1932

Abstract

Infectious diseases affect individual health and have widespread societal impacts. New ex vivo models are critical to understand pathogenesis, host response, and features necessary to develop preventive and therapeutic treatments. Pluripotent and tissue stem cell–derived organoids provide new tools for the study of human infections. Organoid models recapitulate many characteristics of in vivo disease and are providing new insights into human respiratory, gastrointestinal, and neuronal host–microbe interactions. Increasing culture complexity by adding the stroma, interorgan communication, and the microbiome will improve the use of organoids as models for infection. Organoid cultures provide a platform with the capability to improve human health related to infectious diseases.

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2022-01-27
2024-04-25
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Literature Cited

  1. 1. 
    GBD 2016 DALYs and HALE Collab 2017. Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390:101001260–344
    [Google Scholar]
  2. 2. 
    Michaud CM. 2009. Global burden of infectious diseases. Encycl. Microbiol. 2009 444–54
    [Google Scholar]
  3. 3. 
    Colzani E. 2019. Beyond morbidity and mortality: the burden of infectious diseases on healthcare services. Epidemiol. Infect. 147:e251
    [Google Scholar]
  4. 4. 
    VanDussen KL, Marinshaw JM, Shaikh N et al. 2015. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 64:6911–20
    [Google Scholar]
  5. 5. 
    Co JY, Margalef-Catala M, Li X et al. 2019. Controlling epithelial polarity: a human enteroid model for host–pathogen interactions. Cell Rep 26:92509–20
    [Google Scholar]
  6. 6. 
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al. 1998. Embryonic stem cell lines derived from human blastocysts. Science 282:53911145–47
    [Google Scholar]
  7. 7. 
    Takahashi K, Tanabe K, Ohnuki M et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:5861–72
    [Google Scholar]
  8. 8. 
    McCracken KW, Howell JC, Wells JM, Spence JR 2011. Generating human intestinal tissue from pluripotent stem cells in vitro. Nat. Protoc. 6:121920–28
    [Google Scholar]
  9. 9. 
    van den Berg CW, Ritsma L, Avramut MC et al. 2018. Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. Stem Cell Rep 10:3751–65
    [Google Scholar]
  10. 10. 
    Mansour AA, Gonçalves JT, Bloyd CW et al. 2018. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36:5432–41
    [Google Scholar]
  11. 11. 
    Watson CL, Mahe MM, Munera J et al. 2014. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20:111310–14
    [Google Scholar]
  12. 12. 
    Artegiani B, Hendriks D, Beumer J et al. 2020. Fast and efficient generation of knock-in human organoids using homology-independent CRISPR-Cas9 precision genome editing. Nat. Cell Biol. 22:3321–31
    [Google Scholar]
  13. 13. 
    Wong AP, Bear CE, Chin S et al. 2012. Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat. Biotechnol. 30:9876–82
    [Google Scholar]
  14. 14. 
    Huang SX, Islam MN, O'Neill J et al. 2014. Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat. Biotechnol. 32:184–91
    [Google Scholar]
  15. 15. 
    Dye BR, Hill DR, Ferguson MA et al. 2015. In vitro generation of human pluripotent stem cell derived lung organoids. eLife 4:e05098
    [Google Scholar]
  16. 16. 
    Sachs N, Papaspyropoulos A, Zomer-van Ommen DD et al. 2019. Long-term expanding human airway organoids for disease modeling. EMBO J 38:4e100300
    [Google Scholar]
  17. 17. 
    Konishi S, Gotoh S, Tateishi K et al. 2016. Directed induction of functional multi-ciliated cells in proximal airway epithelial spheroids from human pluripotent stem cells. Stem Cell Rep 6:118–25
    [Google Scholar]
  18. 18. 
    Heo I, Dutta D, Schaefer DA et al. 2018. Modelling Cryptosporidium infection in human small intestinal and lung organoids. Nat. Microbiol. 3:7814–23
    [Google Scholar]
  19. 19. 
