The Role of Interferons in Long Covid Infection

Abstract

Although the new generation of vaccines and anti-COVID-19 treatment regimens facilitated the management of acute COVID-19 infections, concerns about post-COVID-19 syndrome or Long Covid are rising. This issue can increase the incidence and morbidity of diseases such as diabetes, and cardiovascular, and lung infections, especially among patients suffering from neurodegenerative disease, cardiac arrhythmias, and ischemia. There are numerous risk factors that cause COVID-19 patients to experience post-COVID-19 syndrome. Three potential causes attributed to this disorder include immune dysregulation, viral persistence, and autoimmunity. Interferons (IFNs) are crucial in all aspects of post-COVID-19 syndrome etiology. In this review, we discuss the critical and double-edged role of IFNs in post-COVID-19 syndrome and how innovative biomedical approaches that target IFNs can reduce the occurrence of Long Covid infection.

Introduction

Postinfectious disorders beyond COVID-19

At the beginning of the coronavirus outbreak, research mainly focused on early-stage symptoms of COVID-19 and its effects on mortality. However, over time, the importance of studying the long-term effects of this disease became more apparent. Long Covid, also known as post-COVID, post-COVID condition (PCC), postacute sequelae SARS-CoV-2 infection (PASC), chronic COVID syndrome, and acute COVID-2, refers to the long-term effects of COVID-19 (Nittas et al, 2022). According to the World Health Organization, it is a condition that usually occurs 3 months after COVID-19 infection with symptoms, lasts for no <2 months, and other causes cannot explain (World Health Organization, 2021). The U.S. Centers for Disease Control and Prevention (CDC) believes that PCC identification would be at least 4 weeks after the infection (Centers for Disease Control and Prevention, 2022).

The National Institute for Health and Care Excellence of United Kingdom distinguishes between a post-COVID-19 syndrome lasting longer than 12 weeks and an ongoing symptomatic COVID-19 duration of 4–12 weeks (National Institute for Health and Care Excellence, 2021). The phrase “Long Covid” is often employed to define signs and indications that occur or develop following an acute COVID-19. It covers both the post-COVID-19 syndrome (12 weeks or longer) and ongoing symptomatic COVID-19 (from 4 to 12 weeks). The extent of this condition is unclear and can lead to numerous health problems in affected patients, including psychological and physical symptoms that interfere with daily activities. Higher Age, high index of body mass, and female sex may increase the probability (Sudre et al, 2021). Long after the acute phase of COVID-19, a significant number of individuals report persistent symptoms.

According to the Office for National Statistics of United Kingdom (ONS), as of May 1, 2022, ∼2.0 million persons (3.1% of the total population) in the United Kingdom were suffering from self-reported Long Covid (Office for National Statistics, 2020). ONS estimates that about 1/5th of respondents who test positive for COVID-19 show symptoms for 5 weeks or longer, and about 1/10th of respondents who test positive for COVID-19 show symptoms over 12 weeks or longer (Office for National Statistics, 2022). It has been reported that 4 months after initial COVID-19 symptoms, 70% of those at low risk of COVID-19 death with persistent indications experienced damage in some organs (Dennis et al, 2021).

Common signs and symptoms of Long Covid

People with Long Covid experience various symptoms affecting multiple organs, including the cardiovascular system, respiratory system, kidneys, liver, pancreas, spleen, skin, neurological system, and digestive system (Bourmistrova et al, 2022; Dennis et al, 2021; Genovese et al, 2021; Liao et al, 2022; Nalbandian et al, 2021; Nguyen and Tosti, 2022). It is also linked to a higher risk of developing new health conditions such as incident diabetes in men, neurological problems, and autoimmune diseases (Acosta-Ampudia et al, 2022; Bourmistrova et al, 2022; Rojas et al, 2022; Wander et al, 2022). Also, people with Long Covid may have an elevated risk of developing cerebrovascular disorders like cardiac arrhythmias, ischemic and nonischemic heart disease, pericarditis, myocarditis, heart failure, and thromboembolic disease (Xie et al, 2022).

Some of the prevalent reported symptoms with Long Covid are fatigue, headache, upper respiratory symptoms (dyspnea, sore throat, persistent cough, and altered sense of smell or taste), gastroenterological symptoms (diarrhea, nausea, acid reflux, stomach pain, and loss of appetite), chest pain or tightness, cognitive and psychological complaints (post-traumatic stress disorder, brain fog, insomnia, depression, concentration impairment, memory issues, and anxiety), palpitations, dizziness, tingling, joint pain, tinnitus, ear pain, nausea, persistent fever, dermatologic complaints (rashes and hair loss), and a decline in quality of life (Aiyegbusi et al, 2021; Nalbandian et al, 2021; Premraj et al, 2022; Weng et al, 2021).

Possible etiology of Long Covid

Several studies have investigated how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can lead to Long Covid infection. The 3 most important causes suggested are immune dysregulations, viral persistence, and autoimmunity. These are biological factors that commonly contribute to long-term symptoms due to viral infections. On the other hand, individual patients may develop Long Covid through different biological factors such as organ damage, clotting/coagulation issues, and host-microbiome/virome interactions, and reservoirs of SARS-CoV-2 may persist in particular tissues, or neurotrophic pathogens can be reactivated (Proal and VanElzakker, 2021). However, a precise reason behind PCS is yet to be proven.

Despite the above causes, gender is one of the risk factors that showed a noticeable association with the Long Covid syndrome. Women are more likely than men to develop Long Covid symptoms (Bai et al, 2022). The reasons why the female gender is more at risk of Long Covid might be more immune response and autoimmunity, which is common in middle-age women. Men have different adaptive and innate immune responses than women, and probably hormonal mediators play a key role in these variations (Ciarambino et al, 2021). Higher age has been identified as another risk factor.

A study has shown that the number of people older than 70 years, who reported symptoms lasting 4 weeks or longer, has been more than those 18–49 years of age (Sudre et al, 2021). Autoantibodies neutralizing type I interferon (IFN) sharply increase with age, and evidence has shown that this is prevalent in COVID patients older than 70 years (Bastard et al, 2021).

Immune dysregulations in post-COVID disorders

Dysfunctional innate and adaptive immune mechanisms can cause uncontrolled immune responses that have been called immune dysregulation disorders, which in patients with COVID can be characterized by an alteration of innate and adaptive immune cells or cytokines. In addition, some of these changes are able to sustain in convalescent individuals for a prolonged period after infection and can cause postinfectious syndromes similar to SARS-CoV-1 and Ebola (Clark et al, 2015; Ngai et al, 2010). A study has shown that the population of CD8⁺ and CD4⁺ T cells, which express PD-1, and T regulatory cells were decreased in PACs, and on the contrary, the number of B cells and the CD14⁺, CD16⁺, and CCR5⁺ monocytic subset was increased considerably compared to healthy controls (Patterson et al, 2021).

Furthermore, Wen et al (2020) by use of the single-cell RNA sequencing technique have indicated that the ratio of CD4⁺ and CD8⁺ T cells decreased remarkably in recovered individuals' peripheral blood mononuclear cells, whereas plasma B cells and CD14⁺ monocytes with high inflammatory gene expression significantly increased. Another study has reported that, while the level of NKG2A in CD8⁺ T cells and natural killer (NK) cells increased in SARS-CoV-2-infected patients, it returned to baseline in convalescence (Zheng et al, 2020). Also, some studies have identified the existence of SARS-CoV-2–specific T cells in convalescent patients (Grifoni et al, 2020; Ni et al, 2020).

