Murine model of cytomegalovirus latency and reactivation

Efficient resolution of acute cytopathogenic infection through innate and adaptive host immune mechanisms followed by lifelong maintenance of the viral genome in host tissues in a state of replicative latency interrupted by episodes of virus reactivation for transmission is the result of aeons of co-evolution of cytomegaloviruses and their respective host species. Genetic adaptation of a particular cytomegalovirus to its specific host is reflected by private gene families not found in other members of the cytomegalovirus group, whereas basic functions of the viral replicative cycle are encoded by public gene families shared between different cytomegaloviruses or even with herpesviruses in general. Private genes include genes coding for immunoevasins, a group of glycoproteins specifically dedicated to dampen recognition by the host's innate and adaptive immune surveillance to protect the virus against elimination.
Recent data in the mouse model of cytomegalovirus latency have indicated that viral replicative latency established in the immunocompetent host is a dynamic state characterized by episodes of viral gene desilencing and immune sensing of the reactivated viral gene expression by CD8 T cells recognizing the presentation of antigenic peptides at immunological checkpoints. This sensing maintains viral replicative latency by triggering antiviral effector functions that terminate the viral gene expression program before infectious viral progeny are assembled. According to the immune sensing hypothesis of latency control, immunological checkpoints are unique for each infected individual in reflection of host MHC (HLA) polymorphism and the proteome(s) of the viral variant(s) harbored in latency.

Project related publications

Leng SX, Kamil J, Purdy JG, Lemmermann NA, Reddehase MJ, Goodrum FD 2017. Recent advances in CMV tropism, latency, and diagnosis during aging. Geroscience 39:251-259

Reddehase MJ 2016. Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation. Front Immunol 7:294

Dekhtiarenko I, Ratts RB, Blatnik R, Lee LN, Fischer S, Borkner L, Oduro JD, Marandu TF, Hoppe S, Ruzsics Z, Sonnemann JK, Mansouri M, Meyer C, Lemmermann NA, Holtappels R, Arens R, Klenerman P, Früh K, Reddehase MJ, Riemer AB, Cicin-Sain L 2016. Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors. PLoS Pathog 12:e1006072

Holtappels R*, Lemmermann NA*, Podlech J, Ebert S, Reddehase MJ 2016. Reconstitution of CD8 T Cells Protective against Cytomegalovirus in a Mouse Model of Hematopoietic Cell Transplantation: Dynamics and Inessentiality of Epitope Immunodominance. Front Immunol 7:232.

Fink A, Büttner JK, Thomas D, Holtappels R, Reddehase MJ*, Lemmermann NA* 2014. Noncanonical expression of a murine cytomegalovirus early protein CD8 T-cell epitope as an immediate early epitope based on transcription from an upstream gene. Viruses 6:808-31

Seckert CK, Griessl M, Büttner JK, Scheller S, Simon CO, Kropp KA, Renzaho A, Kühnapfel B, Grzimek NK, Reddehase MJ 2012. Viral latency drives 'memory inflation': a unifying hypothesis linking two hallmarks of cytomegalovirus infection. Med Microbiol Immunol 201:551-66.

Seckert CK, Schader SI, Ebert S, Thomas D, Freitag K, Renzaho A, Podlech J, Reddehase MJ, Holtappels R 2011. Antigen-presenting cells of haematopoietic origin prime cytomegalovirus-specific CD8 T-cells but are not sufficient for driving memory inflation during viral latency. J Gen Virol 92:1994-2005.

Marquardt A, Halle S, Seckert CK, Lemmermann NA, Veres TZ, Braun A, Maus UA, Förster R, Reddehase MJ, Messerle M, Busche A 2011. Single cell detection of latent cytomegalovirus reactivation in host tissue. J Gen Virol 92:1279-91

Kern M, Popov A, Scholz K, Schumak B, Djandji D, Limmer A, Eggle D, Sacher T, Zawatzky R, Holtappels R, Reddehase MJ, Hartmann G, Debey-Pascher S, Diehl L, Kalinke U, Koszinowski U, Schultze J, Knolle PA 2010. Virally infected mouse liver endothelial cells trigger CD8+ T-cell immunity. Gastroenterology. 138:336-46.

Seckert CK, Renzaho A, Tervo HM, Krause C, Deegen P, Kühnapfel B, Reddehase MJ, Grzimek NK 2009. Liver sinusoidal endothelial cells are a site of murine cytomegalovirus latency and reactivation. J Virol 83:8869-84.

Reddehase MJ, Simon CO, Seckert CK, Lemmermann N, Grzimek NK 2008. Murine model of cytomegalovirus latency and reactivation. Curr Top Microbiol Immunol 325:315-31.

Seckert CK, Renzaho A, Reddehase MJ, Grzimek NK 2008. Hematopoietic stem cell transplantation with latently infected donors does not transmit virus to immunocompromised recipients in the murine model of cytomegalovirus infection. Med Microbiol Immunol. 197:251-9.

Simon CO, Kühnapfel B, Reddehase MJ, Grzimek NK 2007. Murine cytomegalovirus major immediate-early enhancer region operating as a genetic switch in bidirectional gene pair transcription. J Virol 81:7805-10.

Simon CO, Seckert CK, Dreis D, Reddehase MJ, Grzimek NK 2005. Role for tumor necrosis factor alpha in murine cytomegalovirus transcriptional reactivation in latently infected lungs. J Virol 79:326-40.