Visualization of herpes virus infections and immune response as well as their modulation
Immune cells (green) are visualized with 2-Photonen microscopy. Virus infected cells (red) are intact. The picture was taken from a 24h-infected popliteal lymph node of a mouse producing GFP-expressed immune cells
How does the immune system protect us against chronic viral infections? Beta-herpesviruses can chronically infect humans and mice, but only immunocompromised individuals suffer from disease. Thus, the intact immune response does play an important role in controlling a beta-herpesvirus infection.
In this project, we apply a combination of the in vivo 2-photon microscopy technique and infections with beta-herpesvirus reporter viruses, in order to directly investigate, in real time, how immune cells interact with virus-infected cells and keep the infection in check.
Scientific work programme
In this project, we are investigating the in vivo infection with the mouse cytomegalovirus (MCMV, murine herpesvirus-1) and the induction of CMV-specific immunity. In close collaboration between the MHH departments of immunology and virology, we have been able to unravel how different types of immune cells attack virus-infected cells in vivo, applying different mouse models. By visualizing individual cells we discovered that single cytotoxic T cells were unable to detect infected cells when the viral immune evasion mechanisms were intact. Only upon deletion of two important MCMV immune evasion genes the infected target cells became visible to the immune cells and could be destroyed (Halle et al., Immunity 2016).
We also explore how MCMV infection spreads in the lungs of infected new-born mice (Stahl et al., Mucosal Immunology 2015, Stahl et al., PLoS Pathogens 2013, Marquardt et al., and Journal of General Virology 2011).
Taken together, by applying high-resolution techniques we can closely monitor MCMV infection on the single cell level in different organs to better understand the protective immune response and particularly how it prevents chronic persistence of the infection in immunocompetent hosts.
Reinhold Förster is talking about his research at the CRC 900
Reinhold Förster has been part of the CRC since it was founded in 2010. His project B1, in cooperation with Martin Messerle, is concerned with the visualisation of the immune response during herpesvirus infections, using 2-photon-microscopy.
Publications of the project B1
- Control of primary mouse cytomegalovirus infection in lung nodular inflammatory 1 foci by cooperation of Interferon-gamma expressing CD4 and CD8 T cells. Lueder Y, Heller K, Ritter C, Keyser KA, Wagner K, Liu X, Messerle M, Stahl FR, Halle S, Förster R PLoS Pathog. 2018 Aug 28;14(8):e1007252.
- Repulsive behavior in germinal Centers. Moschovakis GL, Förster R. Science. 2017 May 19;356(6339):703-704.
Dendritic cell migration in health and disease. Worbs T, Hammerschmidt SI, Förster R. Nat Rev Immunol. 2016 Nov 28.
Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics. Schulz O, Hammerschmidt SI, Moschovakis GL, Förster R. Annu Rev Immunol. 2016 May 20;34:203-42.
In Vivo Killing Capacity of Cytotoxic T Cells Is Limited and Involves Dynamic Interactions and T Cell Cooperativity. Halle S, Keyser KA, Stahl FR, Busche A, Marquardt A, Zheng X, Galla M, Heissmeyer V, Heller K, Boelter J, Wagner K, Bischoff Y, Martens R, Braun A, Werth K, Uvarovskii A, Kempf H, Meyer-Hermann M, Arens R, Kremer M, Sutter G, Messerle M, Förster R. Immunity. 2016 Feb 16;44(2):233-45.
Mck2-dependent infection of alveolar macrophages promotes replication of MCMV in nodular inflammatory foci of the neonatal lung. Stahl FR, Keyser KA, Heller K, Bischoff Y, Halle S, Wagner K, Messerle M, Förster R. Mucosal Immunol. 2015 Jan;8(1):57-67.
IL-17-induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs. Fleige H, Ravens S, Moschovakis GL, Bölter J, Willenzon S, Sutter G, Häussler S, Kalinke U, Prinz I, Förster R. J Exp Med. 2014 Apr 7;211(4):643-51.
Nodular inflammatory foci are sites of T cell priming and control of murine cytomegalovirus infection in the neonatal lung. Stahl FR, Heller K, Halle S, Keyser KA, Busche A, Marquardt A, Wagner K, Boelter J, Bischoff Y, Kremmer E, Arens R, Messerle M, Förster R. PLoS Pathog. 2013;9(12):e1003828.
Absence of Siglec-H in MCMV infection elevates interferon alpha production but does not enhance viral clearance. Puttur F, Arnold-Schrauf C, Lahl K, Solmaz G, Lindenberg M, Mayer CT, Gohmert M, Swallow M, van Helt C, Schmitt H, Nitschke L, Lambrecht BN, Lang R, Messerle M, Sparwasser T. PLoS Pathog. 2013;9(9):e1003648.
Priming of CD8+ T cells against cytomegalovirus-encoded antigens is dominated by cross-presentation. Busche A, Jirmo AC, Welten SP, Zischke J, Noack J, Constabel H, Gatzke AK, Keyser KA, Arens R, Behrens GM, Messerle M. J Immunol. 2013 Mar 15;190(6):2767-77.
The human cytomegalovirus UL51 protein is essential for viral genome cleavage-packaging and interacts with the terminase subunits pUL56 and pUL89. Borst EM, Kleine-Albers J, Gabaev I, Babic M, Wagner K, Binz A, Degenhardt I, Kalesse M, Jonjic S, Bauerfeind R, Messerle M. J Virol. 2013 Feb;87(3):1720-32.