The cytokine interleukin (IL)-1β is one of the key mediators of inflammatory responses, activated by infection, and consequently can activate other proinflammatory cytokines, such as IL-6 (Nieto-Torres et al, 2014). IL-6 and IL-1β make a contribution in the cytokine storm and play a key role in inflammatory mechanisms (Conti et al, 2020; Zhou et al, 2020). IFN-γ (type II IFN) is a cytokine produced by a large number of neutrophil granulocytes, macrophages, lymphocytes, dendritic cells, and monocytes, and participates in inflammatory processes, signal transduction, and antiviral immunity. Also, it can act as a proinflammatory or anti-inflammatory cytokine (Lees, 2015).

Cytokines, by regulating inflammation, control both adaptive and innate immune systems, and influence the immune responses. Therefore, dysregulation of cytokine expression might be involved in Long Covid symptoms. The elevated levels of IL-1β, IL-6, IFN-γ, and TNF-α (tumor necrosis factor-alpha) have been detected in blood and plasma samples of people who recovered from COVID-19. On the contrary, CCL4 and GM-CSF were at remarkably lower degrees in comparison with healthy controls (Andrade et al, 2021; Files et al, 2021; Ong et al, 2021; Patterson et al, 2021).

Viral persistence

Viral persistence is equivalent to evasion of the host's immune system or failure to eradicate the virus from the infected host. More to the point, viruses are able to adjust the expression of each host gene and consequently their genome to acquire a residence in a nonlytic state inside the cells. So viruses can gain special strategies of replication (Oldstone, 2006). In most cases, the types of diseases that persisting viruses cause are often novel and unpredictable. A theory has been proposed that persistent virus would possibly stimulate each direct dendritic cell activation and cell damage, possibly ending in autoimmunity.

However, from a virologist's view, persistent infection and autoimmunity are considered 2 entirely different mechanisms, which might be a result of SARS-CoV-2 (Jacobs, 2021). Like all microorganisms, some methods are applied by SARS-CoV-2 to escape and deactivate the host immune reaction (Li et al, 2020c). Taefehshokr et al (2020) showed that these contain the potential to duplicate inside double-membrane vesicles that host microorganism pattern recognition receptors (PRRs) are unable to discover. The transfer of viral RNA genome from the envelope into the cytoplasm takes place after SARS-CoV-2 enters the cells, initiating the process of translation.

When RNA replicates, formation of new viral particles occurs, through the incorporation of fragments of the host cell membrane in the new viral envelope (Li et al, 2020c; Taefehshokr et al, 2020). Superantigens (Sags), are microbial products first discovered from examination of the overstimulation of T cells by Staphylococcal Enterotoxin B (Brown and Bhardwaj, 2021). It has shown that Sags have a substantial effect on the host's T cells and play a central role in SARS-CoV-2 infections (Darif et al, 2021). They are able to provoke a large amount of T cell population, setting off a huge immune response. Also, the stimulation power of Sags is much more compared to regular antigens as up to 10% of T cells respond, while common antigens might typically trigger simply 0.001%–0.01% of T cells (Dar et al, 2016; Guedez et al, 1997).

The mechanism of action of Sags is to bind to the variable region of the T cell receptor (TCR) and MHC class II molecules on the antigen-presenting cells, which results in the stimulating of several T cell lineages and production of IL-2 and different inflammatory cytokines (Fraser, 2011; Wieczorek et al, 2017). Therefore, Sags are considered a significant factor in the progress of autoimmune diseases by crossing the MHC class II molecule of B cells with the TCR on T cells (Marrack and Kappler, 1990; Rokni et al, 2020).

Besides serving as pathogen-associated molecular patterns, virus particles can promote a substantial innate primary immune response, which might be owing to its Sags following recognition by Toll-like receptor 7 (TLR7). Bartoletti et al (2021) found that the mortality rate in critically ill COVID-19 patients is decreased by corticosteroids as well as suggested a necessity for immune suppression. In many patients, Sags response is normally downregulated and consequently, the Sags-induced immune stimulations are all, but effective in creating immune responses (Miyashita et al, 1995). The virus can replicate inside body, particularly where the response of the immune system is moderately fragile due to the negative immunological feedback loop (Hassett et al, 2020; Nabavi, 2020).

One common approach to limit virus replication is using partial activation of the IFN reaction, which is an incredibly potent antiviral reaction that has co-developed among viruses and hosts for many years and is a planned response playing a pivotal part in the regulation of a number of viral infections. Regulating this innate immunity has a role in viral persistence (Lanford et al, 2011; Schultz et al, 2015); on the other hand, Long Covid is an immunologic response to the persistence of SARS-CoV-2 (Buonsenso et al, 2022).

Autoimmunity

There have been many factors that may cause the initiation or intensification of autoimmune diseases such as bacterial infections, viral fungal, and genetic predisposition. Furthermore, such agents have affected vulnerable people to autoimmunity at 3 levels: the specific antigen and its presentation, the target tissue, and the general reactivity of the immune system (Campbell, 2014; Khan and Wang, 2019). Several pathogenic viruses are believed to trigger and initiate autoimmune diseases, including Hepatitis A and C virus, Rubella virus, HTLV-1, Cytomegalovirus, Herpes virus-6, Parvovirus B19, and Epstein-Barr-virus, and Coronavirus (Ehrenfeld et al, 2020; Smatti et al, 2019).

It has been proposed that the shared pathogenetic mechanisms and clinical-radiological conditions among COVID-19 and the hyperinflammatory illnesses could advocate that SARS-CoV-2 is able to promote a rapid autoimmune or autoinflammatory dysregulation, leading to the severe opening pneumonia, in genetically prone people (Caso et al, 2020; Tan et al, 2021). Inherited disorders of type I IFN immunity and auto-antibodies, which neutralize type I IFNs, caused lethal COVID-19 lung inflammation by meddling with type I IFN immunity in blood plasmacytoid dendritic cells and tissue-resident respiratory epithelial cells (Escobedo et al, 2021; Ricci et al, 2021; van der Wijst et al, 2021; Zhang et al, 2022), and the diffusion of the virus during the first few days of illness is promoted by both of these elements. Moreover, ∼15% of acute COVID-19 patients had auto-antibodies to IFN-α, IFN-ω, and IFN-β in their blood samples.

In addition, the defensive power of type I IFN-α2, IFN-β, and IFN-ω against SARS-CoV-2 is hindered by such auto-antibodies in a culture dish. Also, these autoantibodies have no longer been observed both in infected individuals who have been symptomless or had gentle phenotypes or in healthy people. Simultaneously, such studies establish a method by that individuals at the highest risk of severe COVID-19 are identified (Bastard et al, 2020; Beccuti et al, 2020). Nevertheless, other types of autoimmunity related to SARS-CoV-2 infection are X-linked recessive TLR7 and plasmacytoid dendritic cell deficiency (Onodi et al, 2021; Zhang et al, 2007).

