No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Modeling Infectious Diseases in Mice with a “Humanized” Immune System

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Authors: Yan Li1,2, James P. Di Santo3,4
  • Editors: Pascale Cossart5, Craig R. Roy6, Philippe Sansonetti7
    Affiliations: 1: Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France; 2: Inserm U1223, Paris, France; 3: Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France; 4: Inserm U1223, Paris, France; 5: Institut Pasteur, Paris, France; 6: Yale University School of Medicine, New Haven, Connecticut; 7: Institut Pasteur, Paris, France
  • Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0019-2019
  • Received 29 August 2018 Accepted 10 January 2019 Published 05 April 2019
  • James P. Di Santo, james.di-sant[email protected]
image of Modeling Infectious Diseases in Mice with a “Humanized” Immune System
    Preview this microbiology spectrum article:
    Zoom in

    Modeling Infectious Diseases in Mice with a “Humanized” Immune System, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/7/2/BAI-0019-2019-1.gif /docserver/preview/fulltext/microbiolspec/7/2/BAI-0019-2019-2.gif
  • Abstract:

    Human immune system (HIS) mice are created by transplanting human immune cells or their progenitor cells into highly immunodeficient recipient mouse hosts, thereby “humanizing” their immune systems. Over past decades, the field of HIS mice has evolved rapidly, as modifications of existing immunodeficient mouse strains have been developed, resulting in increasing levels of human tissue engraftment as humanization is optimized. Current HIS mouse models not only permit elevated levels of human cell engraftment but also demonstrate graft stability. As such, HIS mice are being extensively used to study the human innate and adaptive immune response against microbial infections . Compared to nonhumanized animal models, which are frequently infected with surrogate or adapted microbes, the HIS mouse models allow the analysis of interactions between human immune cells and pathogenic microbes, making them a more clinically relevant model. This article reviews the development of HIS mice and covers the different strategies used to humanize mice, as well as discussing the use of HIS mice for studying bacterial infections that cause human disease.

  • Citation: Li Y, Di Santo J. 2019. Modeling Infectious Diseases in Mice with a “Humanized” Immune System. Microbiol Spectrum 7(2):BAI-0019-2019. doi:10.1128/microbiolspec.BAI-0019-2019.


1. Shultz LD, Ishikawa F, Greiner DL. 2007. Humanized mice in translational biomedical research. Nat Rev Immunol 7:118–130 http://dx.doi.org/10.1038/nri2017. [PubMed]
2. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. 2012. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12:786–798 http://dx.doi.org/10.1038/nri3311. [PubMed]
3. Ito R, Takahashi T, Katano I, Ito M. 2012. Current advances in humanized mouse models. Cell Mol Immunol 9:208–214 http://dx.doi.org/10.1038/cmi.2012.2. [PubMed]
4. Manz MG. 2007. Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity 26:537–541 http://dx.doi.org/10.1016/j.immuni.2007.05.001. [PubMed]
