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

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.

The Mechanism of Interleukin-35 in Chronic Hepatitis B

Interleukin-35 (IL-35) is a newly identified inhibitory cytokine. It has recently been found to play an extremely important role in chronic hepatitis B disease, which makes it likely to be a target for new therapies for hepatitis B malady. IL-35 modulates a variety of immune mechanisms to cause persistent viral infections, such as affecting the ratio of helper T cells, reducing the activity of cytotoxic T cells, hindering the antigen presentation capacity for dendritic cells, and increasing the transcription level of hepatitis B virus. On the other hand, IL-35 can control the inflammation caused by hepatitis B liver injury. Therefore, to seek a breakthrough in curing hepatitis B disease, the contradictory part of IL-35 in the occurrence and development of this sickness is worthy of further discussion and research. This article will systematically review the biological effects of IL-35 and the specific mechanisms affecting the disease.

Persistent COVID-19 Symptoms Minimally Impact the Development of SARS-CoV-2-Specific T Cell Immunity

SARS-CoV-2 represents an unprecedented public health challenge. While the majority of SARS-CoV-2-infected individuals with mild-to-moderate COVID-19 resolve their infection with few complications, some individuals experience prolonged symptoms lasting for weeks after initial diagnosis. Persistent viral infections are commonly accompanied by immunologic dysregulation, but it is unclear if persistent COVID-19 impacts the development of virus-specific cellular immunity. To this end, we analyzed SARS-CoV-2-specific cellular immunity in convalescent COVID-19 patients who experienced eight days or fewer of COVID-19 symptoms or symptoms persisting for 18 days or more. We observed that persistent COVID-19 symptoms were not associated with the development of an overtly dysregulated cellular immune response. Furthermore, we observed that reactivity against the N protein from SARS-CoV-2 correlates with the amount of reactivity against the seasonal human coronaviruses 229E and NL63. These results provide insight into the processes that regulate the development of cellular immunity against SARS-CoV-2 and related human coronaviruses.

CD85k Contributes to Regulatory T Cell Function in Chronic Viral Infections

Regulatory T cells (Tregs) prevent excessive immune responses and limit immune pathology upon infections. To fulfill this role in different immune environments elicited by different types of pathogens, Tregs undergo functional specialization into distinct subsets. During acute type 1 immune responses, type 1 Tregs are induced and recruited to the site of ongoing Th1 responses to efficiently control Th1 responses. However, whether a similar specialization process also takes place following chronic infections is still unknown. In this study, we investigated Treg specialization in persistent viral infections using lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV) infection as models for chronic and latent infections, respectively. We identify CD85k as a Th1-specific co-inhibitory receptor with sustained expression in persistent viral infections and show that recombinant CD85k inhibits LCMV-specific effector T cells. Furthermore, expression of the CD85k ligand ALCAM is induced on LCMV-specific and exhausted T cells during chronic LCMV infection. Finally, we demonstrate that type 1 Tregs arising during chronic LCMV infection suppress Th1 effector cells in an ALCAM-dependent manner. These results extend the current knowledge of Treg specialization from acute to persistent viral infections and reveal an important functional role of CD85k in Treg-mediated suppression of type 1 immunity.

Viral Infections and Interferons in the Development of Obesity

Obesity is now a prevalent disease worldwide and has a multi-factorial etiology. Several viruses or virus-like agents including members of adenoviridae, herpesviridae, slow virus (prion), and hepatitides, have been associated with obesity; meanwhile obese patients are shown to be more susceptible to viral infections such as during influenza and dengue epidemics. We examined the co-factorial role of viral infections, particularly of the persistent cases, in synergy with high-fat diet in induction of obesity. Antiviral interferons (IFNs), as key immune regulators against viral infections and in autoimmunity, emerge to be a pivotal player in the regulation of adipogenesis. In this review, we examine the recent evidence indicating that gut microbiota uphold intrinsic IFN signaling, which is extensively involved in the regulation of lipid metabolism. However, the prolonged IFN responses during persistent viral infections and obesogenesis comprise reciprocal causality between virus susceptibility and obesity. Furthermore, some IFN subtypes have shown therapeutic potency in their anti-inflammation and anti-obesity activity.

THE EXPERIENCE OF THE USE OF ALLOKINE-ALPHA IN TREATMENT OF CHRONIC PERSISTING VIRAL MIXT-INFECTIONS IN MEN

Relevance. Chronic persistent viral infections are a category of andro-urological problems that currently have no defi nite solutions.The aim of the study is to evaluate the eff ectiveness of treatment of chronic infl ammatory diseasesof the prostate gland (persistent viral mixed infections: combinations of herpes simplex virus (first and second types) and human papilloma virus using the drug “Allokin-alpha”(Alloferonum)), in comparison with recombinant human interferon-2b.Materials and methods. The study was conducted on a contingent of 60 patients of the clinic “Men’s Health”, Kyiv. The study design suggested the use of 2 parallel groups of 30 patients receiving treatment according to diff erent therapeutic models.The results of the study. When comparing therapeutic models using parenteral administration of Alloferonum in the composition of the drug “Allokin-alpha” and parenteral administration of recombinant human interferon-2b in parallel groups of patients suff ering from chronic persistent mixed infections, a number of diff erences regarding serological and clinical effi cacy and long-term eff ects were found.Findings. The eff ectiveness of the elimination of chronic persistent viral mixed infections for Alloferonum was 66,7%, for recombinant human interferon-2b in - 40%. The catamnestic eff ects of therapeutic models also diff ered. For Alloferonum 6 months after the course of treatment, the recovery of serological activity of viruses occurred in 13,4% of patients, the return of systemic clinical manifestations was observed in 23,3% of patients, the return of symptoms of specifi c prostatitis - in 10,0% of patients. For recombinant human interferon-2b, similar fi gures were 23,0%, 33,3% and 20,0%, respectively.