Interferons

The types of IFNs

As a family of cytokines, IFNs have a significant part in the host's adaptive and innate immune responses in vertebrates. Known human IFNs are classified into types I, II, and III based on the use of their receptor (Akamatsu et al, 2021). Type I IFNs including 13 IFN-αs, IFN-β, IFN-ɛ, IFN-κ, and IFN-ω, can be produced by many cell types (Severa et al, 2020). IFN type II (IFN-γ) is largely produced by CD4⁺ and CD8⁺ T cells and NK and NK T cells, which are involved in adaptive and innate immune systems (Schoenborn and Wilson, 2007). A great amount of type III IFNs consisting of IFN-λ1, IFN-λ2, and IFN-λ3 are produced by epithelial cells of hepatocytes and type 2 myeloid dendritic cells (Grajales-Reyes and Colonna, 2020; Syedbasha and Egli, 2017).

The expression of type I and II IFN receptors takes place on approximately every nucleated cell, while the expression of IFN type III receptors occurs on epithelial, neutrophil, and dendritic cells (Galani et al, 2017). As a responding mechanism to viral infection, distinct IFNs are secreted by the detection of viral nucleic acid in the cytoplasm through intracellular PRRs. IFNs are affected by inducing ∼2,000 products of IFN-stimulated genes (ISGs), and their expression is predominantly controlled through the Janus kinase ( JAK)/signal transducer and activator of transcription (STAT) pathway (Fig. 1) (Onomoto et al, 2021; Schoggins, 2019).

FIG. 1.

The signaling pathway of IFNs from extracellular to nucleus. (A) Interferon receptor alpha 1 (IFNRA1) by forming a heterodimer with IFNRA2 binds to Type I IFNs. Janus Kinase 1 (Jak1) interacts with the Signal Transducer, Activator of Transcription 1 (STAT1), and IFNRA1. (B) Tyrosine kinase 2 (Tyk2) interacts with STAT2 as well as with IFNRA2. IFNLR1 forms a heterodimer with IL-10RB for binding to Type III IFNs. Jak1/STAT and JAK2/STAT1 also interact with IFNGR1 and IFNGR, respectively. IFNGR1 forms a heterodimer with IFNGR2 that binds to Type II IFNs. (C) Upon phosphorylation of the STAT1 or STAT2, the STAT1 homodimers by going to the nucleus activate the transcription of genes with the GAS (gamma interferon activation sites) promoters; while STAT1 and STAT2 heterodimers IRF9 (interferon regulatory factor 9) complex in the nucleus activates the transcription of genes with the ISRE (interferon-stimulated responsive element) promoters. IFN, interferon.

Long Covid lasts longer than 12 weeks. Type I and III IFN levels, also IFN-γ, highly increase in individuals after resolution of active SARS-CoV-2 infection at month 4 after infection. It is shown that an increased expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) is consistently high at 8 months after initial mild-moderate infection in the Long Covid group compared to asymptomatic controls (recovered patients). Due to the IFN-γ high level produced by CD8⁺ T cells at 8 months after infection, it has recently been considered a predictor of postacute COVID-syndrome (Phetsouphanh et al, 2022).

In another study, the production of IFN-γ has been studied in CD4⁺, Treg, and CD8⁺ T cells, and the results showed an increase in the production of IFN-γ in Treg cells in severe convalescent patients at 3 months after the infection. This result was not observed for mild-moderate patients and healthy individuals. However, 6 months after the infection, IFN-γ production was significantly decreased in both CD4⁺ and Treg cells, especially in severe Long Covid patients (Wiech et al, 2022). Colarusso et al (2021) found that IFN-β is significantly lower in severe Long Covid compared to moderate Long Covid patients.

The role of IFNs in COVID-19 (both protective and deleterious effects)

The SARS-CoV-2 virus' cytopathic effects lead to the death of lung alveolar epithelial cells. Differentiation and proliferation of adjacent progenitor epithelial cells recover the lung (Kikkert, 2020). Type I IFNs are considered more proinflammatory in comparison to type III IFNs, even though both type I and III IFNs are regarded as significant mediators of the innate immune responses (Galani et al, 2017). Increased IFN-λ stimulates apoptosis and p53 gene expression, which results in impaired repair of damaged lung epithelial cells and increased morbidity of COVID-19 disease (Fig. 2A–E) (Hadjadj et al, 2020; Major et al, 2020). It was shown that in patients with severe COVID-19, the production, signaling, and activity of type I IFNs are impaired, which appears to be associated with inherent errors in the signaling cascade or the production of autoantibodies, particularly to IFN-α or IFN-ω.

FIG. 2.

Human RT infection by SARS-CoV-2. RT infection by the virus may be inhibited by pre-existing neutralizing antibodies resulting from the previous infection with seasonal coronaviruses (A). The secretion of proinflammatory cytokines (B), activation of the respiratory endothelium (C), and expression of NK receptor ligands (MHC class I chain-related protein A or B) on the epithelial cells cause inflammation in RT (C′). The activation of endothelial cells induces the infiltration of NK-like T cells that express NK receptors such as NKG2D (D). The binding of these cells to MICA/B causes the destruction of epithelial cells expressing NKR ligands (E). In response to viral infections, the epithelial cells secrete the type I/III IFNs. Autoantibodies against IFN-α and IFN-ω (F) are observed in severe cases of the diseases. In addition, increased secretion of type III IFN (IFN-λ) (F) leads to impaired epithelial cell proliferation and tissue repair through the tumor suppressor p53 gene expression and protein pathway. Cytokine storms and the resulting cell death programs (PANoptosis) lead to the perpetuation of local cytokine storms and the death of more epithelial cells in RT (G). Propagation of cytokine storms (H) to other tissues and organs is provoked by cytokine shock syndromes.

Interestingly, the presence of these autoantibodies was relatively higher in elderly and patients who were males and had severe COVID-19 (Ackermann et al, 2020; Beck and Aksentijevich, 2020; Zhang et al, 2020a). Also, cohort longitudinal analysis shows higher IFN-α2 amounts in female patients compared to their male counterparts (Takahashi et al, 2020). In viral infections, type II IFN or IFN-γ helps to differentiate CD8⁺ T cells into cytotoxic T lymphocytes (CTLs). CTLs with the production of effector molecules and cytokines confine the replication of virus and destroy cells that are infected.

Also, IFN-γ increases CD4⁺ and CD8⁺ memory cells (Karki et al, 2021; Whitmire et al, 2007). Recent studies show that a high amount of IFN-γ is produced in moderate to severe COVID-19 patients (Sadanandam et al, 2020). From among the increased 10 different cytokines in such patients, only the combination of IFN-α and IFN-γ induces the PANoptosis process as an innate immune inflammatory-programmed cell death pathway. Interestingly, these cytokines in combination with other inflammatory cytokines or alone cannot promote this process (Sadanandam et al, 2020). Recent studies show that in addition to the important role of the combination of IFN-γ and IFN-α in lethal cytokine shock, it is similarly related to the recovery-like stage of COVID-19 patients (Fig. 2F–H) (Ziegler et al, 2020).

The signaling pathway of IFNs in Long Covid

The JAK-STAT pathway is activated by binding the ligand to type I, II, and III IFN receptors. After the activation of receptors by ligand binding, kinases associated with these receptors are mediated by IFN signaling. The produced type I IFNs by the host as the first defense mechanism, by binding to complex IFN-α/-β receptors (IFNAR), induce different downstream ISG expressions. Upon phosphorylation of the STAT1/STAT2 by Jak1 and tyrosine kinase 2 (Tyk2), the phosphorylated STAT1/STAT2 heterodimers along with IRF9 (interferon regulatory factor 9) form an ISGF3 complex, which, after entering to the nucleus, stimulates the transcription of genes that possess promoters called ISRE (interferon-stimulated responsive element) (Cao et al, 2019; Fish and Platanias, 2014; Schneider et al, 2014).