    Porotto M, Ferren M, Chen YW et al. 2019. Authentic modeling of human respiratory virus infection in human pluripotent stem cell–derived lung organoids. mBio 10:300723-19
    [Google Scholar]
  20. 20. 
    Zhou J, Li C, Sachs N et al. 2018. Differentiated human airway organoids to assess infectivity of emerging influenza virus. PNAS 115:266822–27
    [Google Scholar]
  21. 21. 
    Hui KPY, Ching RHH, Chan SKH et al. 2018. Tropism, replication competence, and innate immune responses of influenza virus: an analysis of human airway organoids and ex-vivo bronchus cultures. Lancet Respir. Med. 6:11846–54
    [Google Scholar]
  22. 22. 
    van der Sanden SMG, Sachs N, Koekkoek SM et al. 2018. Enterovirus 71 infection of human airway organoids reveals VP1-145 as a viral infectivity determinant. Emerg. Microbes Infect. 7:184
    [Google Scholar]
  23. 23. 
    Matsuyama S, Nao N, Shirato K et al. 2020. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. PNAS 117:137001–3
    [Google Scholar]
  24. 24. 
    Lamers MM, Beumer J, van der Vaart J et al. 2020. SARS-CoV-2 productively infects human gut enterocytes. Science 369:649950–54
    [Google Scholar]
  25. 25. 
    Salahudeen AA, Choi SS, Rustagi A et al. 2020. Progenitor identification and SARS-CoV-2 infection in human distal lung organoids. Nature 588:7839670–75
    [Google Scholar]
  26. 26. 
    Han Y, Duan X, Yang L et al. 2021. Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature 589:7841270–75
    [Google Scholar]
  27. 27. 
    Bartfeld S, Bayram T, van de Wetering M et al. 2015. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 148:1126–36
    [Google Scholar]
  28. 28. 
    Schlaermann P, Toelle B, Berger H et al. 2016. A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro. Gut 65:2202–13
    [Google Scholar]
  29. 29. 
    McCracken KW, Catá EM, Crawford CM et al. 2014. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516:7531400–4
    [Google Scholar]
  30. 30. 
    Wroblewski LE, Piazuelo MB, Chaturvedi R et al. 2015. Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 64:5720–30
    [Google Scholar]
  31. 31. 
    Bertaux-Skeirik N, Feng R, Schumacher MA et al. 2015. CD44 plays a functional role in Helicobacter pylori–induced epithelial cell proliferation. PLOS Pathog 11:2e1004663
    [Google Scholar]
  32. 32. 
    Huang JY, Sweeney EG, Sigal M et al. 2015. Chemodetection and destruction of host urea allows Helicobacter pylori to locate the epithelium. Cell Host Microbe 18:2147–56
    [Google Scholar]
  33. 33. 
    Spence JR, Mayhew CN, Rankin SA et al. 2011. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470:7332105–9
    [Google Scholar]
  34. 34. 
    Sato T, Vries RG, Snippert HJ et al. 2009. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:7244262–65
    [Google Scholar]
  35. 35. 
    Sato T, Stange DE, Ferrante M et al. 2011. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141:51762–72
    [Google Scholar]
  36. 36. 
    Noel G, Baetz NW, Staab JF et al. 2017. A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions. Sci. Rep. 7:45270
    [Google Scholar]
  37. 37. 
    In J, Foulke-Abel J, Zachos NC et al. 2016. Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell–derived colonoids. Cell Mol. Gastroenterol. Hepatol. 2:148–62
    [Google Scholar]
  38. 38. 
    Rajan A, Vela L, Zeng XL et al. 2018. Novel segment- and host-specific patterns of enteroaggregative Escherichia coli adherence to human intestinal enteroids. mBio 9:102419-17
    [Google Scholar]
  39. 39. 
