MAPKAPK 2 and 3 promote viral replication and resolution of intrahepatic myeloid-cell aggregates upon CMV infection

Background & aims Cytomegalovirus (CMV) circumvents sterile immunity and establishes a state of latency from which the virus reactivates under immunosuppressive conditions causing substantial morbidity and mortality. Multiple organs are targets of CMV infection, however the liver represents a prime site of CMV replication and latency. We could recently demonstrate that an acute infection with murine (M)CMV induces activation of the MAPKAP kinase (MK)2, which is critical for the generation of a cytokine response to MCMV and drives an IFNAR1-dependent circuit that controls IL-10 production and limits aggregation of CD11b⁺ myeloid cells in the liver. These intrahepatic myeloid-cell aggregates recruit cytotoxic CD8⁺ T cells and enable their local expansion without causing severe liver pathology. Aim of this study is to understand the MK2-controlled mechanisms that regulate formation of these myeloid-cell aggregates and influence viral replication. Moreover, the role of MK2’s homologous kinase MK3, previously unexplored in this context, should be clarified.

Methods Mice deficient in MK2 and/or MK3 were infected with MCMV and sacrificed after incubation periods up to 2 weeks. Serum, organs and immune cells were isolated and transcripts, proteins and viral titers were analyzed.

Results Our data suggest that beside MK2 its homologous kinase MK3 is also involved in controlling cytokine and chemokine release upon MCMV infection. In the MK2^-/- liver, but also in the MK3^-/- or MK2/3^-/- liver the resolution of myeloid-cell aggregates involving CD11b⁺ as well as CD68⁺ cells is delayed, Ly6C⁺ monocytes dissolve with delay only in the MK2/3^-/- liver. Furthermore, the accumulation of proliferating CD8⁺ T cells is enhanced when MK2 and/or MK3 are deleted. Viral replication in the liver as well as in the lung of MK2^-/-, MK3^-/- and MK2/3^-/- animals is diminished, whereas it is unaffected in the spleen.

Conclusion The results indicate that upon CMV infection the interplay of MK2 and MK3 regulates a molecular and cellular environment within the liver that facilitates viral replication, but also controls resolution of myeloid-cell aggregates and recruitment of CD8⁺ T cells. Therefore, it is conceivable that viruses such as CMV exploit MK2- and/or MK2/3-dependent mechanisms to avoid local formation of immune cell aggregates and that this is part of a program involved in immune escape and possibly also establishment of latency.

Publication History

Article published online:
04 January 2021