Modeling Infectious Diseases in Mice with a "Humanized" Immune System

Overview

Journal Microbiol Spectr

Specialty Microbiology

Date 2019 Apr 7

PMID 30953434

Citations 11

Authors

Yan Li

James P Di Santo

Affiliations

Soon will be listed here.

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.

Citing Articles

Navigating ESKAPE Pathogens: Considerations and Caveats for Animal Infection Models Development.

Yu H, Xu Y, Imani S, Zhao Z, Ullah S, Wang Q ACS Infect Dis. 2024; 10(7):2336-2355.

PMID: 38866389 PMC: 11249778. DOI: 10.1021/acsinfecdis.4c00007.

Establishment of a human microbiome- and immune system-reconstituted dual-humanized mouse model.

Ka Y, Ito R, Nozu R, Tomiyama K, Ueno M, Ogura T Exp Anim. 2023; 72(3):402-412.

PMID: 37019665 PMC: 10435363. DOI: 10.1538/expanim.23-0025.

Next-generation humanized NSG-SGM3 mice are highly susceptible to infection.

Hung S, Kasperkowitz A, Kurz F, Dreher L, Diessner J, Ibrahim E Front Immunol. 2023; 14:1127709.

PMID: 36969151 PMC: 10037040. DOI: 10.3389/fimmu.2023.1127709.

Intranasal multivalent adenoviral-vectored vaccine protects against replicating and dormant M.tb in conventional and humanized mice.

Afkhami S, DAgostino M, Vaseghi-Shanjani M, Lepard M, Yang J, Lai R NPJ Vaccines. 2023; 8(1):25.

PMID: 36823425 PMC: 9948798. DOI: 10.1038/s41541-023-00623-z.

Protocol for generating human immune system mice and hydrodynamic injection to analyze human hematopoiesis .

Ren D, Liu W, Ding S, Li Y STAR Protoc. 2022; 3(1):101217.

PMID: 35265863 PMC: 8899045. DOI: 10.1016/j.xpro.2022.101217.

References

Noguchi M, Yi H, Rosenblatt H, Filipovich A, Adelstein S, Modi W . Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993; 73(1):147-57. DOI: 10.1016/0092-8674(93)90167-o. View

Yu H, Borsotti C, Schickel J, Zhu S, Strowig T, Eynon E . A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood. 2017; 129(8):959-969. PMC: 5324713. DOI: 10.1182/blood-2016-04-709584. View

Shinkai Y, Rathbun G, Lam K, Oltz E, Stewart V, Mendelsohn M . RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992; 68(5):855-67. DOI: 10.1016/0092-8674(92)90029-c. View

Cimbro R, Vassena L, Arthos J, Cicala C, Kehrl J, Park C . IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa. Blood. 2012; 120(13):2610-9. PMC: 3460683. DOI: 10.1182/blood-2012-06-434779. View

Shultz L, Schweitzer P, Christianson S, Gott B, Schweitzer I, Tennent B . Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol. 1995; 154(1):180-91. View

Huntington N, Alves N, Legrand N, Lim A, Strick-Marchand H, Plet A . Autonomous and extrinsic regulation of thymopoiesis in human immune system (HIS) mice. Eur J Immunol. 2011; 41(10):2883-93. DOI: 10.1002/eji.201141586. View

Malynn B, Blackwell T, Fulop G, Rathbun G, Furley A, Ferrier P . The scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism. Cell. 1988; 54(4):453-60. DOI: 10.1016/0092-8674(88)90066-9. View

Verstraete K, van Schie L, Vyncke L, Bloch Y, Tavernier J, Pauwels E . Structural basis of the proinflammatory signaling complex mediated by TSLP. Nat Struct Mol Biol. 2014; 21(4):375-82. DOI: 10.1038/nsmb.2794. View

Park L, Martin U, Garka K, Gliniak B, Di Santo J, Muller W . Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med. 2000; 192(5):659-70. PMC: 2193276. DOI: 10.1084/jem.192.5.659. View

10.

Shultz L, Brehm M, Garcia-Martinez J, Greiner D . Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012; 12(11):786-98. PMC: 3749872. DOI: 10.1038/nri3311. View

11.

DiSanto J, Muller W, Fischer A, Rajewsky K . Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci U S A. 1995; 92(2):377-81. PMC: 42743. DOI: 10.1073/pnas.92.2.377. View

12.

Heuts F, Gavier-Widen D, Carow B, Juarez J, Wigzell H, Rottenberg M . CD4+ cell-dependent granuloma formation in humanized mice infected with mycobacteria. Proc Natl Acad Sci U S A. 2013; 110(16):6482-7. PMC: 3631626. DOI: 10.1073/pnas.1219985110. View

13.

Ali N, Flutter B, Rodriguez R, Sharif-Paghaleh E, Barber L, Lombardi G . Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype. PLoS One. 2012; 7(8):e44219. PMC: 3429415. DOI: 10.1371/journal.pone.0044219. View

14.

Denton P, Garcia J . Humanized mouse models of HIV infection. AIDS Rev. 2011; 13(3):135-48. PMC: 3741405. View

15.

Spits H, Di Santo J . The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2010; 12(1):21-7. DOI: 10.1038/ni.1962. View

16.

Fulop G, Phillips R . The scid mutation in mice causes a general defect in DNA repair. Nature. 1990; 347(6292):479-82. DOI: 10.1038/347479a0. View

17.

Greiner D, Hesselton R, Shultz L . SCID mouse models of human stem cell engraftment. Stem Cells. 1998; 16(3):166-77. DOI: 10.1002/stem.160166. View

18.

Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty S, Teichmann L . Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014; 32(4):364-72. PMC: 4017589. DOI: 10.1038/nbt.2858. View

19.

Li Y, Masse-Ranson G, Garcia Z, Bruel T, Kok A, Strick-Marchand H . A human immune system mouse model with robust lymph node development. Nat Methods. 2018; 15(8):623-630. DOI: 10.1038/s41592-018-0071-6. View

20.

Marodon G, Desjardins D, Mercey L, Baillou C, Parent P, Manuel M . High diversity of the immune repertoire in humanized NOD.SCID.gamma c-/- mice. Eur J Immunol. 2009; 39(8):2136-45. DOI: 10.1002/eji.200939480. View