Type I Interferon Signaling Controls Gammaherpesvirus Latency In Vivo

• Type of Material: Article
• Authors: Johannes Schwerk, Helmholtz Centre for Infection Research (HZI); Lucas Kemper, Helmholtz Centre for Infection Research (HZI); Kendra A Bussey, Technische Universität Braunschweig; Stefan Lienenklaus, Hannover Medical School; Siegfried Weiss, Hannover Medical School; Luka Čičin-Šain, Helmholtz Centre for Infection Research (HZI); Andrea Kroeger, Helmholtz Centre for Infection Research (HZI); Ulrich Kalinke, 9Institute for Experimental Infection Research, Twincore, Germany; Christopher Collins, Emory University; Samuel Speck, Emory University; Martin Messerle, Hannover Medical School; Dagmar Wirth, Helmholtz Centre for Infection Research (HZI); Melanie M Brinkmann, Tech Univ Carolo Wilhelmina Braunschweig; Hansjörg Hauser, Helmholtz Centre for Infection Research (HZI); Mario Köster, Helmholtz Centre for Infection Research (HZI)
• Language: English
• Date: 2022-12-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/pathogens11121554
• Title of Journal or Parent Work: PATHOGENS
• Volume: 11
• Issue: 12
• Grant/Funding Information: This study was supported by funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) for the Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), for the research grant Ho 2236/8-1, for the priority program SPP1656, and for the Collaborative Research Center SFB 900/CRC 900 (Projektnummer 158989968). Further funding was received from the German Ministry of Education and Research (01KI1003D) and from the “Niedersächsisches Ministerium für Wissenschaft und Kultur”, Europäischer Fonds für regionale Entwicklung grant (80029155). J.S. was supported by the Hannover Biomedical Research School (HBRS), the Center for Infection Biology (ZIB), as well as by the Helmholtz Centre for Infection Research Graduate School.
• Keywords: Microbiology; INFECTION; MEDIATED CONTROL; chronic infection; REACTIVATION; B-CELLS; type I interferon; MOUSE MODEL; IMMUNITY; VIRUS; Life Sciences & Biomedicine; GAMMA-HERPESVIRUS; ALPHA/BETA; Science & Technology; latency; murine gammaherpesvirus 68; HOST
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

Gammaherpesviruses, such as Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus, are important human pathogens involved in lymphoproliferative disorders and tumorigenesis. Herpesvirus infections are characterized by a biphasic cycle comprised of an acute phase with lytic replication and a latent state. Murine gammaherpesvirus 68 (MHV-68) is a well-established model for the study of lytic and latent life cycles in the mouse. We investigated the interplay between the type I interferon (IFN)-mediated innate immune response and MHV-68 latency using sensitive bioluminescent reporter mice. Adoptive transfer of latently infected splenocytes into type I IFN receptor-deficient mice led to a loss of latency control. This was revealed by robust viral propagation and dissemination of MHV-68, which coincided with type I IFN reporter induction. Despite MHV-68 latency control by IFN, the continuous low-level cell-to-cell transmission of MHV-68 was detected in the presence of IFN signaling, indicating that IFN cannot fully prevent viral dissemination during latency. Moreover, impaired type I IFN signaling in latently infected splenocytes increased the risk of virus reactivation, demonstrating that IFN directly controls MHV-68 latency in infected cells. Overall, our data show that locally constrained type I IFN responses control the cellular reservoir of latency, as well as the distribution of latent infection to potential new target cells.