Type III IFNs bind to heterodimers IFNLR1/IL-10RB (interleukin-10 receptor B). Activated ISGF3 resulting from IFN-II action, stimulates the transcription of ISGs with the ISRE promoters. Both type I and type III IFNs along with promoting the formation of STAT1/STAT1 homodimers. Phosphorylated STAT1 homodimers as IFN-γ-activated factor (GAF) by going to the nucleus and binding to the Gamma interferon activation site (GAS) (IFN-γ-activated site) elements, which exist in the promoter of some ISGs, stimulate the transcription of genes with the GAS promoters.

The receptor of type II IFN (IFN-γ) is composed of IFNGR1 and IFNGR2 subunits. The binding of IFN-γ to its heterodimeric receptor activates JAK1/2 associated with the receptor that induces the formation of GAF resulting in stimulating transcription of genes with GAS elements (Akamatsu et al, 2021; Platanias, 2005). It is demonstrated that the Envelope protein (E) of the SARS-CoV-2 virus triggers the transcription of ISGs, unlike creating a permissible environment for the virus replication, while Nucleocapsid (N) and Membrane (M) proteins inhibit the IFN-Is signaling pathway (Li et al, 2020b), and nonstructural protein (NSP1) blocks IFN-α stimulation by inhibiting STAT1 phosphorylation (Xia et al, 2020).

It has been shown that diverse ISGs, including STAT2, MX2, and IRF7, are upregulated during COVID-19 infection, which are able to suppress viral replication (Israelow et al, 2020). Several studies have indicated that insufficient production of type I IFNs or mutations in the IRF7 and TLR3 genes leads to more vulnerability to COVID-19 infection and illness severity (Li et al 2020a; van der Made et al, 2020). Fallerini et al demonstrated that TLR7 missense variants negatively affect TLR7 downstream signaling and IFN-associated expression of genes (Fallerini et al, 2021). Experiments show that homozygosity of the interferon-induced trans-membrane protein 3 (IFITM3) gene rs12252 C allele is associated with disease severity in COVID-19 patients (Zhang et al, 2020b).

Furthermore, a significant correlation has been observed between severity of the illness and the existence of variants in genes associated with inflammatory responses such as TYK2. High expression of TYK2 and low expression of IFNAR2 are linked with life-threatening COVID-19 (Pairo-Castineira et al, 2021).

Bastard et al (2020) found IgG auto-Abs against IFN-α, IFN-ω, or both in some of the patients with a severe infection that had a role in neutralizing IFNs in these patients. In addition, their research showed that patients in whom auto-Abs against IFN-α2 were present possessed auto-Abs against 13 IFN-α subtypes, although some also had neutralizing auto-Abs against IFN-β. Interestingly, auto-Abs against IFN-Is are not a result of infection and pre-exist to infection (Bastard et al, 2020).

Another study revealed an increased presence of auto-Abs against IFN-Is in the COVID-19 patient's group compared to the control group and there is a positive correlation between the number of these auto-Abs and the severity of the disease (Wang et al, 2021). Furthermore, in inflammatory conditions, other microbiomes and viromes could also be involved in the production of autoantibodies and cause a wide variety of auto-Abs reactivity. Such complicated situation could describe a considerable percentage of clinical variations identified in Long Covid patients (Ortona and Malorni, 2022).

Methods of diagnosing and treating Long Covid

Although the serious medical effects of Long Covid are increasing, there are still no definitive diagnostic criteria (www.clinicallabmanager.com/). The diagnosis of long-term COVID-19 is complex, because it may not show symptoms for a long time, and if symptoms do occur, they may differ from one individual to the others and change over time, so symptoms are difficult to relate to COVID-19 (Ahmad et al, 2021). Prolonged symptoms of COVID-19, also called PASC (post-COVID syndrome), can emulate other health conditions.

In fact, these symptoms are sometimes caused by an undiagnosed health condition or an underlying disease caused by COVID-19 (Centers for Disease Control and Prevention, 2022; Lopez-Leon et al, 2021). Hence, it is necessary to confirm the initial infection and then rule out other diseases with similar symptoms such as rheumatoid arthritis or lupus, and as the differential diagnosis is continued, the Long Covid is diagnosed. The type of treatment is usually determined based on individual symptoms and includes antiviral drugs and modulation of IFNs, immunotherapies such as plasma exchange, and steroids (Michaud, 2021).

The diagnostic methods used by clinicians are X-ray, ultrasound, computed tomography, or magnetic resonance imaging to recognize alterations, including inflammation or scarring in the lungs or heart. Laboratory testing may be helpful for Long Covid's diagnosis (The New York Times, 2022). Lung performance tests are the primary test to determine lung function, volume, and performance. Another widely used test is the blood test for measuring heart rate, blood pressure, oxygen saturation, thyroid hormones, and inflammatory markers. Polymerase chain reaction is not a decisive tool to diagnosing Long Covid.

Neutrophils are one of the early signs of SARS-CoV-2 infection (Taefehshokr et al, 2020). Finally, based on experiences, serological tests to measure cytokines and IFNs are more accurate and helpful in diagnosing Long Covid infection, because type 1 and type 3 IFNs are often produced in the early stages of a viral infection and cause inflammation by activating immune cells called T cells (Stanifer et al, 2020).

The role of IFNs in the diagnosis and treatment of Long Covid

Researchers have considered IFN-α as an effective treatment for Long Covid syndrome (Zhang et al, 2020a) because the innate immune system endows the production of IFN-α as the first defense line against viruses (Fung and Liu, 2019; Zhang et al, 2020a). Patients with severe COVID-19 show IFN insufficiency, which can potentially lead to immune escape from the virus (Blanco-Melo et al, 2020). A recent study showed that patients experienced a serious clinical condition in the absence of IFN-α (Schoggins, 2019; Trouillet-Assant et al, 2020). The Chinese National Health Commission guidelines suggested recombinant aerosol IFN-α for treatment of SARS-CoV-2, because IFN-α prevents the virus replication, in vitro (Mantlo et al, 2020).

Therefore, it seems that the early administration of IFNs can prevent the rapid spread of the virus and subsequent cytokine storms (Davidson et al, 2016; Taefehshokr et al, 2020). However, due to its immune-regulating role, IFN-α can cause side effects such as severe inflammatory response, tissue damage, and pathogenicity (Zhang et al, 2020a). Nevertheless, the problem is that long-term COVID patients have an overactive innate immunity with a deficiency of B and T cells, which manifests itself as a high expression of type I and III IFN that remains elevated continuously for 8 months after infection (Davidson et al, 2016). Studies have shown that administration of IFNs before a severe viral infection and the onset of the inflammatory phase of the disease can have a protective effect.

Nevertheless, IFN treatment after the onset of inflammation and exacerbation of the disease can lead to long-term immunopathology (Channappanavar et al, 2019). Therefore, it has been necessary to pay attention to the appropriate administration time for the optimal performance of IFNs. Further analysis of the clinical efficacy of IFN for COVID-19 patients with varying degrees of severity and selecting the appropriate timing and its optimal regimes could result in safe and more effective treatment for COVID-19 (Zanoni, 2021).