5. Isaacson JHC, Cattanach BM. 1962. Two new ‘hairless’ mutants—sha and Hfh11. Mouse News Lett 27:31.
6. Schorpp M, Hofmann M, Dear TN, Boehm T. 1997. Characterization of mouse and human nude genes. Immunogenetics 46:509–515 http://dx.doi.org/10.1007/s002510050312. [PubMed]
7. Fogh J, Fogh JM, Orfeo T. 1977. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst 59:221–226 http://dx.doi.org/10.1093/jnci/59.1.221. [PubMed]
8. Ganick DJ, Sarnwick RD, Shahidi NT, Manning DD. 1980. Inability of intravenously injected monocellular suspensions of human bone marrow to establish in the nude mouse. Int Arch Allergy Appl Immunol 62:330–333 http://dx.doi.org/10.1159/000232530. [PubMed]
9. Bosma GC, Custer RP, Bosma MJ. 1983. A severe combined immunodeficiency mutation in the mouse. Nature 301:527–530 http://dx.doi.org/10.1038/301527a0. [PubMed]
10. Malynn BA, Blackwell TK, Fulop GM, Rathbun GA, Furley AJ, Ferrier P, Heinke LB, Phillips RA, Yancopoulos GD, Alt FW. 1988. The scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism. Cell 54:453–460 http://dx.doi.org/10.1016/0092-8674(88)90066-9. [PubMed]
11. Fulop GM, Phillips RA. 1990. The scid mutation in mice causes a general defect in DNA repair. Nature 347:479–482 http://dx.doi.org/10.1038/347479a0. [PubMed]
12. Greiner DL, Hesselton RA, Shultz LD. 1998. SCID mouse models of human stem cell engraftment. Stem Cells 16:166–177 http://dx.doi.org/10.1002/stem.160166. [PubMed]
13. Biedermann KA, Sun JR, Giaccia AJ, Tosto LM, Brown JM. 1991. scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc Natl Acad Sci USA 88:1394–1397 http://dx.doi.org/10.1073/pnas.88.4.1394. [PubMed]
14. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. 1992. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68:869–877 http://dx.doi.org/10.1016/0092-8674(92)90030-G. [PubMed]
15. Shinkai Y, et al. 1992. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68:855–867 http://dx.doi.org/10.1016/0092-8674(92)90029-C. [PubMed]
16. Shultz LD, Lang PA, Christianson SW, Gott B, Lyons B, Umeda S, Leiter E, Hesselton R, Wagar EJ, Leif JH, Kollet O, Lapidot T, Greiner DL. 2000. NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells. J Immunol 164:2496–2507 http://dx.doi.org/10.4049/jimmunol.164.5.2496. [PubMed]
17. Shultz LD, et al. 1995. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol 154:180–191. [PubMed]
18. Takenaka K, Prasolava TK, Wang JC, Mortin-Toth SM, Khalouei S, Gan OI, Dick JE, Danska JS. 2007. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat Immunol 8:1313–1323 http://dx.doi.org/10.1038/ni1527. [PubMed]
19. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. 1993. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147–157 http://dx.doi.org/10.1016/0092-8674(93)90167-O. [PubMed]
20. Di Santo JP, Müller W, Guy-Grand D, Fischer A, Rajewsky K. 1995. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci USA 92:377–381 http://dx.doi.org/10.1073/pnas.92.2.377.
21. Colucci F, Guy-Grand D, Wilson A, Turner M, Schweighoffer E, Tybulewicz VLJ, Di Santo JP. 2000. A new look at Syk in αβ and γδ T cell development using chimeric mice with a low competitive hematopoietic environment. J Immunol 164:5140–5145 http://dx.doi.org/10.4049/jimmunol.164.10.5140. [PubMed]
22. Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, Ueyama Y, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T. 2002. NOD/SCID/γ c null mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100:3175–3182 http://dx.doi.org/10.1182/blood-2001-12-0207. [PubMed]
23. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG. 2004. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304:104–107 http://dx.doi.org/10.1126/science.1093933. [PubMed]
24. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, Watanabe T, Akashi K, Shultz LD, Harada M. 2005. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γchain null mice. Blood 106:1565–1573 http://dx.doi.org/10.1182/blood-2005-02-0516. [PubMed]
25. Legrand N, Huntington ND, Nagasawa M, Bakker AQ, Schotte R, Strick-Marchand H, de Geus SJ, Pouw SM, Böhne M, Voordouw A, Weijer K, Di Santo JP, Spits H. 2011. Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. Proc Natl Acad Sci USA 108:13224–13229 http://dx.doi.org/10.1073/pnas.1101398108. [PubMed]
26. Huntington ND, Alves NL, Legrand N, Lim A, Strick-Marchand H, Plet A, Weijer K, Jacques Y, Spits H, Di Santo JP. 2011. Autonomous and extrinsic regulation of thymopoiesis in human immune system (HIS) mice. Eur J Immunol 41:2883–2893 http://dx.doi.org/10.1002/eji.201141586. [PubMed]
27. Marodon G, Desjardins D, Mercey L, Baillou C, Parent P, Manuel M, Caux C, Bellier B, Pasqual N, Klatzmann D. 2009. High diversity of the immune repertoire in humanized NOD.SCID.γc –/– mice. Eur J Immunol 39:2136–2145 http://dx.doi.org/10.1002/eji.200939480. [PubMed]
28. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E. 2013. Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol 13:145–149 http://dx.doi.org/10.1038/nri3365. [PubMed]
29. Spits H, Di Santo JP. 2011. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol 12:21–27 http://dx.doi.org/10.1038/ni.1962. [PubMed]
30. Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. 2004. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol 5:64–73 http://dx.doi.org/10.1038/ni1022. [PubMed]
31. Li Y, Masse-Ranson G, Garcia Z, Bruel T, Kök A, Strick-Marchand H, Jouvion G, Serafini N, Lim AI, Dusseaux M, Hieu T, Bourgade F, Toubert A, Finke D, Schwartz O, Bousso P, Mouquet H, Di Santo JP. 2018. A human immune system mouse model with robust lymph node development. Nat Methods 15:623–630 http://dx.doi.org/10.1038/s41592-018-0071-6. [PubMed]
32. Verstraete K, van Schie L, Vyncke L, Bloch Y, Tavernier J, Pauwels E, Peelman F, Savvides SN. 2014. Structural basis of the proinflammatory signaling complex mediated by TSLP. Nat Struct Mol Biol 21:375–382 http://dx.doi.org/10.1038/nsmb.2794. [PubMed]
33. Park LS, Martin U, Garka K, Gliniak B, Di Santo JP, Muller W, Largaespada DA, Copeland NG, Jenkins NA, Farr AG, Ziegler SF, Morrissey PJ, Paxton R, Sims JE. 2000. Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med 192:659–670 http://dx.doi.org/10.1084/jem.192.5.659. [PubMed]
34. Li Y, Chen Q, Zheng D, Yin L, Chionh YH, Wong LH, Tan SQ, Tan TC, Chan JK, Alonso S, Dedon PC, Lim B, Chen J. 2013. Induction of functional human macrophages from bone marrow promonocytes by M-CSF in humanized mice. J Immunol 191:3192–3199 http://dx.doi.org/10.4049/jimmunol.1300742. [PubMed]
35. Li Y, Mention JJ, Court N, Masse-Ranson G, Toubert A, Spits H, Legrand N, Corcuff E, Strick-Marchand H, Di Santo JP. 2016. A novel Flt3-deficient HIS mouse model with selective enhancement of human DC development. Eur J Immunol 46:1291–1299 http://dx.doi.org/10.1002/eji.201546132. [PubMed]
36. Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, Corcuff E, Mortier E, Jacques Y, Spits H, Di Santo JP. 2009. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med 206:25–34 http://dx.doi.org/10.1084/jem.20082013. [PubMed]
37. Chen Q, He F, Kwang J, Chan JK, Chen J. 2012. GM-CSF and IL-4 stimulate antibody responses in humanized mice by promoting T, B, and dendritic cell maturation. J Immunol 189:5223–5229 http://dx.doi.org/10.4049/jimmunol.1201789. [PubMed]
