Google Scholar · View at Scopus
  226. M. Chilosi, V. Poletti, A. Zamò et al., “Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis,” American Journal of Pathology, vol. 162, no. 5, pp. 1495–1502, 2003. View at Publisher · View at Google Scholar · View at Scopus
  227. M. Zeisberg, C. Yang, M. Martino et al., “Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition,” Journal of Biological Chemistry, vol. 282, no. 32, pp. 23337–23347, 2007. View at Publisher · View at Google Scholar · View at Scopus
  228. C. Yan, W. A. Grimm, W. L. Garner et al., “Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2,” American Journal of Pathology, vol. 176, no. 5, pp. 2247–2258, 2010. View at Publisher · View at Google Scholar · View at Scopus
  229. J. P. Thiery, H. Acloque, R. Y. J. Huang, and M. A. Nieto, “Epithelial-mesenchymal transitions in development and disease,” Cell, vol. 139, no. 5, pp. 871–890, 2009. View at Publisher · View at Google Scholar · View at Scopus
  230. A.-P. Morel, M. Lièvre, C. Thomas, G. Hinkal, S. Ansieau, and A. Puisieux, “Generation of breast cancer stem cells through epithelial-mesenchymal transition,” PLoS ONE, vol. 3, no. 8, Article ID e2888, 2008. View at Publisher · View at Google Scholar · View at Scopus
  231. U. Wellner, J. Schubert, U. C. Burk et al., “The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs,” Nature Cell Biology, vol. 11, no. 12, pp. 1487–1495, 2009. View at Publisher · View at Google Scholar · View at Scopus
  232. S. A. Mani, W. Guo, M.-J. Liao et al., “The epithelial-mesenchymal transition generates cells with properties of stem cells,” Cell, vol. 133, no. 4, pp. 704–715, 2008. View at Publisher · View at Google Scholar · View at Scopus
  233. O. G. McDonald, H. Wu, W. Timp, A. Doi, and A. P. Feinberg, “Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition,” Nature Structural & Molecular Biology, vol. 18, no. 8, pp. 867–874, 2011. View at Publisher · View at Google Scholar · View at Scopus
  234. M. Lombaerts, T. van Wezel, K. Philippo et al., “E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines,” British Journal of Cancer, vol. 94, no. 5, pp. 661–671, 2006. View at Publisher · View at Google Scholar · View at Scopus
  235. N. Dumont, M. B. Wilson, Y. G. Crawford, P. A. Reynolds, M. Sigaroudinia, and T. D. Tlsty, “Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 39, pp. 14867–14872, 2008. View at Publisher · View at Google Scholar · View at Scopus
  236. S.-O. Lim, J.-M. Gu, M. S. Kim et al., “Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter,” Gastroenterology, vol. 135, no. 6, pp. 2128–2140.e8, 2008. View at Publisher · View at Google Scholar
  237. H. Peinado, E. Ballestar, M. Esteller, and A. Cano, “Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex,” Molecular and Cellular Biology, vol. 24, no. 1, pp. 306–319, 2004. View at Publisher · View at Google Scholar
  238. S. K. Bose, K. Meyer, A. M. Di Bisceglie, R. B. Ray, and R. Ray, “Hepatitis C virus induces epithelial-mesenchymal transition in primary human hepatocytes,” Journal of Virology, vol. 86, no. 24, pp. 13621–13628, 2012. View at Publisher · View at Google Scholar · View at Scopus
  239. L. Zhao, R. Yang, L. Cheng, M. Wang, Y. Jiang, and S. Wang, “LPS-induced epithelial-mesenchymal transition of intrahepatic biliary epithelial cells,” Journal of Surgical Research, vol. 171, no. 2, pp. 819–825, 2011. View at Publisher · View at Google Scholar · View at Scopus
  240. V. Pozharskaya, E. Torres-González, M. Rojas et al., “Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis,” PLoS ONE, vol. 4, no. 10, Article ID e7559, 2009. View at Publisher · View at Google Scholar · View at Scopus
  241. G. Cane, A. Ginouvès, S. Marchetti et al., “HIF-1alpha mediates the induction of IL-8 and VEGF expression on infection with Afa/Dr diffusely adhering E. coli and promotes EMT-like behaviour,” Cellular Microbiology, vol. 12, no. 5, pp. 640–653, 2010. View at Publisher · View at Google Scholar · View at Scopus
  242. E. Papini, B. Satin, N. Norais et al., “Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin,” The Journal of Clinical Investigation, vol. 102, no. 4, pp. 813–820, 1998. View at Publisher · View at Google Scholar · View at Scopus
  243. M. R. Amieva, R. Vogetmann, A. Covacci, L. S. Tompkins, W. J. Nelson, and S. Falkow, “Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA,” Science, vol. 300, no. 5624, pp. 1430–1434, 2003. View at Publisher · View at Google Scholar · View at Scopus
  244. N. Murata-Kamiya, Y. Kurashima, Y. Teishikata et al., “Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells,” Oncogene, vol. 26, no. 32, pp. 4617–4626, 2007. View at Publisher · View at Google Scholar · View at Scopus
  245. F. Yin, A. M. Grabowska, P. A. Clarke et al., “Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7,” Gut, vol. 59, no. 8, pp. 1037–1045, 2010. View at Publisher · View at Google Scholar · View at Scopus
