Highlights d Numerous SARS-CoV-2 proteins synergize to suppress immune sensing and signaling d Nsp14 targets IFNAR1 for lysosomal degradation d ORF3a and ORF7a block autophagy by different mechanisms d Synergistic treatment with IFN-g and -l1 is highly effective against SARS-CoV-2

Non-persistent viruses classically cause transient, acute infections triggering immune responses aimed at the elimination of the pathogen. Successful viruses evolved strategies to manipulate and evade these anti-viral defenses. Symptoms during the acute phase are often linked to dysregulated immune responses that disappear once the patient recovers. In some patients, however, symptoms persist or new symptoms emerge beyond the acute phase. Conditions resulting from previous transient infection are termed post-acute sequelae (PAS) and were reported for a wide range of non-persistent viruses such as rota-, influenza- or polioviruses. Here we provide an overview of non-persistent viral pathogens reported to be associated with diverse PAS, among them chronic fatigue, auto-immune disorders, or neurological complications and highlight known mechanistic details. Recently, the emergence of post-acute sequelae of COVID-19 (PASC) or long COVID highlighted the impact of PAS. Notably, PAS of non-persistent infections often resemble symptoms of persistent viral infections, defined by chronic inflammation. Inflammation maintained after the acute phase may be a key driver of PAS of non-persistent viruses. Therefore, we explore current insights into aberrant activation of innate immune signaling pathways in the post-acute phase of non-persistent viruses. Finally, conclusions are drawn and future perspectives for treatment and prevention of PAS are discussed.

Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ARF1 as a crucial negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene expression. Disease-associated, GTPase-defective, ARF1 results in increased cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial fusion causing cGAS activation by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show that ARF1 has an unexpected dual role in maintaining cGAS-STING homeostasis, through the promotion of mitochondrial fusion and STING recycling.