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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Human cytomegalovirus encodes an MHC class I-like molecule (UL142) that functions to inhibit NK cell lysis
Mark R Wills1, Omodele Ashiru, Matthew B Reeves
1Department of Medicine, School of Clinical Medicine, University of Cambridge, United Kingdom. mrw1004@cam.ac.uk
Abstract:
Clinical and low passage strains of human CMV (HCMV) encode an additional MHC class I-related molecule UL142, in addition to the previously described UL18. The UL142 open reading frame is encoded within the ULb' region which is missing from a number of common high passage laboratory strains. Cells expressing UL142 following transfection, and fibroblasts infected with a recombinant adenovirus-expressing UL142, were used to screen both polyclonal NK cells and NK cell clones, in a completely autologous system. Analysis of 100 NK cell clones derived from five donors, revealed 23 clones that were inhibited by fibroblasts expressing UL142 alone. Small-interfering RNA-mediated knockdown of UL142 mRNA expression in HCMV-infected cells resulted in increased sensitivity to lysis. From these data we conclude that UL142 is a novel HCMV-encoded MHC class I-related molecule which inhibits NK cell killing in a clonally dependent manner.
Insights
Human cytomegalovirus (HCMV) encodes a novel MHC class I-related molecule, UL142, which inhibits natural killer (NK) cell killing. This UL142 molecule impacts NK cell activity in a clonally dependent manner.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Human cytomegalovirus (HCMV) is a prevalent pathogen that employs immune evasion strategies.
- HCMV encodes MHC class I homologs, including UL18, to modulate host immune responses.
- The ULb' region of HCMV, encoding UL142, is often absent in laboratory strains.
Purpose of the Study:
- To investigate the function of the HCMV-encoded MHC class I-related molecule UL142.
- To determine the effect of UL142 on natural killer (NK) cell activity.
- To characterize UL142's role in HCMV immune evasion.
Main Methods:
- Expression of UL142 in transfected cells and HCMV-infected fibroblasts.
- Screening of polyclonal and clonal NK cells using an autologous system.
- Assessment of NK cell inhibition by UL142-expressing cells.
- Small-interfering RNA (siRNA) mediated knockdown of UL142 mRNA.
Main Results:
- HCMV UL142 is a novel MHC class I-related molecule.
- UL142 expression on infected cells inhibited NK cell killing in a clonally dependent manner.
- Knockdown of UL142 enhanced NK cell-mediated lysis of HCMV-infected cells.
Conclusions:
- UL142 is a newly identified HCMV immune evasion molecule.
- UL142 actively suppresses NK cell cytotoxicity.
- UL142 represents a target for understanding HCMV pathogenesis and immune control.
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