AG129 Mice

Catalog Number: I001125

Strain Name: 129S2/SvPasCya-Ifnar1em2Ifngr1em1/Cya

Genetic Background: 129S2/SvPasCya

Reproduction: Homozygote x Homozygote

 

Strain Description

Interferons (IFNs) are potent cytokines that serve as a critical component of the body's first line of defense against viral infections, playing a key role in inflammation and immune control by directly inducing pathogen-inhibiting molecules that suppress viral replication [1]. Arthropod-borne viruses (arboviruses) like Dengue virus (DENV), Zika virus (ZIKV), and Yellow Fever virus (YFV) encode proteins that antagonize the IFN response, helping these viruses evade host immunity and maintain sufficient viral loads in the blood (viremia) to sustain the vector-host transmission. Arboviruses pose a significant public health threat, affecting around 3.9 billion people in tropical and subtropical regions. However, most preclinical studies suggest that arboviruses cannot inhibit IFN responses in mice, rendering immunocompetent mice resistant to infection, with low viral loads and limited circulation, thus limiting their use in infection research [2-3]. As a result, immunodeficient mouse models with defects in multiple IFN signaling pathways have become essential tools for studying arbovirus pathogenesis and vaccine development [2-4].

Studies have demonstrated that wild-type mice of strains like C57BL/6, CD-1, or 129 rarely exhibit clinical symptoms after infection with arboviruses such as ZIKV. However, the virus has been detected in the blood, ovaries, and spleen of ZIKV-infected 129 mice, suggesting that this strain may be more susceptible to arboviruses [5-6]. Because the virus can persist in the bloodstream without causing disease or death, the 129 strain can be used to evaluate the teratogenic effects of such viruses. Furthermore, the 129 strain is commonly used in interferon signaling-deficient models related to other viral infections [7-8].

The IFNAR1 gene encodes a key component of the type I IFN receptor, while the IFNGR1 gene encodes the ligand-binding chain (α) of the type II (γ) IFN receptor. AG129 mice, which are knockout models for both the type I (α/β) IFN receptor (Ifnar1) and the type II (γ) IFN receptor (Ifngr1), lack functional IFNAR1 and IFNGR1 proteins, resulting in deficiencies in α/β/γ interferon receptor signaling and heightened susceptibility to viral infections. Homozygous AG129 mice are viable and fertile, and exhibit increased sensitivity to arboviral infections, generating viremia similar to that seen in humans. Compared to IFNα/β/γR KO mice on the C57BL/6 background, the 129-background AG129 mice exhibit more pronounced neurological symptoms after infection [6,9].

Strain Strategy

  • Ifnar1 Knockout Strategy (A129 Mice): The Ifnar1 gene on mouse chromosome 16 was knocked out by deleting exons 2-8 using gene-editing technology.



  • Ifngr1 Knockout Strategy (G129 Mice): The Ifngr1 gene on mouse chromosome 10 was knocked out by deleting exons 2-6 using gene-editing technology.


    AG129 mice were generated by breeding Ifnar1 KO (A129) mice (Catalog Number: I001199) with Ifngr1 KO (G129) mice (Catalog Number: I001200), both on a 129 background.

Application

  • Investigating the pathogenesis and developing vaccines for arboviruses such as DENV, ZIKV, YFV, and CHIKV.
  • Studying antiviral immune responses, interferon stimulation, and JAK-STAT signaling.

Validation Data

1. Expression of Ifnar1 and Ifngr1

Figure 1. Expression of Ifnar1 and Ifngr1 genes in the brain, duodenum, and thymus tissues from wild-type (WT), Ifnar1 KO (A129), and Ifngr1 KO (G129) mice. RT-qPCR results show that Ifnar1 gene expression was completely knocked out in the brain and duodenum tissues of Ifnar1 KO mice, and Ifngr1 gene expression was completely knocked out in the brain, duodenum, and thymus tissues of Ifngr1 KO mice.

ND: Not detected.

2. Proportions of Immune Cells in Peripheral Blood

a. Lymphocyte (T, B) and natural killer cell (NKC)


b. CD11b+ myeloid cell, macrophage, dendritic cell (DC), and granulocyte



Figure 2. Flow cytometry analysis of T and B cells, NKCs, CD11b+ myeloid cells, macrophages, dendritic cells, and granulocytes in peripheral blood of Ifnar1 KO (A129) and Ifngr1 KO (G129) mice. Compared to WT mice, Ifnar1 KO and Ifngr1 KO mice showed increased T cell proportions and decreased B cells and NKCs in peripheral blood. Additionally, the proportion of CD11b+ myeloid cells was reduced, but no significant differences were observed in the proportions of granulocytes, macrophages, and dendritic cells.



References

[1] Müller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M. Functional role of type I and type II interferons in antiviral defense. Science. 1994 Jun 24;264(5167):1918-21.
[2] van den Broek MF, Müller U, Huang S, Zinkernagel RM, Aguet M. Immune defence in mice lacking type I and/or type II interferon receptors. Immunol Rev. 1995 Dec;148:5-18.
[3] Marín-Lopez A, Calvo-Pinilla E, Moreno S, Utrilla-Trigo S, Nogales A, Brun A, Fikrig E, Ortego J. Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor. Viruses. 2019 Jan 8;11(1):35.
[4] Grant A, Ponia SS, Tripathi S, Balasubramaniam V, Miorin L, Sourisseau M, Schwarz MC, Sánchez-Seco MP, Evans MJ, Best SM, García-Sastre A. Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling. Cell Host Microbe. 2016 Jun 8;19(6):882-90.
[5] Lazear HM, Govero J, Smith AM, Platt DJ, Fernandez E, Miner JJ, Diamond MS. A Mouse Model of Zika Virus Pathogenesis. Cell Host Microbe. 2016 May 11;19(5):720-30.
[6] Rossi SL, Tesh RB, Azar SR, Muruato AE, Hanley KA, Auguste AJ, Langsjoen RM, Paessler S, Vasilakis N, Weaver SC. Characterization of a Novel Murine Model to Study Zika Virus. Am J Trop Med Hyg. 2016 Jun 1;94(6):1362-1369.
[7] Meyts I, Casanova JL. Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway. Eur J Immunol. 2021 May;51(5):1039-1061.
[8] Zivcec M, Spiropoulou CF, Spengler JR. The use of mice lacking type I or both type I and type II interferon responses in research on hemorrhagic fever viruses. Part 2: Vaccine efficacy studies. Antiviral Res. 2020 Feb;174:104702.
[9] Aliota MT, Caine EA, Walker EC, Larkin KE, Camacho E, Osorio JE. Characterization of Lethal Zika Virus Infection in AG129 Mice. PLoS Negl Trop Dis. 2016 Apr 19;10(4):e0004682.