  246. J. Baud, C. Varon, S. Chabas, L. Chambonnier, F. Darfeuille, and C. Staedel, “Helicobacter pylori initiates a mesenchymal transition through ZEB1 in gastric epithelial cells,” PLoS ONE, vol. 8, no. 4, Article ID e60315, 2013. View at Publisher · View at Google Scholar · View at Scopus
  247. M. Kessler, J. Zielecki, O. Thieck, H.-J. Mollenkopf, C. Fotopoulou, and T. F. Meyer, “Chlamydia trachomatis disturbs epithelial tissue homeostasis in fallopian tubes via paracrine Wnt signaling,” American Journal of Pathology, vol. 180, no. 1, pp. 186–198, 2012. View at Publisher · View at Google Scholar · View at Scopus
  248. W. C. Prozialeck, M. J. Fay, P. C. Lamar, C. A. Pearson, I. Sigar, and K. H. Ramsey, “Chlamydia trachomatis disrupts N-cadherin-dependent cell-cell junctions and sequesters beta-catenin in human cervical epithelial cells,” Infection and Immunity, vol. 70, no. 5, pp. 2605–2613, 2002. View at Publisher · View at Google Scholar · View at Scopus
  249. J. Sun, J. Kintner, and R. V. Schoborg, “The host adherens junction molecule nectin-1 is downregulated in Chlamydia trachomatis-infected genital epithelial cells,” Microbiology, vol. 154, no. 5, pp. 1290–1299, 2008. View at Publisher · View at Google Scholar · View at Scopus
  250. M. J. Holland, D. Jeffries, M. Pattison et al., “Pathway-focused arrays reveal increased matrix metalloproteinase-7 (Matrilysin) transcription in trachomatous trichiasis,” Investigative Ophthalmology and Visual Science, vol. 51, no. 8, pp. 3893–3902, 2010. View at Publisher · View at Google Scholar · View at Scopus
  251. H.-C. Chen, Y.-T. Zhu, S.-Y. Chen, and S. C. G. Tseng, “Wnt signaling induces epithelial-mesenchymal transition with proliferation in ARPE-19 cells upon loss of contact inhibition,” Laboratory Investigation, vol. 92, no. 5, pp. 676–687, 2012. View at Publisher · View at Google Scholar · View at Scopus
  252. D. A. Cusanovich, C. Billstrand, X. Zhou et al., “The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes,” Human Molecular Genetics, vol. 21, no. 9, pp. 2111–2123, 2012. View at Publisher · View at Google Scholar · View at Scopus
  253. P. Jia and Z. Zhao, “Network-assisted analysis to prioritize GWAS results: principles, methods and perspectives,” Human Genetics, vol. 133, no. 2, pp. 125–138, 2014. View at Publisher · View at Google Scholar · View at Scopus
  254. P. Holmans, E. K. Green, J. S. Pahwa et al., “Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder,” The American Journal of Human Genetics, vol. 85, no. 1, pp. 13–24, 2009. View at Publisher · View at Google Scholar · View at Scopus
  255. R. Braun and K. Buetow, “Pathways of distinction analysis: a new technique for multi-SNP analysis of GWAS data,” PLoS Genetics, vol. 7, no. 6, Article ID e1002101, 2011. View at Publisher · View at Google Scholar · View at Scopus
  256. C. S. Greene, N. M. Penrod, J. Kiralis, and J. H. Moore, “Spatially uniform reliefF (SURF) for computationally-efficient filtering of gene-gene interactions,” BioData Mining, vol. 2, article 5, 2009. View at Publisher · View at Google Scholar · View at Scopus
  257. M. D. Ritchie, L. W. Hahn, N. Roodi et al., “Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer,” The American Journal of Human Genetics, vol. 69, no. 1, pp. 138–147, 2001. View at Publisher · View at Google Scholar · View at Scopus
  258. P. Jia and Z. Zhao, “Searching joint association signals in CATIE schizophrenia genome-wide association studies through a refined integrative network approach,” BMC Genomics, vol. 13, supplement 6, article S15, 2012. View at Publisher · View at Google Scholar
  259. S. Purcell, B. Neale, K. Todd-Brown et al., “PLINK: a tool set for whole-genome association and population-based linkage analyses,” The American Journal of Human Genetics, vol. 81, no. 3, pp. 559–575, 2007. View at Publisher · View at Google Scholar · View at Scopus
  260. L. S. Chen, C. M. Hutter, J. D. Potter et al., “Insights into colon cancer etiology via a regularized approach to gene set analysis of GWAS data,” The American Journal of Human Genetics, vol. 86, no. 6, pp. 860–871, 2010. View at Publisher · View at Google Scholar · View at Scopus
  261. D. Knights, M. S. Silverberg, R. K. Weersma et al., “Complex host genetics influence the microbiome in inflammatory bowel disease,” Genome Medicine, vol. 6, article 107, 2014. View at Publisher · View at Google Scholar
  262. B. P. Fairfax, S. Makino, J. Radhakrishnan et al., “Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles,” Nature Genetics, vol. 44, no. 5, pp. 502–510, 2012. View at Publisher · View at Google Scholar · View at Scopus
  263. D. Wong, W. Lee, P. Humburg et al., “Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach,” Genome Biology, vol. 15, no. 10, p. 494, 2014. View at Publisher · View at Google Scholar
  264. D. E. Sturdevant, K. Virtaneva, C. Martens et al., “Host-microbe interaction systems biology: lifecycle transcriptomics and comparative genomics,” Future Microbiology, vol. 5, no. 2, pp. 205–219, 2010. View at Publisher · View at Google Scholar · View at Scopus