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Vaccine properties of a mouse CMV expressing ligand for the NKG2D receptor

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in congenitaly infected and immunocompromised individuals. Therefore, development of an effective HCMV vaccine has been ranked as a top priority. NKG2D is a potent activating receptor expressed by the cells of innate and adaptive immunity. Its importance in CMV immunesurveillance is indicated by the elaborative viral evasion mechanisms evolved to avoid NKG2D. In order to study this powerful signaling pathway we designed a recombinant mouse CMV expressing the high affinity NKG2D ligand RAE-1γ (RAE-1γMCMV). Expression of RAE-1γ by MCMV resulted in profound virus attenuation in vivo and lower latent virus DNA loads. RAE-1γMCMV infection was efficiently controlled by immunodeficient hosts, including mice lacking type I interferons receptor and mice immunosuppressed by sublethal γ-irradiation. Features of neonatal RAE-1γMCMV infection were also diminished. Despite tight innate immune control, RAE-1γMCMV infection elicited strong, long-lasting protective immunity. Moreover, upon maternal vaccination with MCMV expressing NKG2D ligand, transplacental transfer of antiviral antibodies protected neonatal mice from CMV disease. RAE-1γ transgene exhibited no sequence variation throughout infection despite of selective pressure. Live, attenuated viruses have large potential to serve as a vaccine vectors. The capacity of recombinant RAE-1γMCMV to serve as a vaccine vector for other viral and bacterial pathogens is currently under investigation. Altogether, our results indicate that a recombinant virus encoding a ligand for NKG2D receptor might provide a new, powerful approach for development of a safe and immunogenic CMV vaccine as well as CMV-based vaccine vector.

Cytomegalovirus; NKG2D receptor; NKG2D ligands; CMV vaccine; CMV vaccine vector

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