    Leslie JL, Huang S, Opp JS et al. 2015. Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect. Immun. 83:1138–45
    [Google Scholar]
  40. 40. 
    Engevik MA, Yacyshyn MB, Engevik KA et al. 2015. Human Clostridium difficile infection: altered mucus production and composition. Am. J. Physiol. Gastrointest. Liver Physiol. 308:6G510–24
    [Google Scholar]
  41. 41. 
    Wang X, Yamamoto Y, Wilson LH et al. 2015. Cloning and variation of ground state intestinal stem cells. Nature 522:7555173–78
    [Google Scholar]
  42. 42. 
    Kuhlmann FM, Santhanam S, Kumar P et al. 2016. Blood group O–dependent cellular responses to cholera toxin: parallel clinical and epidemiological links to severe cholera. Am. J. Trop. Med. Hyg. 95:2440–43
    [Google Scholar]
  43. 43. 
    Nakamoto N, Sasaki N, Aoki R et al. 2019. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat. Microbiol. 4:3492–503
    [Google Scholar]
  44. 44. 
    Yin Y, Bijvelds M, Dang W et al. 2015. Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. Antivir. Res. 123:120–31
    [Google Scholar]
  45. 45. 
    Finkbeiner SR, Zeng XL, Utama B et al. 2012. Stem cell–derived human intestinal organoids as an infection model for rotaviruses. mBio 3:4e00159-12
    [Google Scholar]
  46. 46. 
    Saxena K, Blutt SE, Ettayebi K et al. 2016. Human intestinal enteroids: a new model to study human rotavirus infection, host restriction, and pathophysiology. J. Virol. 90:143–56
    [Google Scholar]
  47. 47. 
    Chang-Graham AL, Danhof HA, Engevik MA et al. 2019. Human intestinal enteroids with inducible neurogenin-3 expression as a novel model of gut hormone secretion. Cell Mol. Gastroenterol. Hepatol. 8:2209–29
    [Google Scholar]
  48. 48. 
    Drummond CG, Bolock AM, Ma C et al. 2017. Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage–specific manner. PNAS 114:71672–77
    [Google Scholar]
  49. 49. 
    Holly MK, Smith JG. 2018. Adenovirus infection of human enteroids reveals interferon sensitivity and preferential infection of goblet cells. J. Virol. 92:9e00250-18
    [Google Scholar]
  50. 50. 
    Kolawole AO, Mirabelli C, Hill DR et al. 2019. Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape. PLOS Pathog 15:10e1008057
    [Google Scholar]
  51. 51. 
    Zhou J, Li C, Zhao G et al. 2017. Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. Sci. Adv. 3:11eaao4966
    [Google Scholar]
  52. 52. 
    Zang R, Gomez Castro MF, McCune BT et al. 2020. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci. Immunol. 5:47eabc3582
    [Google Scholar]
  53. 53. 
    Zhou J, Li C, Liu X et al. 2020. Infection of bat and human intestinal organoids by SARS-CoV-2. Nat. Med. 26:71077–83
    [Google Scholar]
  54. 54. 
    Chang-Graham AL, Perry JL, Engevik MA et al. 2020. Rotavirus induces intercellular calcium waves through ADP signaling. Science 370:6519eabc3621
    [Google Scholar]
  55. 55. 
    Ettayebi K, Crawford SE, Murakami K et al. 2016. Replication of human noroviruses in stem cell–derived human enteroids. Science 353:63061387–93
    [Google Scholar]
  56. 56. 
    Murakami K, Tenge VR, Karandikar UC et al. 2020. Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids. PNAS 117:31700–10
    [Google Scholar]
  57. 57. 
    Lancaster MA, Renner M, Martin CA et al. 2013. Cerebral organoids model human brain development and microcephaly. Nature 501:7467373–79
    [Google Scholar]
  58. 58. 
    Quadrato G, Nguyen T, Macosko EZ et al. 2017. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545:765248–53
    [Google Scholar]
  59. 59. 
