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Published on: January 15, 2018
NKp30-dependent cytolysis of filovirus-infected human dendritic cells
Claudette L Fuller1, Gordon Ruthel, Kelly L Warfield
1United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
Abstract:
Understanding how protective innate immune responses are generated is crucial to defeating highly lethal emerging pathogens. Accumulating evidence suggests that potent innate immune responses are tightly linked to control of Ebola and Marburg filoviral infections. Here, we report that unlike authentic or inactivated Ebola and Marburg, filovirus-derived virus-like particles directly activated human natural killer (NK) cells in vitro, evidenced by pro-inflammatory cytokine production and enhanced cytolysis of permissive target cells. Further, we observed perforin- and CD95L-mediated cytolysis of filovirus-infected human dendritic cells (DCs), primary targets of filovirus infection, by autologous NK cells. Gene expression knock-down studies directly linked NK cell lysis of infected DCs to upregulation of the natural cytotoxicity receptor, NKp30. These results are the first to propose a role for NK cells in the clearance of infected DCs and the potential involvement of NKp30-mediated cytolysis in control of viral infection in vivo. Further elucidation of the biology of NK cell activation, specifically natural cytotoxicity receptors like NKp30 and NKp46, promises to aid our understanding of microbial pathology.
Insights
Filovirus-like particles activate natural killer (NK) cells, which then kill infected dendritic cells (DCs) via NKp30. This NK cell response is key to controlling filoviral infections.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Emerging viral pathogens like Ebola and Marburg pose significant threats.
- Innate immune responses are critical for controlling filoviral infections.
Purpose of the Study:
- To investigate the role of natural killer (NK) cells in filoviral infections.
- To determine the mechanisms by which NK cells combat filovirus-infected cells.
Main Methods:
- In vitro activation of human NK cells using filovirus-derived virus-like particles.
- Assessment of NK cell-mediated cytotoxicity against filovirus-infected human dendritic cells (DCs).
- Gene expression knock-down studies to identify key molecular players, including NKp30.
Main Results:
- Filovirus-like particles directly activated human NK cells, inducing cytokine production and enhanced cytolysis.
- Autologous NK cells effectively killed filovirus-infected human DCs through perforin and CD95L.
- Upregulation of the natural cytotoxicity receptor NKp30 was directly linked to NK cell-mediated lysis of infected DCs.
Conclusions:
- NK cells play a crucial role in clearing filovirus-infected DCs.
- NKp30-mediated cytolysis is a potential mechanism for controlling filoviral infections in vivo.
- Further research into NK cell activation, particularly via NKp30 and NKp46, can advance understanding of viral pathology.
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