Kurzfassung

The evasion of intrinsic, innate, and adaptive immune responses is a common feature of tumors and chronic viral infections. Various viruses interfere with the presentation of antigenic peptides by MHC class-I to limit recognition of infected cells. Additionally, ligands of activating and inhibitory receptors are regulated to downmodulate the natural killer (NK) cell response. Another option for viruses to evade the immune response is a direct interference with intracellular pathways that...The evasion of intrinsic, innate, and adaptive immune responses is a common feature of tumors and chronic viral infections. Various viruses interfere with the presentation of antigenic peptides by MHC class-I to limit recognition of infected cells. Additionally, ligands of activating and inhibitory receptors are regulated to downmodulate the natural killer (NK) cell response. Another option for viruses to evade the immune response is a direct interference with intracellular pathways that induce an antiviral state of infected cells is.
In eons of co-evolution, the species-adapted cytomegaloviruses (CMVs) have evolved multiple strategies dedicated to subvert the immune response. On the other hand, for the respective host it was required to evolve mechanisms to overrule viral immune evasion mechanisms to limit disease pathology by keeping the virus in a balanced state. This results in viral latency, a state during which the immune system suppresses productive infection but fails to clear viral genomes from the host tissues.
Most of the research done so far focused on the viral side, whereas much less is known on how the host counters viral immune evasion and to which extent viral and host proteins interact. One known countermeasure is the exhaustion of the inhibitory capacity of viral immune evasion proteins by interferon (IFN)-enhanced antigen processing and presentation. Another possibility is the regulation of viral immune evasion gene expression by the host. Understanding how virus and host interact and how the host manages to keep viruses under control even under conditions of viral immune evasion may reveal new concepts and targets to enhance immune recognition also of malignant cells.
The well-characterized model of murine CMV (mCMV) has been decisive for the discovery of CMV immune evasion mechanisms and made it feasible to study their roles in vivo. Most of the known immune evasion genes of mCMV cluster in two gene families, the m02 (m02-m16) and the m145 (m141-m158) family. In our first objective, we will comprehensively map the interactome of mCMV immune evasion proteins. We will generate a library of recombinant viruses that allows, after in vivo biotinylation, the targeted pulldown of each viral immune evasion protein and its respective interaction partners. Subsequently, the interacting proteins will be identified by quantitative mass spectrometry (MS) enabling the identification of yet unknown binding partners and novel pathways of immune evasion.
The swiss-army-knife m152/gp40, which is an MHC-I-like molecule, targets multiple cellular proteins to subvert intrinsic, innate, and adaptive immune responses. m152 not only modulates the NKG2D ligand RAE1 and classical MHC-I complexes inhibiting the recognition of infected cells by NK and CD8 T cells, respectively, but also interacts with STING to slow down the induction of type-I IFNs. Evidence from the current funding period indicates that the transcription of m152 is controlled by an 'IFN regulatory factor element (IRFE)' located in the promoter region of the m152 gene. During acute infection, the IRFE is targeted by suppressive IFN response factors (IRFs) resulting in a delayed transcription of m152. This identified the m152 promotor region as a target for host countermeasures. Further, our results indicate a cell type-specific suppression of m152 transcription. In contrast, we have first experimental evidence that the IRFE acts as an activating regulator of m152 transcription during viral latency. In objectives two and three, we now propose experiments to analyze the regulation and function of the regulatory elements in the m152 promoter region during acute and latent mCMV infection.» weiterlesen» einklappen