    Camp JG, Badsha F, Florio M et al. 2015. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. PNAS 112:5115672–77
    [Google Scholar]
  60. 60. 
    Dezonne RS, Sartore RC, Nascimento JM et al. 2017. Derivation of functional human astrocytes from cerebral organoids. Sci. Rep. 7:45091
    [Google Scholar]
  61. 61. 
    Huang B, West N, Vider J et al. 2019. Inflammatory responses to a pathogenic West Nile virus strain. BMC Infect. Dis. 19:1912
    [Google Scholar]
  62. 62. 
    Lafaille FG, Pessach IM, Zhang SY et al. 2012. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491:7426769–73
    [Google Scholar]
  63. 63. 
    Desole G, Sinigaglia A, Riccetti S et al. 2019. Modelling neurotropic flavivirus infection in human induced pluripotent stem cell–derived systems. Int. J. Mol. Sci. 20:215404
    [Google Scholar]
  64. 64. 
    Markus A, Lebenthal-Loinger I, Yang IH et al. 2015. An in vitro model of latency and reactivation of varicella zoster virus in human stem cell–derived neurons. PLOS Pathog 11:6e1004885
    [Google Scholar]
  65. 65. 
    Cosset E, Martinez Y, Preynat-Seauve O et al. 2015. Human three-dimensional engineered neural tissue reveals cellular and molecular events following cytomegalovirus infection. Biomaterials 53:296–308
    [Google Scholar]
  66. 66. 
    Sundaramoorthy V, Godde N, Farr RJ et al. 2020. Modelling lyssavirus infections in human stem cell-derived neural cultures. Viruses 12:4359
    [Google Scholar]
  67. 67. 
    Ryan SK, Gonzalez MV, Garifallou JP et al. 2020. Neuroinflammation and EIF2 signaling persist despite antiretroviral treatment in an hiPSC tri-culture model of HIV infection. Stem Cell Rep 14:5991
    [Google Scholar]
  68. 68. 
    Qian X, Nguyen HN, Song MM et al. 2016. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165:51238–54
    [Google Scholar]
  69. 69. 
    Garcez PP, Correia Loiola E, Madeiro da Costa R et al. 2016. Zika virus impairs growth in human neurospheres and brain organoids. Science 352:6287816–18
    [Google Scholar]
  70. 70. 
    Cugola FR, Fernandes IR, Russo FB et al. 2016. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534:7606267–71
    [Google Scholar]
  71. 71. 
    Watanabe M, Buth JE, Vishlaghi N et al. 2017. Self-organized cerebral organoids with human-specific features predict effective drugs to combat Zika virus infection. Cell Rep 21:2517–32
    [Google Scholar]
  72. 72. 
    Song E, Zhang C, Israelow B et al. 2021. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J. Exp. Med. 218:3e20202135
    [Google Scholar]
  73. 73. 
    Takasato M, Er PX, Chiu HS et al. 2015. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526:7574564–68
    [Google Scholar]
  74. 74. 
    Schutgens F, Rookmaaker MB, Margaritis T et al. 2019. Tubuloids derived from human adult kidney and urine for personalized disease modeling. Nat. Biotechnol. 37:3303–13
    [Google Scholar]
  75. 75. 
    Takebe T, Sekine K, Enomura M et al. 2013. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499:7459481–84
    [Google Scholar]
  76. 76. 
    Huch M, Gehart H, van Boxtel R et al. 2015. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160:1–2299–312
    [Google Scholar]
  77. 77. 
    Shlomai A, Schwartz RE, Ramanan V et al. 2014. Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell–derived hepatocellular systems. PNAS 111:3312193–98
    [Google Scholar]
  78. 78. 
    Baktash Y, Madhav A, Coller KE, Randall G. 2018. Single particle imaging of polarized hepatoma organoids upon hepatitis C virus infection reveals an ordered and sequential entry process. Cell Host Microbe 23:3382–94
    [Google Scholar]
  79. 79. 
