Proposed model for adapting host responses over time via changes in levels of select ISG proteins regulated by secondary cues.

Binding of IFN to its cognate receptor induces the transcription and translation of ISG mRNAs. The presence of secondary cues (glucose or galactose) can alter antiviral responses via selective stabilization of some but not all ISG proteins to shape ISG repertoires. Sensing of metabolite consumption during viral replication could result in a feedforward loop adapting ISG responses at the protein level to promote adaptation of antiviral defenses. Response 1: If the virus is replicating at low levels (left), it is consuming relevant metabolites at a reduced rate. Changes in cellular metabolite pools are sensed by an unknown cellular factor/s which trigger a response that impacts protein levels of some but not all immune defense proteins to manage the infection. Response 2: If the virus is replicating at high levels (right), the virus is consuming necessary metabolites at a rapid rate which leads to major changes in the concentrations of these metabolite pools. Sensing of these changes in metabolite pools results in adaptation of antiviral defenses by altering the protein composition of the antiviral response to counter increased viral replication which may involve increased recruitment of different immune cell types. Changes at the protein level may allow for rapid adaptation of transcriptionally-induced antiviral responses. The diagram was generated with BioRender.