38. Willinger T, Rongvaux A, Takizawa H, Yancopoulos GD, Valenzuela DM, Murphy AJ, Auerbach W, Eynon EE, Stevens S, Manz MG, Flavell RA. 2011. Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc Natl Acad Sci USA 108:2390–2395 http://dx.doi.org/10.1073/pnas.1019682108. [PubMed]
39. Li Y, Strick-Marchand H, Lim AI, Ren J, Masse-Ranson G, Dan Li, Jouvion G, Rogge L, Lucas S, Bin Li, Di Santo JP. 2017. Regulatory T cells control toxicity in a humanized model of IL-2 therapy. Nat Commun 8:1762 http://dx.doi.org/10.1038/s41467-017-01570-9. [PubMed]
40. Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, Saito Y, Marches F, Halene S, Palucka AK, Manz MG, Flavell RA. 2014. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol 32:364–372 http://dx.doi.org/10.1038/nbt.2858. [PubMed]
41. Mestas J, Hughes CC. 2004. Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738 http://dx.doi.org/10.4049/jimmunol.172.5.2731. [PubMed]
42. Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M, Doi T, Sone A, Suzuki N, Fujiwara H, Yasukawa M, Ishikawa F. 2010. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2rγ null humanized mice. Proc Natl Acad Sci USA 107:13022–13027 http://dx.doi.org/10.1073/pnas.1000475107. [PubMed]
43. Suzuki M, Takahashi T, Katano I, Ito R, Ito M, Harigae H, Ishii N, Sugamura K. 2012. Induction of human humoral immune responses in a novel HLA-DR-expressing transgenic NOD/Shi-scid/γc null mouse. Int Immunol 24:243–252 http://dx.doi.org/10.1093/intimm/dxs045. [PubMed]
44. Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, Shultz LD. 2017. Humanized mouse models of clinical disease. Annu Rev Pathol 12:187–215 http://dx.doi.org/10.1146/annurev-pathol-052016-100332. [PubMed]
45. Victor Garcia J. 2016. Humanized mice for HIV and AIDS research. Curr Opin Virol 19:56–64 http://dx.doi.org/10.1016/j.coviro.2016.06.010. [PubMed]
46. Masse-Ranson G, Mouquet H, Di Santo JP. 2018. Humanized mouse models to study pathophysiology and treatment of HIV infection. Curr Opin HIV AIDS 13:143–151 http://dx.doi.org/10.1097/COH.0000000000000440. [PubMed]
47. Denton PW, García JV. 2011. Humanized mouse models of HIV infection. AIDS Rev 13:135–148. [PubMed]
48. Yu H, Borsotti C, Schickel JN, Zhu S, Strowig T, Eynon EE, Frleta D, Gurer C, Murphy AJ, Yancopoulos GD, Meffre E, Manz MG, Flavell RA. 2017. A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood 129:959–969 http://dx.doi.org/10.1182/blood-2016-04-709584. [PubMed]
49. Lang J, Zhang B, Kelly M, Peterson JN, Barbee J, Freed BM, Di Santo JP, Matsuda JL, Torres RM, Pelanda R. 2017. Replacing mouse BAFF with human BAFF does not improve B-cell maturation in hematopoietic humanized mice. Blood Adv 1:2729–2741 http://dx.doi.org/10.1182/bloodadvances.2017010090. [PubMed]
50. Cimbro R, Vassena L, Arthos J, Cicala C, Kehrl JH, Park C, Sereti I, Lederman MM, Fauci AS, Lusso P. 2012. IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa. Blood 120:2610–2619 http://dx.doi.org/10.1182/blood-2012-06-434779. [PubMed]
51. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, Wege AK, Haase AT, Garcia JV. 2006. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12:1316–1322 http://dx.doi.org/10.1038/nm1431. [PubMed]
52. Denton PW, Nochi T, Lim A, Krisko JF, Martinez-Torres F, Choudhary SK, Wahl A, Olesen R, Zou W, Di Santo JP, Margolis DM, Garcia JV. 2012. IL-2 receptor γ-chain molecule is critical for intestinal T-cell reconstitution in humanized mice. Mucosal Immunol 5:555–566 http://dx.doi.org/10.1038/mi.2012.31. [PubMed]
53. Greenblatt MB, Vbranac V, Tivey T, Tsang K, Tager AM, Aliprantis AO. 2012. Graft versus host disease in the bone marrow, liver and thymus humanized mouse model. PLoS One 7:e44664 CORRECTION PLoS One 8:10.1371/annotation/e413f2a1-5767-4c82-9e27-dd556155f124 http://dx.doi.org/10.1371/journal.pone.0044664.
