Cytomegalovirus (CMV) is a member of the β-herpesvirus family, which is widely spread among the world population and causes lifelong latent infection. In immunocompetent individuals the primary infection normally is asymptomatic. However, the virus can cause severe diseases, e.g. upon reactivation in immunocompromised patients and in newborns by vertical transmission. To develop treatment strategies, it is imperative to understand the interplay between immune mechanisms that are essential for CMV control.
To dissect the role of different recognition mechanisms in CMV infection, mice with deficiencies for combinations of recognition platforms, including Toll‑like receptors (TLR) and RIG‑I‑like helicases (RLH), as well as mice devoid of STING, which is involved in DNA recognition, were i.v. infected with MCMVΔm157.
60% of TLR/RLH-/- mice succumbed to MCMV infection within 7 days, whereas basically all TLR-/-, RLH-/-, and STING-/- mice survived the infection without signs of severe disease. Analysis of CMV infected IFN-β reporter mice with deficiencies in the recognition platforms revealed that in the liver early IFN-β was induced in a STING-dependent manner, primarily in myeloid cells, but not in hepatocytes. Interestingly, STING-/- mice showed elevated virus titers in the liver 1 dpi when compared with WT mice. Nevertheless, viral dissemination was controlled. In spleen early IFN-β induction was independent of the analyzed recognition platforms, whereas in the later phase TLR/RLH-signaling deficiency caused delayed IFN-β induction. Similar to IFNAR-/- mice, in spleen and liver of TLR/RLH-/- mice high viral titers were detected. Furthermore, TLR/RLH/STING-/- mice were unable to mount type I IFN responses upon CMV infection and died within 6 days.
In conclusion, our results indicate that upon MCMVΔm157 infection TLR-, RLH-, and STING-dependent signaling contribute to the induction of protective IFN-I responses. While STING-dependent signaling is not essential to promote survival of CMV infected animals, it is needed to trigger early hepatic IFN-β.