Increase of IFNs following inflammation can result in serious illness and injury, prolong the disease, and make treatment more challenging, so the treatment of COVID-19 disease includes reducing the inflammatory response caused by IFN in various organs (Akamatsu et al, 2021; Yang et al, 2021). Thereby, measurement of IFN level and analysis of its subtypes during SARS-CoV-2 infection can provide more accurate treatment for viral infection, as well as immune response damage (Yang and Shen, 2020).

IFNs might serve as drug candidates for enhancing antiviral effects, while minimizing immunopathology when those subtypes are identified or combined with other antiviral drugs. It has been tested clinically in patients with long COVID-19, in combination with lopinavir/ritonavir (LPV/r). In contrast to those receiving oral LPV/r, patients receiving intravenous injection of IFN-α2b, in combination with LPV/r, experience shorter hospital stays and higher viral clearance rates (Sodeifian et al, 2022). In addition, administering IFN-α2b with arbidol decreased the duration of infection and inflammatory cytokine IL-6 levels in the upper respiratory tract (Zhou et al, 2020a). Furthermore, Cuban clinical studies have confirmed the efficacy of IFN-α2b against COVID-19 (Pereda et al, 2020). Similarly, patients with severe Middle East respiratory syndrome-related coronavirus infection treated with a combination of IFN-α2a and ribavirin experienced a significantly improved survival rate of 14 days (Shalhoub et al, 2015).

This study's findings show that IFN-I treatment is an effective treatment for COVID-19. Although delayed IFN-I treatment was unable to effectively inhibit virus replication, it was associated with an increase in proinflammatory cytokine expression and neutrophil infiltration in the lungs, resulting in fatal pneumonia. Therefore, IFNs for COVID-21 must be used with a balance between antiviral and immunological effects (104). An Adam Mickiewicz University study confirms these findings that limiting signaling cascades set off by inflammatory cytokines and IFNs is key to preventing systemic inflammation. Thus, targeting STAT family members can be suggested as a new treatment strategy in patients with severe COVID-19 (Yang et al, 2021).

Other antiviral drugs include (eg, favipiravir, remdesivir, LPV/r, and ribavirin), polyclonal or monoclonal antibodies against SARS-CoV-2 (eg, casirivimab/imdevimab, bamlanivimab/etesevimab), plasma during convalescence and immune modulating factors (eg, IFNs, corticosteroids, tocilizumab, and baricitinib) Recommended for treatment (Tsang et al, 2021). Angiotensin-converting enzyme inhibitors or angiotensin II type I receptor blockers are recommended for patients with COVID-19 (Jean et al, 2020; Vallianou et al, 2021). Also, the serum level of creatine kinase and lactate dehydrogenase could portent a positive reaction to COVID-19 treatment (Yuan et al, 2020).

The results of a randomized study showed patients who received a combination of lupinavir and IFN-β1a/ritonavir/ritonavir uratazanavir/with hydroxychloroquine in the primary stage of disease received faster treatment (Ader et al, 2021). Therefore, research is now directed toward immunomodulatory agents other than antiviral drugs. With the combined use of IFNs, the optimal timing, and route of its use, a safe and effective antiviral treatment for COVID-19 can be created (Sodeifian et al, 2022).

Conclusion

In conclusion, in this review, we discussed the double-edged role of IFNs in Long Covid infection. Three potential causes attributed to this syndrome are viral persistence, autoimmunity, and immune dysregulation. The signaling pathway of type I IFNs is impaired owing to inherent errors in the signaling cascade and autoantibodies that neutralize IFN-α and IFN-ω causing lethal COVID-19, especially in elderly people.

Declaration

All authors are supported by institutions engaged in education or medical research.

Footnotes

Authors' Contributions

M.K., S.F., and F.G.-H. conceived and designed the study and collected the data. S.G. and N.B. prepared figures. H.R.R.J., N.Z., and N.B. participated in editing and revising the initial drafts of the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by a grant from the Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran (Grant No. 64815).

References

Ackermann

, Verleden

, Kuehnel

, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med, 2020; 383(2):120–128; doi: 10.1056/NEJMoa2015432

Acosta-Ampudia

, Monsalve

, Rojas

, et al. Persistent autoimmune activation and proinflammatory state in post-Coronavirus disease 2019 syndrome. J Infect Dis, 2022; 225(12):2155–2162; doi: 10.1093/infdis/jiac017

Ader

, Peiffer-Smadja

, Poissy

, et al. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin Microbiol Infect, 2021; 27(12):1826–1837; doi: 10.1016/j.cmi.2021.05.020

Ahmad

, Shaik

, Ahmad

, et al. “LONG COVID”: An insight. Eur Rev Med Pharmacol Sci, 2021; 25(17):5561–5577; doi: 10.26355/eurrev_202109_26669

Aiyegbusi

, Hughes

, Turner

, et al. Symptoms, complications and management of long COVID: A review. J R Soc Med, 2021; 114(9):428–442; doi: 10.1177/01410768211032850

Akamatsu

, de Castro

, Takano

, et al. Off balance: Interferons in COVID-19 lung infections. EBioMedicine, 2021; 73:103642; doi: 10.1016/j.ebiom.2021.103642

Andrade

, Siqueira

, Soares

WdA

, et al. Long-COVID and post-COVID health complications: An up-to-date review on clinical conditions and their possible molecular mechanisms. Viruses, 2021; 13:700.

Bai

, Tomasoni

, Falcinella

, et al. Female gender is associated with long COVID syndrome: A prospective cohort study. Clin Microbiol Infect, 2022; 28(4):611.e619–611.e616.

Bartoletti

, Marconi

, Scudeller

, et al. Efficacy of corticosteroid treatment for hospitalized patients with severe COVID-19: A multicentre study. Clin Microbiol Infect, 2021; 27(1):105–111; doi: 10.1016/j.cmi.2020.09.014

10.

Bastard

, Gervais

, Le Voyer

, et al. Autoantibodies neutralizing type I IFNs are present in ∼4% of uninfected individuals over 70 years old and account for ∼20% of COVID-19 deaths. Sci Immunol, 2021; 6(62):eabl4340; doi: 10.1126/sciimmunol.abl4340

11.

Bastard

, Rosen

, Zhang

, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science, 2020; 370(6515):eabd4585; doi: 10.1126/science.abd4585

12.

Beccuti

, Ghizzoni

, Cambria

, et al. A COVID-19 pneumonia case report of autoimmune polyendocrine syndrome type 1 in Lombardy, Italy: Letter to the editor. J Endocrinol Invest, 2020; 43(8):1175–1177; doi: 10.1007/s40618-020-01323-4

13.

Beck

, Aksentijevich

. Susceptibility to severe COVID-19. Science, 2020; 370(6515):404–405; doi: 10.1126/science.abe7591

14.

Blanco-Melo

, Nilsson-Payant

, Liu

, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell, 2020; 181(5):1036–1045.e1039; doi: 10.1016/j.cell.2020.04.026

15.

Bourmistrova

, Solomon

, Braude

, et al. Long-term effects of COVID-19 on mental health: A systematic review. J Affect Disord, 2022; 299:118–125; doi: 10.1016/j.jad.2021.11.031

16.

Brown

, Bhardwaj

. Super(antigen) target for SARS-CoV-2. Nat Rev Immunol, 2021; 21(2):72; doi: 10.1038/s41577-021-00502-5

17.

Buonsenso

, Piazza

, Boner

, et al. Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome. Allergy Asthma Proc, 2022; 43(3):187–193; doi: 10.2500/aap.2022.43.220018

18.

