Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections

Abstract

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.

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“…Post-acute sequelae (PAS) in the context of viral respiratory infections do not represent a fundamentally new observation, since PAS were already described as a consequence of other non-persistent viral infections in the pre-COVID era [ 11 ]. Of note, recent data suggest that the clinical symptoms, which are now referred to as LCS, likewise occur after infection with seasonal influenza [ 12 ].…”

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“…However, IFNs are detrimental in the long run by promoting inflammation. The excessive presence of IFNs (and other pro-inflammatory cytokines) often defines the severity of the diseases and possibly even long-term consequences of the infection [ 61 , 62 ]. Consequently, anti-viral IFN therapy is usually efficient but also associated with severe side effects.…”

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“…See text and [44] for a detailed discussion. (c) Evolution of SARS-CoV-2 can cause more severe variants if transmission from infected persons takes place before severe illness as observed for COVID-19 with an early viral response phase followed by pulmonary and later an autoimmune phase related to long-COVID and, in worst case, death [51].…”