Im Rennen der Roten Königin : Evolutionäres Wettrüsten zwischen Herpesviren und ihren Wirten

Trilling, Mirko GND

Viruses and hosts exist in an infinite evolutionary competition. The selection pressure elicited by the virus leads to the development and gradual improvement of the immune system of the host. Simultaneously, the immune system selects viruses that adapt by more and more sophisticated immune evasion strategies. The resulting stalemate situation is quasi-stable and exhibits the characteristics of a so-called Red Queen Race, in which maximum adaptation and evolution are necessary to maintain the status quo. Applying recombinant DNA techniques of mouse cytomegalovirus (MCMV) and/or its natural host enables us to manipulate this delicate balance and study the resulting consequences. STAT2 is essential for the antiviral activity of interferons. In the absence of STAT2, mice become moribund during the first week of MCMV infection. This suggests that STAT2 is indispensable for mice to survive MCMV infections. As a reaction to the selection pressure elicited by STAT2-dependent processes, MCMV evolved the STAT2 antagonist pM27, which exploits DDB1 and Cullin-RING ubiquitin ligases (CRLs) to instruct the poly-ubiquitination and subsequent proteasomal degradation of STAT2. Drugs that interfere with the activity of the proteasome, ubiquitination or CRLs restore STAT2 in cells infected with MCMV or human CMV and elicit pronounced antiviral activity. An MCMV mutant lacking pM27 (ΔM27-MCMV) is strongly attenuated in vivo. The residual replication does not cause disease in mice, but is sufficient to induce pronounced humoral immune responses. Vaccination with ΔM27-MCMV raises protective immune responses in mice. We are currently in the process of translating the findings to human cytomegalovirus.

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Trilling, Mirko: Im Rennen der Roten Königin. Evolutionäres Wettrüsten zwischen Herpesviren und ihren Wirten. 2020.

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