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.

Keywords: PASC; acute; chronic; cytokines; inflammation; innate immunity; interferon; long COVID; long hauler syndrome; post-acute; post-acute sequelae; virus.

Figure 1

Schematic overview of symptoms, virus load and inflammation levels in the pre-acute, acute and post-acute phase of a (non-persistent) viral infection. After the initial infection and an incubation period (pre-acute phase, gray) a patient enters the acute phase with PCR-detectable virus loads and a peak of inflammation (blue) usually accompanied by acute clinical symptoms. The post-acute phase (light blue), which is usually days to weeks after the beginning of the acute phase is characterized by no viral replication, slow replication or viral components/virions in hidden reservoirs that are undetectable by diagnostic PCR. Different types of symptoms are indicated by arrows. During the post-acute phase inflammation levels may rise again eventually leading to a state of chronic inflammation.

Figure 2

The complex development and amplification of chronic inflammation after an acute viral infection. Viruses trigger the innate immune sensors by PAMPs, but also manipulate the signaling pathways to negate the anti-viral effects of innate immune activation. In addition, many viral pathogens cause tissue damage (grey box), leading to commensal infiltration and further innate immune activation via DAMPs or MAMPs. Dysregulation of immune pathways by viruses, auto-antigen mimicry and tissue damage facilitate the induction of auto-antibodies. Eventually, all these factors cause aberrant activation of immune cells and normal cells leading to (chronic) secretion of inflammatory cytokines. Co-infections further fuel and amplify imbalancing of innate immunity by providing PAMPs but also manipulating cellular signaling cascades. The aberrant activity is further amplified by immune ageing. MΦ, macrophages; Tc, T cells; DCs, dendritic cells; non-immune cells (grey).