humanized mouse model
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2022 ◽  
Vol 219 (2) ◽  
Author(s):  
Elza Evren ◽  
Emma Ringqvist ◽  
Jean-Marc Doisne ◽  
Anna Thaller ◽  
Natalie Sleiers ◽  
...  

Despite their importance in lung health and disease, it remains unknown how human alveolar macrophages develop early in life. Here we define the ontogeny of human alveolar macrophages from embryonic progenitors in vivo, using a humanized mouse model expressing human cytokines (MISTRG mice). We identified alveolar macrophage progenitors in human fetal liver that expressed the GM-CSF receptor CD116 and the transcription factor MYB. Transplantation experiments in MISTRG mice established a precursor–product relationship between CD34−CD116+ fetal liver cells and human alveolar macrophages in vivo. Moreover, we discovered circulating CD116+CD64−CD115+ macrophage precursors that migrated from the liver to the lung. Similar precursors were present in human fetal lung and expressed the chemokine receptor CX3CR1. Fetal CD116+CD64− macrophage precursors had a proliferative gene signature, outcompeted adult precursors in occupying the perinatal alveolar niche, and developed into functional alveolar macrophages. The discovery of the fetal alveolar macrophage progenitor advances our understanding of human macrophage origin and ontogeny.


Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 35
Author(s):  
Nilakshi Barua ◽  
Ying Yang ◽  
Lin Huang ◽  
Margaret Ip

The vancomycin-resistance associated sensor/regulator, VraSR two-component regulatory-system (VraSR), regulates virulence and the response of Staphylococcus aureus (SA) to environmental stress. To investigate the role of VraSR in SA skin and soft tissue infections (SSTI), we inactivated the VraSR of a clinical CA-MRSA ST30 strain by insertional mutation in vraR gene using the TargeTron-Gene Knockout System. We constructed an organotypic keratinocyte fibroblast co-culture (3D-skin model) and a humanized mouse as SSTI infection models. In the 3D-skin model, inactivation of VraSR in the strains ST30 and USA300 showed 1-log reduction in adhesion and internalization (p < 0.001) compared to the respective wildtype. The mutant strains of ST30 (p < 0.05) and USA300-LAC (p < 0.001) also exhibited reduced apoptosis. The wildtype ST30 infection in the humanized mouse model demonstrated increased skin lesion size and bacterial burden compared to BALB/c mice (p < 0.01). The response of the humanized mouse towards the MRSA infection exhibited human similarity indicating that the humanized mouse SSTI model is more suitable for evaluating the role of virulence determinants. Inactivation of VraSR in ST30 strain resulted in decreased skin lesion size in the humanized mouse SSTI model (p < 0.05) and reduction in apoptotic index (p < 0.01) when compared with the wildtype. Our results reveal that inactivating the VraSR system may be a potent anti-virulence approach to control MRSA infection.


Author(s):  
Esen Sefik ◽  
Benjamin Israelow ◽  
Haris Mirza ◽  
Jun Zhao ◽  
Rihao Qu ◽  
...  

2021 ◽  
pp. ji2100122
Author(s):  
Yixin Wang ◽  
Lei Wang ◽  
Cong Fu ◽  
Xue Wang ◽  
Siyao Zuo ◽  
...  

2021 ◽  
Vol 177 ◽  
pp. S98
Author(s):  
Paula Trigo Alonso ◽  
Enrique Luengo ◽  
Cristina Fernández-Mendívil ◽  
Ángel Nuñez ◽  
Marta del Campo ◽  
...  

2021 ◽  
Vol 11 ◽  
Author(s):  
Hyeree Choi ◽  
Michelle Ho ◽  
Opeyemi S. Adeniji ◽  
Leila Giron ◽  
Devivasha Bordoloi ◽  
...  

Sialic acid-binding Immunoglobulin-like lectin-9 (Siglec-9) is a glyco-immune negative checkpoint expressed on several immune cells. Siglec-9 exerts its inhibitory effects by binding to sialoglycan ligands expressed on cancer cells, enabling them to evade immunosurveillance. We developed a panel of human anti-Siglec-9 hybridoma clones by immunizing mice with Siglec-9-encoding DNA and Siglec-9 protein. The lead antibodies, with high specificity and functionality against Siglec-9, were identified through screening of clones. The in vitro cytotoxicity assays showed that our lead antibody enhances anti-tumor immune activity. Further, in vivo testing utilizing ovarian cancer humanized mouse model showed a drastic reduction in tumor volume. Together, we developed novel antibodies that augment anti-tumor immunity through interference with Siglec-9-mediated immunosuppression.


2021 ◽  
Vol 12 ◽  
Author(s):  
Arlisa Alisjahbana ◽  
Yu Gao ◽  
Natalie Sleiers ◽  
Elza Evren ◽  
Demi Brownlie ◽  
...  

Innate lymphoid cells (ILCs) contribute to immune defense, yet it is poorly understood how ILCs develop and are strategically positioned in the lung. This applies especially to human ILCs due to the difficulty of studying them in vivo. Here we investigated the ontogeny and migration of human ILCs in vivo with a humanized mouse model (“MISTRG”) expressing human cytokines. In addition to known tissue-resident ILC subsets, we discovered CD5-expressing ILCs that predominantly resided within the lung vasculature and in the circulation. CD5+ ILCs contained IFNγ-producing mature ILC1s as well as immature ILCs that produced ILC effector cytokines under polarizing conditions in vitro. CD5+ ILCs had a distinct ontogeny compared to conventional CD5- ILCs because they first appeared in the thymus, spleen and liver rather than in the bone marrow after transplantation of MISTRG mice with human CD34+ hematopoietic stem and progenitor cells. Due to their strategic location, human CD5+ ILCs could serve as blood-borne sentinels, ready to be recruited into the lung to respond to environmental challenges. This work emphasizes the uniqueness of human CD5+ ILCs in terms of their anatomical localization and developmental origin compared to well-studied CD5- ILCs.


Immunity ◽  
2021 ◽  
Author(s):  
Sven Kratochvil ◽  
Chen-Hsiang Shen ◽  
Ying-Cing Lin ◽  
Kai Xu ◽  
Usha Nair ◽  
...  

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