Campbell

. Autoimmunity and the gut. Autoimmune Dis, 2014; 2014:152428; doi: 10.1155/2014/152428

19.

Cao

, Ji

, Zeng

, et al. P200 family protein IFI204 negatively regulates type I interferon responses by targeting IRF7 in nucleus. PLoS Pathog, 2019; 15(10):e1008079; doi: 10.1371/journal.ppat.1008079

20.

Caso

, Costa

, Ruscitti

, et al. Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects?. Autoimmun Rev, 2020; 19(5):102524; doi: 10.1016/j.autrev.2020.102524

21.

Centers for Disease Control and Prevention. Long COVID or Post-COVID Conditions. 2022. Available from: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html [Last accessed: May 21, 2022].

22.

Channappanavar

, Fehr

, Zheng

, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest, 2019; 129(9):3625–3639; doi: 10.1172/jci126363

23.

Ciarambino

, Para

, Giordano

. Immune system and COVID-19 by sex differences and age. Womens Health (Lond), 2021; 17:17455065211022262.

24.

Clark

, Kibuuka

, Millard

, et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: A retrospective cohort study. Lancet Infect Dis, 2015; 15(8):905–912.

25.

Colarusso

, Maglio

, Terlizzi

, et al. Post-COVID-19 patients who develop lung fibrotic-like changes have lower circulating levels of IFN-β but higher levels of IL-1α and TGF-β. Biomedicines, 2021; 9(12):1931; doi: 10.3390/biomedicines9121931

26.

Conti

, Ronconi

, Caraffa

, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-inflammatory strategies. J Biol Regul Homeost Agents, 2020; 34(2):327–331.

27.

Dar

, Janahi

, Haque

, et al. Superantigen influence in conjunction with cytokine polymorphism potentiates autoimmunity in systemic lupus erythematosus patients. Immunol Res, 2016; 64(4):1001–1012; doi: 10.1007/s12026-015-8768-4

28.

Darif

, Hammi

, Kihel

, et al. The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong?. Microb Pathog, 2021; 153:104799; doi: 10.1016/j.micpath.2021.104799

29.

Davidson

, McCabe

, Crotta

, et al. IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment. EMBO Mol Med, 2016; 8(9):1099–1112; doi: 10.15252/emmm.201606413

30.

Dennis

, Wamil

, Alberts

, et al. Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: A prospective, community-based study. BMJ Open, 2021; 11(3):e048391; doi: 10.1136/bmjopen-2020-048391

31.

Ehrenfeld

, Tincani

, Andreoli

, et al. Covid-19 and autoimmunity. Autoimmun Rev, 2020; 19(8):102597; doi: 10.1016/j.autrev.2020.102597

32.

Escobedo

, Singh

, Kaushal

. Understanding COVID-19: From Dysregulated Immunity to Vaccination Status Quo. Front Immunol, 2021; 12:765349; doi: 10.3389/fimmu.2021.765349

33.

Fallerini

, Daga

, Mantovani

, et al. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: Findings from a nested case-control study. Elife, 2021; 10:e67569; doi: 10.7554/eLife.67569

34.

Files

, Boppana

, Perez

, et al. Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection. J Clin Invest, 2021; 131(1):e140491.

35.

Fish

, Platanias

. Interferon receptor signaling in malignancy: A network of cellular pathways defining biological outcomes. Mol Cancer Res, 2014; 12(12):1691–1703; doi: 10.1158/1541-7786.Mcr-14-0450

36.

Fraser

. Clarifying the mechanism of superantigen toxicity. PLoS Biol, 2011; 9(9):e1001145; doi: 10.1371/journal.pbio.1001145

37.

Fung

, Liu

. Human coronavirus: Host-pathogen interaction. Annu Rev Microbiol, 2019; 73:529–557; doi: 10.1146/annurev-micro-020518-115759

38.

Galani

, Triantafyllia

, Eleminiadou

, et al. Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness. Immunity, 2017; 46(5):875–890.e876; doi: 10.1016/j.immuni.2017.04.025

39.

Genovese

, Moltrasio

, Berti

, et al. Skin manifestations associated with COVID-19: Current knowledge and future perspectives. Dermatology, 2021; 237(1):1–12; doi: 10.1159/000512932

40.

Grajales-Reyes

, Colonna

. Interferon responses in viral pneumonias. Science, 2020; 369(6504):626–627; doi: 10.1126/science.abd2208

41.

Grifoni

, Weiskopf

, Ramirez

, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell, 2020; 181(7):1489–1501.e1415.

42.

Guedez

, Norrby-Teglund

, Low

, et al. HLA class II alleles associated with outcome of invasive group A streptococcal infections. In: Proceedings of the 37th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, ON, Canada; 1997.

43.

Hadjadj

, Yatim

, Barnabei

, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science, 2020; 369(6504):718–724; doi: 10.1126/science.abc6027

44.

Hassett

, Gedansky

, Migdady

, et al. Neurologic complications of COVID-19. Cleve Clin J Med, 2020; 87(12):729–734; doi: 10.3949/ccjm.87a.ccc058

45.

Israelow

, Song

, Mao

, et al. Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling. J Exp Med, 2020; 217(12):e2020241.

46.

Jacobs

JJL

. Persistent SARS-2 infections contribute to long COVID-19. Med Hypotheses, 2021; 149:110538; doi: 10.1016/j.mehy.2021.110538

47.

Jean

, Lee

, Hsueh

. Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect, 2020; 53(3):436–443; doi: 10.1016/j.jmii.2020.03.034

48.

Karki

, Sharma

, Tuladhar

, et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell, 2021; 184(1):149–168.e117; doi: 10.1016/j.cell.2020.11.025

49.

Khan

, Wang

. Environmental exposures and autoimmune diseases: Contribution of gut microbiome. Front Immunol, 2019; 10:3094; doi: 10.3389/fimmu.2019.03094

50.

Kikkert

. Innate immune evasion by human respiratory RNA viruses. J Innate Immun, 2020; 12(1):4–20; doi: 10.1159/000503030

51.

Lanford

, Feng

, Chavez

, et al. Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA. Proc Natl Acad Sci U S A, 2011; 108(27):11223–11228; doi: 10.1073/pnas.1101939108

52.

Lees

. Interferon gamma in autoimmunity: A complicated player on a complex stage. Cytokine, 2015; 74(1):18–26.

53.

, Fan

, Lai

, et al. Coronavirus infections and immune responses. J Med Virol, 2020a;92(4):424–432; doi: 10.1002/jmv.25685

54.

, Liao

, Wang

, et al. The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res, 2020b;286:198074; doi: 10.1016/j.virusres.2020.198074

55.

, Geng

, Peng

, et al. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal, 2020c;10(2):102–108; doi: 10.1016/j.jpha.2020.03.001

56.

Liao

, Li

, Ma

, et al. 12-Month post-discharge liver function test abnormalities among patients with COVID-19: A single-center prospective cohort study. Front Cell Infect Microbiol, 2022; 12:864933; doi: 10.3389/fcimb.2022.864933

57.

Lopez-Leon

, Wegman-Ostrosky

, Perelman

, et al. More than 50 long-term effects of COVID-19: A systematic review and meta-analysis. Sci Rep, 2021; 11(1):16144; doi: 10.1038/s41598-021-95565-8

58.