54. Mosier DE, Gulizia RJ, Baird SM, Wilson DB. 1988. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335:256–259 http://dx.doi.org/10.1038/335256a0. [PubMed]
55. Tary-Lehmann M, Lehmann PV, Schols D, Roncarolo MG, Saxon A. 1994. Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras. J Exp Med 180:1817–1827 http://dx.doi.org/10.1084/jem.180.5.1817. [PubMed]
56. Ali N, Flutter B, Sanchez Rodriguez R, Sharif-Paghaleh E, Barber LD, Lombardi G, Nestle FO. 2012. Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype. PLoS One 7:e44219 http://dx.doi.org/10.1371/journal.pone.0044219. [PubMed]
57. Harui A, Kiertscher SM, Roth MD. 2011. Reconstitution of huPBL-NSG mice with donor-matched dendritic cells enables antigen-specific T-cell activation. J Neuroimmune Pharmacol 6:148–157 http://dx.doi.org/10.1007/s11481-010-9223-x. [PubMed]
58. King MA, Covassin L, Brehm MA, Racki W, Pearson T, Leif J, Laning J, Fodor W, Foreman O, Burzenski L, Chase TH, Gott B, Rossini AA, Bortell R, Shultz LD, Greiner DL. 2009. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft- versus-host-like disease and the role of host major histocompatibility complex. Clin Exp Immunol 157:104–118 http://dx.doi.org/10.1111/j.1365-2249.2009.03933.x. [PubMed]
59. Büchner SM, Sliva K, Bonig H, Völker I, Waibler Z, Kirberg J, Schnierle BS. 2013. Delayed onset of graft- versus-host disease in immunodeficent human leucocyte antigen-DQ8 transgenic, murine major histocompatibility complex class II-deficient mice repopulated by human peripheral blood mononuclear cells. Clin Exp Immunol 173:355–364 http://dx.doi.org/10.1111/cei.12121. [PubMed]
60. Amaladoss A, Chen Q, Liu M, Dummler SK, Dao M, Suresh S, Chen J, Preiser PR. 2015. De novo generated human red blood cells in humanized mice support Plasmodium falciparum infection. PLoS One 10:e0129825 http://dx.doi.org/10.1371/journal.pone.0129825. [PubMed]
61. Hu Z, Van Rooijen N, Yang YG. 2011. Macrophages prevent human red blood cell reconstitution in immunodeficient mice. Blood 118:5938–5946 http://dx.doi.org/10.1182/blood-2010-11-321414. [PubMed]
62. Chen Q, Amaladoss A, Ye W, Liu M, Dummler S, Kong F, Wong LH, Loo HL, Loh E, Tan SQ, Tan TC, Chang KT, Dao M, Suresh S, Preiser PR, Chen J. 2014. Human natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells. Proc Natl Acad Sci USA 111:1479–1484 http://dx.doi.org/10.1073/pnas.1323318111. [PubMed]
63. Allweiss L, Dandri M. 2016. Experimental in vitro and in vivo models for the study of human hepatitis B virus infection. J Hepatol 64(Suppl) :S17–S31 http://dx.doi.org/10.1016/j.jhep.2016.02.012. [PubMed]
64. Dandri M, Burda MR, Török E, Pollok JM, Iwanska A, Sommer G, Rogiers X, Rogler CE, Gupta S, Will H, Greten H, Petersen J. 2001. Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus. Hepatology 33:981–988 http://dx.doi.org/10.1053/jhep.2001.23314. [PubMed]
65. Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C, Rinfret A, Addison WR, Fischer KP, Churchill TA, Lakey JR, Tyrrell DL, Kneteman NM. 2001. Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7:927–933 http://dx.doi.org/10.1038/90968. [PubMed]
66. Hasegawa M, Kawai K, Mitsui T, Taniguchi K, Monnai M, Wakui M, Ito M, Suematsu M, Peltz G, Nakamura M, Suemizu H. 2011. The reconstituted ‘humanized liver’ in TK-NOG mice is mature and functional. Biochem Biophys Res Commun 405:405–410 http://dx.doi.org/10.1016/j.bbrc.2011.01.042. [PubMed]
67. Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M, Ellis E, Strom S, Kay MA, Finegold M, Grompe M. 2007. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice. Nat Biotechnol 25:903–910 http://dx.doi.org/10.1038/nbt1326. [PubMed]
68. Bissig KD, Le TT, Woods NB, Verma IM. 2007. Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc Natl Acad Sci USA 104:20507–20511 http://dx.doi.org/10.1073/pnas.0710528105. [PubMed]
69. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, Barry W, Ploss A, Rice CM, Su L. 2011. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 140:1334–1344 http://dx.doi.org/10.1053/j.gastro.2011.01.001.
