Type I interferon underlies severe disease associated with Junín virus infection in mice
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, United States
- Utah Veterinary Diagnostic Laboratory, Utah State University, United States
- Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles (UCLA), United States
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, United States
- UCLA Molecular Biology Institute, United States
- UCLA Jonsson Comprehensive Cancer Center, United States
- UCLA AIDS Institute, United States
Figures
Figure 1
Expression of hTfR1 results in severe disease following JUNV infection.
Three-week-old WT, hTfR1 HET or hTfR1 HOM mice (n = 8–9/group) were infected i.p. with 105 CCID50 of JUNV and monitored daily. (A) Survival and (B) weight change of animals relative to the day of …
Figure 2
Age-dependent susceptibility of hTfR1 HOM mice to lethal JUNV disease.
Shown are (A) survival (n = 6/group for the 3- and 4-week-old mice, n = 3/group for the 5- and 6-week-old mice), (B) weight change in 3 to 4 week-old mice, (C) weight change in 5 to 6 week-old mice …
Figure 3
JUNV lethal dose determination in 3-week-old hTfR1 HOM mice.
Shown are (A) survival (n = 7/JUNV challenge group, n = 3 sham-infected controls), (B) weight change relative to the day of virus challenge (group mean and SEM) and (C) clinical disease scores …
Figure 4
Temporal analysis of weight change, clinical disease signs, IFN-α and viral burden during the course of JUNV infection in 3-week-old hTfR1 HOM mice.
Animals (n = 28) were infected i.p. with 104 CCID50 of JUNV and subsets of 4 mice were designated for euthanasia on days 2, 4, 6, 8, 10, 12 and 14 p.i. for blood and tissue collection and analysis. …
Figure 5
Histopathology in 3-week-old hTfR1 HOM mice infected with JUNV.
Representative sections of brain (cerebral cortex) from (A and C) a sham-infected mouse and (B and D) a JUNV-infected mouse at day 12 p.i. (B) Neutrophilic encephalitis characterized by a perivascula…
Figure 6
Immunohistochemistry for JUNV antigen in 3-week-old hTfR1 HOM mice.
Representative sections of brain (midbrain) from (A and C) a sham-infected mouse and (B and D) a JUNV-infected mouse at day 12 p.i. Note the presence of the virus in neurons (brown staining). (E and …
Figure 7
Effect of type I and II IFN response on JUNV infection and disease outcome in 3-week-old hTfR1 HOM mice.
Mice (n = 3/group) of different phenotypic backgrounds were challenged with 105 CCID50 of JUNV and monitored daily for (A) survival, (B) weight change relative to the day of virus challenge (group …
Figure 8
Effect of anti-IFN-α/βR mAb treatment on JUNV pathogenicity in 3-week-old hTfR1 HOM mice.
Animals (n = 3–4/group) were treated with a single 500 µg dose of IFN-α/βR-blocking mAb (with or without additional 250 µg maintenance doses every other day for one or two weeks) and infected i.p. …
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Genetic reagent (Mus musculus) | C57BL/6 hTfR1 knock-in mice (human TFRC replacing the mouse Tfrc) | Genentech | ||
| Genetic reagent (Mus musculus) | AG129 mice deficient in IFN-α/β receptor (R) and IFN-γR (Ifnar-/-; Ifngr-/-) | Washington University Medical School | ||
| Genetic reagent (Mus musculus) | Wild-type (WT) mice (hybrid C57BL/6 × 129 background) | This paper | See Materials and methods | |
| Genetic reagent (Mus musculus) | hTfR1 heterozygous (HET) mice (hybrid C57BL/6 × 129 background) | This paper | See Materials and methods | |
| Genetic reagent (Mus musculus) | hTfR1 homozygous (HOM) mice (hybrid C57BL/6 × 129 background) | This paper | See Materials and methods | |
| Genetic reagent (Mus musculus) | IFN-α/βR-deficient mice (hybrid C57BL/6 × 129 background) | This paper | See Materials and methods | |
| Genetic reagent (Mus musculus) | IFN-α/β and -γR-deficient mice (hybrid C57BL/6 × 129 background) | This paper | See Materials and methods | |
| Genetic reagent (Mus musculus) | hTfR1 HOM–IFN-α/βR-deficient mice (hybrid C57BL/6 × 129 background) | This paper | See Materials and methods | |
| Genetic reagent (Mus musculus) | hTfR1 HOM–IFN-α/β and -γR-deficient mice (hybrid C57BL/6 × 129 background) | This paper | See Materials and methods | |
| Strain, strain background (Junín virus) | Recombinant JUNV Romero strain | University of Texas Medical Branch | ||
| Cell line (Cercopithecus aethiops) | Vero | ATCC | Cat# CCL-81 RRID:CVCL_0059 | |
| Commercial assay or kit | VeriKine Mouse Interferon Alpha ELISA Kit | PBL Assay Science | Cat# 42115–1 | |
| Antibody | Goat anti-mouse IgG1 Fab (polyclonal) | Jackson ImmunoResearch Laboratories | Cat# 115-007-185 RRID:AB_2632498 | (1:10) |
| Antibody | Anti-JUNV nucleoprotein antibody (QC03-BF11) | BEI Resources | Cat# NR-43775 | (1:100) |
| Antibody | Goat anti-mouse IgG (H+L) - HRP secondary antibody (polyclonal) | Thermo Fisher Scientific | Cat# G-21040 RRID:AB_2536527 | (1:100) |
| Antibody | Anti-mouse IFNAR-1 (anti-IFN-α/βR) monoclonal antibody (MAR1-5A3) | Bio X Cell | Cat# BE0241 RRID:AB_2687723 | (500 µg primary dose; 250 µg maintenance dose) |
| Software | GraphPad Prism software | GraphPad Prism (https://www.graphpad.com) | RRID_SCR_002798 | Version 8.4.1 |
