Characterization of genetic humanized mice with transgenic HLA DP401 or DRA but deficient in endogenous murine MHC class Ⅱ genes upon Staphylococcus aureus pneumonia

作者：Feng Li^*; Bowen Niu; Lingling Liu; Mengmin Zhu; Hua Yang; Boyin Qin; Xiuhua Peng; Lixiang Chen; Chunhua Xu; Xiaohui Zhou^*

来源：Animal Models and Experimental Medicine, 2023, 6(06): 585-597.

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 m RNA 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.

• 出版日期2023