70. Kremsdorf D, Strick-Marchand H. 2017. Modeling hepatitis virus infections and treatment strategies in humanized mice. Curr Opin Virol 25:119–125 http://dx.doi.org/10.1016/j.coviro.2017.07.029. [PubMed]
71. Kaushansky A, Mikolajczak SA, Vignali M, Kappe SH. 2014. Of men in mice: the success and promise of humanized mouse models for human malaria parasite infections. Cell Microbiol 16:602–611 http://dx.doi.org/10.1111/cmi.12277. [PubMed]
72. Dusseaux M, Masse-Ranson G, Darche S, Ahodantin J, Li Y, Fiquet O, Beaumont E, Moreau P, Riviere L, Neuveut C, Soussan P, Roingeard P, Kremsdorf D, Di Santo JP, Strick-Marchand H. 2017. Viral load affects the immune response to HBV in mice with humanized immune system and liver. Gastroenterology 153:1647–1661.e9. [PubMed]
73. Libby SJ, Brehm MA, Greiner DL, Shultz LD, McClelland M, Smith KD, Cookson BT, Karlinsey JE, Kinkel TL, Porwollik S, Canals R, Cummings LA, Fang FC. 2010. Humanized nonobese diabetic-scid IL2rγ null mice are susceptible to lethal Salmonella Typhi infection. Proc Natl Acad Sci USA 107:15589–15594 http://dx.doi.org/10.1073/pnas.1005566107. [PubMed]
74. Firoz Mian M, Pek EA, Chenoweth MJ, Ashkar AA. 2011. Humanized mice are susceptible to Salmonella typhi infection. Cell Mol Immunol 8:83–87 http://dx.doi.org/10.1038/cmi.2010.52. [PubMed]
75. Song J, Willinger T, Rongvaux A, Eynon EE, Stevens S, Manz MG, Flavell RA, Galán JE. 2010. A mouse model for the human pathogen Salmonella typhi. Cell Host Microbe 8:369–376 http://dx.doi.org/10.1016/j.chom.2010.09.003. [PubMed]
76. Mian MF, Pek EA, Chenoweth MJ, Coombes BK, Ashkar AA. 2011. Humanized mice for Salmonella typhi infection: new tools for an old problem. Virulence 2:248–252 http://dx.doi.org/10.4161/viru.2.3.16133. [PubMed]
77. Hunter RL, Jagannath C, Actor JK. 2007. Pathology of postprimary tuberculosis in humans and mice: contradiction of long-held beliefs. Tuberculosis (Edinb) 87:267–278 http://dx.doi.org/10.1016/j.tube.2006.11.003. [PubMed]
78. Harper J, Skerry C, Davis SL, Tasneen R, Weir M, Kramnik I, Bishai WR, Pomper MG, Nuermberger EL, Jain SK. 2012. Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions. J Infect Dis 205:595–602 http://dx.doi.org/10.1093/infdis/jir786. [PubMed]
79. Heuts F, Gavier-Widén D, Carow B, Juarez J, Wigzell H, Rottenberg ME. 2013. CD4+ cell-dependent granuloma formation in humanized mice infected with mycobacteria. Proc Natl Acad Sci USA 110:6482–6487 http://dx.doi.org/10.1073/pnas.1219985110. [PubMed]
80. Calderon VE, Valbuena G, Goez Y, Judy BM, Huante MB, Sutjita P, Johnston RK, Estes DM, Hunter RL, Actor JK, Cirillo JD, Endsley JJ. 2013. A humanized mouse model of tuberculosis. PLoS One 8:e63331 http://dx.doi.org/10.1371/journal.pone.0063331. [PubMed]
81. Lee J, Brehm MA, Greiner D, Shultz LD, Kornfeld H. 2013. Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice. BMC Immunol 14:53 http://dx.doi.org/10.1186/1471-2172-14-53. [PubMed]
82. Nusbaum RJ, Calderon VE, Huante MB, Sutjita P, Vijayakumar S, Lancaster KL, Hunter RL, Actor JK, Cirillo JD, Aronson J, Gelman BB, Lisinicchia JG, Valbuena G, Endsley JJ. 2016. Pulmonary tuberculosis in humanized mice infected with HIV-1. Sci Rep 6:21522 http://dx.doi.org/10.1038/srep21522. [PubMed]
