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Contact-Free Co-Culture Model for the Study of Innate Immune Cell Activation During Respiratory Virus Infection
Published on: February 28, 2021
NK-cell receptors NKp46 and NCR1 control human metapneumovirus infection
Mohammad Diab1, Ariella Glasner1, Batya Isaacson1
1The Lautenberg Center for General and Tumor Immunology, the BioMedical Research Institute Israel-Canada of the Faculty of Medicine (IMRIC), The Hebrew University Hadassah Medical School, Jerusalem, Israel.
Abstract:
Natural killer (NK) cells are capable of killing various pathogens upon stimulation of activating receptors. Human metapneumovirus (HMPV) is a respiratory virus, which was discovered in 2001 and is responsible for acute respiratory tract infection in infants and children worldwide. HMPV infection is very common, infecting around 70% of all children under the age of five. Under immune suppressive conditions, HMPV infection can be fatal. Not much is known on how NK cells respond to HMPV. In this study, using reporter assays and NK-cell cytotoxicity assays performed with human and mouse NK cells, we demonstrated that the NKp46-activating receptor and its mouse orthologue Ncr1, both members of the natural cytotoxicity receptor (NCR) family, recognized an unknown ligand expressed by HMPV-infected human cells. We demonstrated that MHC class I is upregulated and MICA is downregulated upon HMPV infection. We also characterized mouse NK-cell phenotype in the blood and the lungs of HMPV-infected mice and found that lung NK cells are more activated and expressing NKG2D, CD43, CD27, KLRG1, and CD69 compared to blood NK cells regardless of HMPV infection. Finally, we demonstrated, using Ncr1-deficient mice, that NCR1 plays a critical role in controlling HMPV infection.
Insights
Natural killer (NK) cells use the NKp46 receptor to recognize human metapneumovirus (HMPV)-infected cells. The natural cytotoxicity receptor 1 (NCR1) is crucial for controlling HMPV infection in mice.
Area of Science:
- Immunology
- Virology
- Cellular Biology
Background:
- Natural killer (NK) cells are crucial immune cells that eliminate pathogens via activating receptors.
- Human metapneumovirus (HMPV) causes significant respiratory infections in children, but NK cell responses remain poorly understood.
- HMPV infection can be severe, particularly in immunocompromised individuals.
Purpose of the Study:
- To investigate the role of NK cells and specific activating receptors in response to HMPV infection.
- To characterize the NK cell response in the context of HMPV infection in both human and mouse models.
- To determine the critical NK cell receptors involved in controlling HMPV.
Main Methods:
- Reporter assays and NK-cell cytotoxicity assays using human and mouse NK cells.
- Analysis of NK cell phenotype in blood and lungs of HMPV-infected mice.
- Utilizing Ncr1-deficient mice to assess the role of the NCR1 receptor.
Main Results:
- The NKp46 receptor (and its mouse orthologue, Ncr1) recognized an unknown ligand on HMPV-infected cells.
- MHC class I expression was upregulated, while MICA was downregulated on infected cells.
- Lung NK cells showed higher activation markers (NKG2D, CD43, CD27, KLRG1, CD69) compared to blood NK cells.
- Ncr1-deficient mice exhibited impaired control of HMPV infection.
Conclusions:
- NKp46/Ncr1 engagement is a key mechanism in NK cell recognition of HMPV-infected cells.
- NCR1 plays a vital role in the innate immune response against HMPV.
- Understanding NK cell responses to HMPV can inform therapeutic strategies for respiratory viral infections.
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