    Driehuis E, Kolders S, Spelier S et al. 2019. Oral mucosal organoids as a potential platform for personalized cancer therapy. Cancer Discov 9:7852–71
    [Google Scholar]
  80. 80. 
    Kessler M, Hoffmann K, Fritsche K et al. 2019. Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation. Nat. Commun. 10:11194
    [Google Scholar]
  81. 81. 
    Kopper O, de Witte CJ, Lohmussaar K et al. 2019. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat. Med. 25:5838–49
    [Google Scholar]
  82. 82. 
    Lõhmussaar K, Oka R, Espejo Valle-Inclan J et al. 2021. Patient-derived organoids model cervical tissue dynamics and viral oncogenesis in cervical cancer. Cell Stem Cell 28:81380–96
    [Google Scholar]
  83. 83. 
    Lee J, Rabbani CC, Gao H et al. 2020. Hair-bearing human skin generated entirely from pluripotent stem cells. Nature 582:7812399–404
    [Google Scholar]
  84. 84. 
    Wang X, Wang S, Guo B et al. 2021. Human primary epidermal organoids enable modeling of dermatophyte infections. Cell Death Dis 12:135
    [Google Scholar]
  85. 85. 
    Nozaki K, Mochizuki W, Matsumoto Y et al. 2016. Co-culture with intestinal epithelial organoids allows efficient expansion and motility analysis of intraepithelial lymphocytes. J. Gastroenterol. 51:3206–13
    [Google Scholar]
  86. 86. 
    Rogoz A, Reis BS, Karssemeijer RA, Mucida D. 2015. A 3-D enteroid-based model to study T-cell and epithelial cell interaction. J. Immunol. Methods 421:89–95
    [Google Scholar]
  87. 87. 
    Cook L, Stahl M, Han X et al. 2019. Suppressive and gut-reparative functions of human type 1 T regulatory cells. Gastroenterology 157:61584–98
    [Google Scholar]
  88. 88. 
    Wagar LE, Salahudeen A, Constantz CM et al. 2021. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27:1125–35
    [Google Scholar]
  89. 89. 
    Maschmeyer I, Lorenz AK, Schimek K et al. 2015. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip 15:122688–99
    [Google Scholar]
  90. 90. 
    Materne EM, Maschmeyer I, Lorenz AK et al. 2015. The multi-organ chip—a microfluidic platform for long-term multi-tissue coculture. J. Vis. Exp. 98:e52526
    [Google Scholar]
  91. 91. 
    Herland A, Maoz BM, Das D et al. 2020. Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nat. Biomed. Eng. 4:4421–36
    [Google Scholar]
  92. 92. 
    Kim HJ, Huh D, Hamilton G, Ingber DE. 2012. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip 12:122165–74
    [Google Scholar]
  93. 93. 
    Jalili-Firoozinezhad S, Gazzaniga FS, Calamari EL et al. 2019. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat. Biomed. Eng. 3:7520–31
    [Google Scholar]
  94. 94. 
    Han X, Zhou Z, Fei L et al. 2020. Construction of a human cell landscape at single-cell level. Nature 581:7808303–9
    [Google Scholar]
  95. 95. 
    Subramanian A, Sidhom EH, Emani M et al. 2019. Single cell census of human kidney organoids shows reproducibility and diminished off-target cells after transplantation. Nat. Commun. 10:15462
    [Google Scholar]
  96. 96. 
    Kanton S, Boyle MJ, He Z et al. 2019. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature 574:7778418–22
    [Google Scholar]
  97. 97. 
    Andor N, Simonds EF, Czerwinski DK et al. 2019. Single-cell RNA-seq of follicular lymphoma reveals malignant B-cell types and coexpression of T-cell immune checkpoints. Blood 133:101119–29
    [Google Scholar]
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