83. Dantes R, Mu Y, Belflower R, Aragon D, Dumyati G, Harrison LH, Lessa FC, Lynfield R, Nadle J, Petit S, Ray SM, Schaffner W, Townes J, Fridkin S, Emerging Infections Program–Active Bacterial Core Surveillance MRSA Surveillance Investigators. 2013. National burden of invasive methicillin-resistant Staphylococcus aureus infections, United States, 2011. JAMA Intern Med 173:1970–1978. [PubMed]
84. Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK, Active Bacterial Core surveillance (ABCs) MRSA Investigators. 2007. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298:1763–1771 http://dx.doi.org/10.1001/jama.298.15.1763. [PubMed]
85. Schaumburg F, Köck R, Mellmann A, Richter L, Hasenberg F, Kriegeskorte A, Friedrich AW, Gatermann S, Peters G, von Eiff C, Becker K, study group. 2012. Population dynamics among methicillin-resistant Staphylococcus aureus isolates in Germany during a 6-year period. J Clin Microbiol 50:3186–3192 http://dx.doi.org/10.1128/JCM.01174-12. [PubMed]
86. Prince A, Wang H, Kitur K, Parker D. 2017. Humanized mice exhibit increased susceptibility to Staphylococcus aureus pneumonia. J Infect Dis 215:1386–1395. [PubMed]
87. Knop J, Hanses F, Leist T, Archin NM, Buchholz S, Gläsner J, Gessner A, Wege AK. 2015. Staphylococcus aureus infection in humanized mice: a new model to study pathogenicity associated with human immune response. J Infect Dis 212:435–444 http://dx.doi.org/10.1093/infdis/jiv073. [PubMed]
88. Tseng CW, Biancotti JC, Berg BL, Gate D, Kolar SL, Müller S, Rodriguez MD, Rezai-Zadeh K, Fan X, Beenhouwer DO, Town T, Liu GY. 2015. Increased susceptibility of humanized NSG mice to Panton-Valentine leukocidin and Staphylococcus aureus skin infection. PLoS Pathog 11:e1005292 http://dx.doi.org/10.1371/journal.ppat.1005292. [PubMed]
89. Belkaid Y, Hand TW. 2014. Role of the microbiota in immunity and inflammation. Cell 157:121–141 http://dx.doi.org/10.1016/j.cell.2014.03.011. [PubMed]
90. Gülden E, Vudattu NK, Deng S, Preston-Hurlburt P, Mamula M, Reed JC, Mohandas S, Herold BC, Torres R, Vieira SM, Lim B, Herazo-Maya JD, Kriegel M, Goodman AL, Cotsapas C, Herold KC. 2017. Microbiota control immune regulation in humanized mice. JCI Insight 2:e91709 http://dx.doi.org/10.1172/jci.insight.91709. [PubMed]
91. Hofer U, Schlaepfer E, Baenziger S, Nischang M, Regenass S, Schwendener R, Kempf W, Nadal D, Speck RF. 2010. Inadequate clearance of translocated bacterial products in HIV-infected humanized mice. PLoS Pathog 6:e1000867 http://dx.doi.org/10.1371/journal.ppat.1000867. [PubMed]
92. Xu SX, Leontyev D, Kaul R, Gray-Owen SD. 2018. Neisseria gonorrhoeae co-infection exacerbates vaginal HIV shedding without affecting systemic viral loads in human CD34+ engrafted mice. PLoS One 13:e0191672 http://dx.doi.org/10.1371/journal.pone.0191672. [PubMed]
93. Unsinger J, McDonough JS, Shultz LD, Ferguson TA, Hotchkiss RS. 2009. Sepsis-induced human lymphocyte apoptosis and cytokine production in “humanized” mice. J Leukoc Biol 86:219–227 http://dx.doi.org/10.1189/jlb.1008615. [PubMed]