Major

, Crotta

, Llorian

, et al. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Science, 2020; 369(6504):712–717; doi: 10.1126/science.abc2061

59.

Mantlo

, Bukreyeva

, Maruyama

, et al. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res, 2020; 179:104811; doi: 10.1016/j.antiviral.2020.104811

60.

Marrack

, Kappler

. The staphylococcal enterotoxins and their relatives. Science, 1990; 248(4956):705–711; doi: 10.1126/science.2185544

61.

Michaud

Evolving Approaches to Testing and Treatment for Long COVID. Better Health Through Laboratory Medicine; 2021. Available from: https://www.aacc.org/cln/articles/2021/november/evolving-approaches-to-testing-and-treatment-for-long-covid [Last accessed: June 1, 2022].

62.

Miyashita

, Yang

, Lam

, et al. A novel form of Epstein-Barr virus latency in normal B cells in vivo. Cell, 1995; 80(4):593–601; doi: 10.1016/0092-8674(95)90513-8

63.

Nabavi

. Long covid: How to define it and how to manage it. BMJ, 2020; 370:m3489; doi: 10.1136/bmj.m3489

64.

Nalbandian

, Sehgal

, Gupta

, et al. Post-acute COVID-19 syndrome. Nat Med, 2021; 27(4):601–615; doi: 10.1038/s41591-021-01283-z

65.

National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. 2021. Available from: https://www.nice.org.uk/guidance/ng188 [Last accessed: June 24, 2022].

66.

Ngai

, Ko

, Ng

, et al. The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status. Respirology, 2010; 15(3):543–550.

67.

Nguyen

, Tosti

. Alopecia in patients with COVID-19: A systematic review and meta-analysis. JAAD Int, 2022; 7:67–77; doi: 10.1016/j.jdin.2022.02.006

68.

, Ye

, Cheng

M-L

, et al. Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity, 2020; 52(6):971–977.e973.

69.

Nieto-Torres

, DeDiego

, Verdiá-Báguena

, et al. Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis. PLoS Pathog, 2014; 10(5):e1004077.

70.

Nittas

, Gao

, West

, et al. Long COVID through a public health lens: An umbrella review. Public Health Rev, 2022; 43:1604501; doi: 10.3389/phrs.2022.1604501

71.

Office for National Statistics. The prevalence of long COVID symptoms and COVID-19 complications. 2020. Available from: https://www.ons.gov.uk/news/statementsandletters/theprevalenceoflongcovidsymptomsandcovid19complications [Last accessed: June 24, 2022].

72.

Office for National Statistics. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK. 2022. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/1june2022 [Last accessed: May 7, 2022].

73.

Oldstone

. Viral persistence: Parameters, mechanisms and future predictions. Virology, 2006; 344(1):111–118; doi: 10.1016/j.virol.2005.09.028

74.

Ong

SWX

, Fong

S-W

, Young

, et al. Persistent symptoms and association with inflammatory cytokine signatures in recovered coronavirus disease 2019 patients. Open Forum Infect Dis, 2021; 8(6):ofab156; doi: 10.1093/ofid/ofab156

75.

Onodi

, Bonnet-Madin

, Meertens

, et al. SARS-CoV-2 induces human plasmacytoid pre-dendritic cell diversification via UNC93B and IRAK4. bioRxiv, 2021; 2021:197343; doi: 10.1101/2020.07.10.197343

76.

Onomoto

, Onoguchi

, Yoneyama

. Regulation of RIG-I-like receptor-mediated signaling: Interaction between host and viral factors. Cell Mol Immunol, 2021; 18(3):539–555; doi: 10.1038/s41423-020-00602-7

77.

Ortona

, Malorni

. Long COVID: To investigate immunological mechanisms and sex/gender related aspects as fundamental steps for tailored therapy. Eur Respir J, 2022; 59(2):2102245; doi: 10.1183/13993003.02245-2021

78.

Pairo-Castineira

, Clohisey

, Klaric

, et al. Genetic mechanisms of critical illness in COVID-19. Nature, 2021; 591(7848):92–98; doi: 10.1038/s41586-020-03065-y

79.

Patterson

, Guevara-Coto

, Yogendra

, et al. Immune-based prediction of COVID-19 severity and chronicity decoded using machine learning. Front Immunol, 2021; 12:2520.

80.

Pereda

, González

, Rivero

, et al. Therapeutic effectiveness of interferon-α2b against COVID-19: The cuban experience. J Interferon Cytokine Res, 2020; 40(9):438–442; doi: 10.1089/jir.2020.0124

81.

Phetsouphanh

, Darley

, Wilson

, et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol, 2022; 23(2):210–216; doi: 10.1038/s41590-021-01113-x

82.

Platanias

. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol, 2005; 5(5):375–386; doi: 10.1038/nri1604

83.

Premraj

, Kannapadi

, Briggs

, et al. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. J Neurol Sci, 2022; 434:120162; doi: 10.1016/j.jns.2022.120162

84.

Proal

, VanElzakker

. Long COVID or post-acute sequelae of COVID-19 (PASC): An overview of biological factors that may contribute to persistent symptoms. Front Microbiol, 2021; 12:698169.

85.

Ricci

, Etna

, Rizzo

, et al. Innate immune response to SARS-CoV-2 infection: From cells to soluble mediators. Int J Mol Sci, 2021; 22(13); doi: 10.3390/ijms22137017

86.

Rojas

, Rodríguez

, Acosta-Ampudia

, et al. Autoimmunity is a hallmark of post-COVID syndrome. J Transl Med, 2022; 20(1):129; doi: 10.1186/s12967-022-03328-4

87.

Rokni

, Ghasemi

, Tavakoli

. Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: Comparison with SARS and MERS. Rev Med Virol, 2020; 30(3):e2107; doi: 10.1002/rmv.2107

88.

Sadanandam

, Bopp

, Dixit

, et al. A blood transcriptome-based analysis of disease progression, immune regulation, and symptoms in coronavirus-infected patients. Cell Death Discov, 2020; 6(1):141; doi: 10.1038/s41420-020-00376-x

89.

Schneider

, Chevillotte

, Rice

. Interferon-stimulated genes: A complex web of host defenses. Annu Rev Immunol, 2014; 32:513–545; doi: 10.1146/annurev-immunol-032713-120231

90.

Schoenborn

, Wilson

. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol, 2007; 96:41–101; doi: 10.1016/s0065-2776(07)96002-2

91.

Schoggins

. Interferon-stimulated genes: What do they all do?. Annu Rev Virol, 2019; 6(1):567–584; doi: 10.1146/annurev-virology-092818-015756

92.

Schultz

, Vernon

, Griffin

. Differentiation of neurons restricts Arbovirus replication and increases expression of the alpha isoform of IRF-7. J Virol, 2015; 89(1):48–60; doi: 10.1128/jvi.02394-14

93.

Severa

, Farina

, Salvetti

, et al. Three decades of interferon-β in multiple sclerosis: Can we repurpose this information for the management of SARS-CoV2 infection?. Front Immunol, 2020; 11:1459; doi: 10.3389/fimmu.2020.01459

94.

Shalhoub

, Farahat

, Al-Jiffri

, et al. IFN-α2a or IFN-α1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother, 2015; 70(7):2129–2132; doi: 10.1093/jac/dkv085

95.

Smatti

, Cyprian

, Nasrallah

, et al. Viruses and autoimmunity: A review on the potential interaction and molecular mechanisms. Viruses, 2019; 11(8); doi: 10.3390/v11080762

96.

