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Updated: Jul 28, 2025
A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection
Published on: February 28, 2019
Characterization of genetic humanized mice with transgenic HLA DP401 or DRA but deficient in endogenous murine MHC
Feng Li1, Bowen Niu1, Lingling Liu1
1Department of Laboratory Animal Science, Shanghai Public Health Clinical Center, Shanghai, China.
Background:
Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in "carrier" or "pathogenic" states. HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S. aureus infection. However, the contribution of HLA DP to S. aureus infection is unknown yet.
Methods:
In this study, we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes. Neo-floxed IAβ+/- mice were crossbred with Ella-Cre and further crossbred with HLA DP401 or HLA-DRA0101 humanized mice. After several rounds of traditional crossbreeding, we finally obtained HLA DP401-IAβ-/- and HLA DRA-IAβ-/- humanized mice, in which human DP401 or DRA0101 molecule was introduced into IAβ-/- mice deficient in endogenous murine MHC class II molecules. A transnasal infection murine model of S. aureus pneumonia was induced in the humanized mice by administering 2 × 108 CFU of S. aureus Newman dropwise into the nasal cavity. The immune responses and histopathology changes were further assessed in lungs in these infected mice.
Results:
We evaluated the local and systemic effects of S. aureus delivered intranasally in HLA DP401-IAβ-/- and HLA DRA-IAβ-/- transgenic mice. S. aureus Newman infection significantly increased the mRNA level of IL 12p40 in lungs in humanized mice. An increase in IFN-γ and IL-6 protein was observed in HLA DRA-IAβ-/- mice. We observed a declining trend in the percentage of F4/80+ macrophages in lungs in HLA DP401-IAβ-/- mice and a decreasing ratio of CD4+ to CD8+ T cells in lungs in IAβ-/- mice and HLA DP401-IAβ-/- mice. A decreasing ratio of Vβ3+ to Vβ8+ T cells was also found in the lymph node of IAβ-/- mice and HLA DP401-IAβ-/- mice. S. aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ-/- genetic background mice.
Conclusion:
These humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S. aureus pneumonia and study what role DP molecule plays in S. aureus infection.
Insights
New humanized mice models expressing HLA DP or HLA DR molecules were developed to study Staphylococcus aureus pneumonia. These models reveal insights into the role of HLA DP in S. aureus infection pathogenesis and immune response.
Area of Science:
- Immunology
- Microbiology
- Genetics
Background:
- Staphylococcus aureus infections are a significant health concern, driven by superantigen exotoxins.
- Human Leukocyte Antigen (HLA) DQ and DR roles in S. aureus infection are known, but HLA DP's role remains unclear.
Purpose of the Study:
- To investigate the contribution of HLA DP to Staphylococcus aureus infection using novel humanized mouse models.
- To establish and characterize HLA DP401-IAβ-/- and HLA DRA-IAβ-/- humanized mice for S. aureus pneumonia research.
Main Methods:
- Generated HLA DP401 and HLA DRA0101 humanized mice by microinjection and crossbreeding.
- Induced a transnasal S. aureus pneumonia model in humanized mice.
- Assessed immune responses and lung histopathology.
Main Results:
- S. aureus infection increased IL-12p40 mRNA in lungs of humanized mice.
- IFN-γ and IL-6 protein levels rose in HLA DRA-IAβ-/- mice.
- Observed decreased F4/80+ macrophages and altered T cell ratios in HLA DP401-IAβ-/- mice, with reduced lung injury in IAβ-/- backgrounds.
Conclusions:
- Developed novel humanized mice models for studying HLA DP's role in S. aureus infection.
- These models are crucial for understanding S. aureus pneumonia pathogenesis and immune responses.