94. Skirecki T, Kawiak J, Machaj E, Pojda Z, Wasilewska D, Czubak J, Hoser G. 2015. Early severe impairment of hematopoietic stem and progenitor cells from the bone marrow caused by CLP sepsis and endotoxemia in a humanized mice model. Stem Cell Res Ther 6:142 http://dx.doi.org/10.1186/s13287-015-0135-9. [PubMed]
95. Ye C, Choi JG, Abraham S, Wu H, Diaz D, Terreros D, Shankar P, Manjunath N. 2012. Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model. Proc Natl Acad Sci USA 109:21052–21057 http://dx.doi.org/10.1073/pnas.1216195109. [PubMed]
96. Schlieckau F, Schulz D, Fill Malfertheiner S, Entleutner K, Seelbach-Goebel B, Ernst W. 2018. A novel model to study neonatal Escherichia coli sepsis and the effect of treatment on the human immune system using humanized mice. Am J Reprod Immunol 80:e12859 http://dx.doi.org/10.1111/aji.12859. [PubMed]

Article metrics loading...



Human immune system (HIS) mice are created by transplanting human immune cells or their progenitor cells into highly immunodeficient recipient mouse hosts, thereby “humanizing” their immune systems. Over past decades, the field of HIS mice has evolved rapidly, as modifications of existing immunodeficient mouse strains have been developed, resulting in increasing levels of human tissue engraftment as humanization is optimized. Current HIS mouse models not only permit elevated levels of human cell engraftment but also demonstrate graft stability. As such, HIS mice are being extensively used to study the human innate and adaptive immune response against microbial infections . Compared to nonhumanized animal models, which are frequently infected with surrogate or adapted microbes, the HIS mouse models allow the analysis of interactions between human immune cells and pathogenic microbes, making them a more clinically relevant model. This article reviews the development of HIS mice and covers the different strategies used to humanize mice, as well as discussing the use of HIS mice for studying bacterial infections that cause human disease.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Timeline for development of immunodeficient mouse strains that form the basis for current HIS models. Indicated strains are described in the text.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0019-2019
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Boosting immune subsets in humanized mice. Cytokines and growth factor supplementation (left) in HIS mice can promote the expansion, differentiation, and function of selected hematopoietic lineages (right). TPO, thrombopoietin.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0019-2019
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

Studying human pathogens in humanized mice. A variety of human pathogens, including viruses, bacteria, and parasites, have been analyzed in HIS mouse models. EBV, Epstein-Barr virus; CMV, cytomegalovirus; HTLV-1, human T cell leukemia virus type 1; KSHV, Kaposi’s sarcoma-associated herpesvirus.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0019-2019
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error