Abstract
ABSTRACTA pathogen encounter induces interferons, which signal via Janus kinases and STAT transcription factors to establish an antiviral state. However, the host and pathogens are situated in a continuous arms race which shapes host evolution toward optimized immune responses and the pathogens toward enhanced immune-evasive properties. Mouse cytomegalovirus (MCMV) counteracts interferon responses by pM27-mediated degradation of STAT2, which directly affects the signaling of type I as well as type III interferons. Using MCMV mutants lacking M27 and mice lacking STAT2, we studied the opposing relationship between antiviral activities and viral antagonism in a natural host-pathogen pair in vitro and in vivo. In contrast to wild-type (wt) MCMV, ΔM27 mutant MCMV was efficiently cleared from all organs within a few days in BALB/c, C57BL/6, and 129 mice, highlighting the general importance of STAT2 antagonism for MCMV replication. Despite this effective and relevant STAT2 antagonism, wt and STAT2-deficient mice exhibited fundamentally different susceptibilities to MCMV infections. MCMV replication was increased in all assessed organs (e.g., liver, spleen, lungs, and salivary glands) of STAT2-deficient mice, resulting in mortality during the first week after infection. Taken together, the results of our study reveal the importance of cytomegaloviral interferon antagonism for viral replication as well as a pivotal role of the remaining STAT2 activity for host survival. This mutual influence establishes a stable evolutionary standoff situation with fatal consequences when the equilibrium is disturbed.IMPORTANCE The host limits viral replication by the use of interferons (IFNs), which signal via STAT proteins. Several viruses evolved antagonists targeting STATs to antagonize IFNs (e.g., cytomegaloviruses, Zika virus, dengue virus, and several paramyxoviruses). We analyzed infections caused by MCMV expressing or lacking the STAT2 antagonist pM27 in STAT2-deficient and control mice to evaluate its importance for the host and the virus in vitro and in vivo. The inability to counteract STAT2 directly translates into exaggerated IFN susceptibility in vitro and pronounced attenuation in vivo. Thus, the antiviral activity mediated by IFNs via STAT2-dependent signaling drove the development of a potent MCMV-encoded STAT2 antagonist which became indispensable for efficient virus replication and spread to organs required for dissemination. Despite this clear impact of viral STAT2 antagonism, the host critically required the remaining STAT2 activity to prevent overt disease and mortality upon MCMV infection. Our findings highlight a remarkably delicate balance between host and virus.
Highlights
A pathogen encounter induces interferons, which signal via Janus kinases and STAT transcription factors to establish an antiviral state
IFN-␥ responsiveness was preserved in STAT2-deficient mouse newborn cells (MNC), albeit in a moderately reduced manner (Fig. 4E). These findings indicate that the entire IFN susceptibility of ΔM27-Mouse cytomegalovirus (MCMV) in vitro is STAT2 dependent and that the biologically relevant function of pM27 suggested by phenotypic analyses in cell culture is the antagonism of Jak-STAT signaling
We found that the MCMV titers correlated with the disease severity: only the one STAT2-deficient mouse with lower MCMV replication showed no signs of disease (Fig. 6B), suggesting that the viral replication itself causes the pathology
Summary
A pathogen encounter induces interferons, which signal via Janus kinases and STAT transcription factors to establish an antiviral state. The antiviral activity mediated by IFNs via STAT2dependent signaling drove the development of a potent MCMV-encoded STAT2 antagonist which became indispensable for efficient virus replication and spread to organs required for dissemination Despite this clear impact of viral STAT2 antagonism, the host critically required the remaining STAT2 activity to prevent overt disease and mortality upon MCMV infection. Since Mus musculus is the natural host of MCMV, as evident from the fact that free-ranging mouse populations show very high MCMV seroprevalences [3], MCMV infections constitute one of the few models in which the history of reciprocal adaptations is taken into account This is important for the understanding of immunity and viral immune evasion since reciprocal adaptation shapes the protein functions of the host and virus [4]. We characterized the function of pM27 and observed that a targeted deletion of M27 strongly attenuates MCMV in vivo replication, which is recovered to a certain extent in mice lacking either the receptor IFNAR1 or the receptor IFNGR1 [11]
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