Sodeifian

, Nikfarjam

, Kian

, et al. The role of type I interferon in the treatment of COVID-19. J Med Virol, 2022; 94(1):63–81; doi: 10.1002/jmv.27317

97.

Stanifer

, Guo

, Doldan

, et al. Importance of type I and III interferons at respiratory and intestinal barrier surfaces. Front Immunol, 2020; 11:608645; doi: 10.3389/fimmu.2020.608645

98.

Sudre

, Murray

, Varsavsky

, et al. Attributes and predictors of long COVID. Nat Med, 2021; 27(4):626–631; doi: 10.1038/s41591-021-01292-y

99.

Syedbasha

, Egli

. Interferon lambda: Modulating immunity in infectious diseases. Front Immunol, 2017; 8:119; doi: 10.3389/fimmu.2017.00119

100.

Taefehshokr

, Taefehshokr

, Hemmat

, et al. Covid-19: Perspectives on innate immune evasion. Front Immunol, 2020; 11:580641; doi: 10.3389/fimmu.2020.580641

101.

Takahashi

, Ellingson

, Wong

, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature, 2020; 588(7837):315–320; doi: 10.1038/s41586-020-2700-3

102.

Tan

, Komarasamy

, Rmt Balasubramaniam

. Hyperinflammatory immune response and COVID-19: A double edged sword. Front Immunol, 2021; 12:742941; doi: 10.3389/fimmu.2021.742941

103.

The prevalence of long COVID symptoms and COVID-19 complications—Office for National Statistics.

104.

The New York Times. Well long covid symptoms treatment.2022. Available from: https://www.nytimes.com/2022/05/21/well/long-covid-symptomstreatment [Last accessed: May 21, 2022].

105.

Trouillet-Assant

, Viel

, Gaymard

, et al. Type I IFN immunoprofiling in COVID-19 patients. J Allergy Clin Immunol, 2020; 146(1):206–208.e202; doi: 10.1016/j.jaci.2020.04.029

106.

Tsang

, Chan

LWC

, Cho

WCS

, et al. An update on COVID-19 pandemic: The epidemiology, pathogenesis, prevention and treatment strategies. Expert Rev Anti Infect Ther, 2021; 19(7):877–888; doi: 10.1080/14787210.2021.1863146

107.

Vallianou

, Tsilingiris

, Christodoulatos

, et al. Anti-viral treatment for SARS-CoV-2 infection: A race against time amidst the ongoing pandemic. Metabol Open, 2021; 10:100096; doi: 10.1016/j.metop.2021.100096

108.

van der Made

, Simons

, Schuurs-Hoeijmakers

, et al. Presence of genetic variants among young men with severe COVID-19. JAMA, 2020; 324(7):663–673; doi: 10.1001/jama.2020.13719

109.

van der Wijst

MGP

, Vazquez

, Hartoularos

, et al. Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19. Sci Transl Med, 2021; 13(612):eabh2624; doi: 10.1126/scitranslmed.abh2624

110.

Wander

, Lowy

, Beste

, et al. The incidence of diabetes among 2,777,768 Veterans with and without recent SARS-CoV-2 infection. Diabetes Care, 2022; 45(4):782–788; doi: 10.2337/dc21-1686

111.

Wang

, Mao

, Klein

, et al. Diverse functional autoantibodies in patients with COVID-19. Nature, 2021; 595(7866):283–288; doi: 10.1038/s41586-021-03631-y

112.

Wen

, Su

, Tang

, et al. Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov, 2020; 6(1):1–18.

113.

Weng

, Li

, et al. Gastrointestinal sequelae 90 days after discharge for COVID-19. Lancet Gastroenterol Hepatol, 2021; 6(5):344–346; doi: 10.1016/s2468-1253(21)00076-5

114.

Whitmire

, Eam

, Benning

, et al. Direct interferon-gamma signaling dramatically enhances CD4+ and CD8+ T cell memory. J Immunol, 2007; 179(2):1190–1197; doi: 10.4049/jimmunol.179.2.1190

115.

Wiech

, Chroscicki

, Swatler

, et al. Remodeling of T cell dynamics during long COVID is dependent on severity of SARS-CoV-2 infection. Front Immunol, 2022; 13:886431; doi: 10.3389/fimmu.2022.886431

116.

Wieczorek

, Abualrous

, Sticht

, et al. Major histocompatibility complex (MHC) class I and MHC class II proteins: Conformational plasticity in antigen presentation. Front Immunol, 2017; 8:292; doi: 10.3389/fimmu.2017.00292

117.

World Health Organization. A clinical case definition of post COVID-19 condition by a Delphi consensus. 2021. World Health Organization, Geneva.

118.

Xia

, Cao

, Xie

, et al. Evasion of type I interferon by SARS-CoV-2. Cell Rep, 2020; 33(1):108234; doi: 10.1016/j.celrep.2020.108234

119.

Xie

, Xu

, Bowe

, et al. Long-term cardiovascular outcomes of COVID-19. Nat Med, 2022; 28(3):583–590; doi: 10.1038/s41591-022-01689-3

120.

Yang

, Wang

, Hui

, et al. Potential role of IFN-α in COVID-19 patients and its underlying treatment options. Appl Microbiol Biotechnol, 2021; 105(10):4005–4015; doi: 10.1007/s00253-021-11319-6

121.

Yang

, Shen

. Targeting the endocytic pathway and autophagy process as a novel therapeutic strategy in COVID-19. Int J Biol Sci, 2020; 16(10):1724–1731; doi: 10.7150/ijbs.45498

122.

Yuan

, Zou

, Zeng

, et al. The correlation between viral clearance and biochemical outcomes of 94 COVID-19 infected discharged patients. Inflamm Res, 2020; 69(6):599–606; doi: 10.1007/s00011-020-01342-0

123.

Zanoni

. Interfering with SARS-CoV-2: Are interferons friends or foes in COVID-19?. Curr Opin Virol, 2021; 50:119–127; doi: 10.1016/j.coviro.2021.08.004

124.

Zhang

, Bastard

, Liu

, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science, 2020a;370(6515):eabd4570; doi: 10.1126/science.abd4570

125.

Zhang

, Bastard

, Cobat

, et al. Human genetic and immunological determinants of critical COVID-19 pneumonia. Nature, 2022; 603(7902):587–598; doi: 10.1038/s41586-022-04447-0

126.

Zhang

, Jouanguy

, Sancho-Shimizu

, et al. Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunol Rev, 2007; 220(1):225–236; doi: 10.1111/j.1600-065X.2007.00564.x

127.

Zhang

, Qin

, Zhao

, et al. Interferon-induced transmembrane protein 3 genetic variant rs12252-C associated with disease severity in coronavirus disease 2019. J Infect Dis, 2020b;222(1):34–37; doi: 10.1093/infdis/jiaa224

128.

Zheng

, Gao

, Wang

, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol, 2020; 17(5):533–535.

129.

Zhou

, MacArthur

, He

, et al. Interferon-α2b treatment for COVID-19 is associated with improvements in lung abnormalities. Viruses, 2020a;13(1); doi: 10.3390/v13010044

130.

Zhou

, Fu

, Zheng

, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+ CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. biorxiv, 2020; 2020:945576.

131.

Ziegler

, Allon

, Nyquist

, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell, 2020; 181(5):1016–1035.e1019.