COVID-19: patients with mild symptoms are characterized by an early induction of IFN-γ secreting SARS-CoV-2-specific T cells

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Antibodies and T cells are components of the human immune system that directly act against viral infections and eliminate infected cells. A new study by scientists from Duke-NUS Medical School, provides evidence that an early presence of SARS-CoV-2-specific T cells in COVID-19 is likely to prevent severe disease. The study, published in Cell Reports, has important implications for the clinical management of COVID-19 patients.

Humoral and cellular adaptive immunity are two immune mechanisms that act against pathogens. Humoral immunity is mediated by antibodies, while cellular immunity does not involve antibodies and is instead facilitated by T cells.

Studying how these immune mechanisms mediate SARS-CoV-2 infections could be beneficial in controlling the progression of the disease. However, their roles in viral control or disease pathogenesis is not fully understood and only a few studies have thoroughly monitored COVID-19 patients longitudinally, especially during the acute phase of infection.

To fill this knowledge gap, the team of researchers at Duke-NUS investigated the changes in virological and immunological parameters in 12 patients with symptomatic acute SARS-CoV-2 infection from onset of the disease to recovery or death.

“We found that patients who control SARS-Cov-2 infection with only mild symptoms are characterized by an early induction of IFN-γ secreting SARS-CoV-2-specific T cells.

The amount of humoral response, however, does not predict the level of COVID-19 disease severity,” said Dr. Anthony Tanoto Tan, Senior Research Fellow at the Duke-NUS’ Emerging Infectious Diseases (EID) program and the co-author of this study.

“Our data supports the idea that SARS-CoV-2-specific T cells play an important role in the rapid control of viral infection and eventual clearance of the disease,” added Dr. Martin Linster, Senior Research Fellow with Duke-NUS’ EID program and the co-author of this study.

This work is a continuation of the team’s previous publication in Nature, where they analyzed SARS-CoV-2-specific T cell response in COVID-19 patients at convalescence. In this study, they have expanded the analysis to the full timeline of SARS-CoV-2 infection from onset to outcome.

“It is time that T cell monitoring should be considered in providing a comprehensive understanding of the immune response against SARS-CoV-2. This would also mean that a vaccine will likely be more effective if a holistic induction of both antibodies and T cells occurs,” said Professor Antonio Bertoletti, from Duke-NUS’ EID program, who is the corresponding author of this study.

“This important study furthers our understanding of the immune response against SARS-CoV-2. It has far-reaching implications including on COVID-19 vaccine design and the subsequent monitoring of vaccine response,” said Professor Patrick Casey, senior vice-dean for research at Duke-NUS.

The team is now studying more symptomatic COVID-19 patients with varying disease severity to further validate their findings.


Interferons as a potential treatment for COVID-19
IFNs are natural broad-spectrum antiviral and anti-inflammatory proteins which bind to their receptors on the surface of different cells and induce JAK-STAT signaling pathway, followed by transcription of IFN-stimulated genes (ISGs) including the antiviral enzyme RNase L, and the proinflammatory chemokine CXCL10 [60], [129].

Type 1 IFNs are a group of cytokines including α, β, ω, ε and κ subtypes [130]. Type I IFNs are mainly generated by infected cells and immune cells. The single member of the type II IFNs named IFN-γ is also expressed by immune cells. Type III IFNs including 4 sub-members of IFN-λ are produced by restricted immune cells and epithelial cells.

Type I and II IFNs induce proinflammatory immune responses via the stimulation of several genes in immune cells. These activated immune cells either kill infected cells or deactivate viruses with antibodies. Others take up the viruses and parts of dead infected cells.

In contrast, type III IFNs act milder, because they typically decline viral replication in infected cells. Another special characteristic of type III IFNs is that they can support epithelial barrier constancy.

Promotion of the type I IFNs is necessary in restricting the proliferation of viruses within the host cells through the early stage of the disease. Type I IFNs have the antiviral activity which inhibit viral replication and can also orchestrate the innate and adaptive immune systems. Many viruses, including MERS-CoV and SARS-CoV, employ numerous strategies to attack the immune response regulated by type I IFNs [131].

SARS-CoV is a virus that induce intense lung damage, expressess several proteins to hinder type I IFNs signaling cascades. However, current studies have confirmed that IFNs are expressed during SARS-CoV-2 infection. Moreover, STAT1 translocation following by ISGs activation could be determined in the infected lungs by SARS-CoV. In parallel with these investigation, plasmacytoid dendritic cells (pDCs) produce IFNs during SARS-CoV infection in vitro. These observations approve the essential role of IFNs throughout viral infections [132].

A study on SARS-CoV showed a successful type I IFN therapy [133], where as another research on larger group hardly revealed any positive effect [134].

Studies in mouse models represented less tissue destruction if the type III IFN response included in the immune response against respiratory infection.

As the receptors of type I IFN (IFNAR) are expressed on the surface of all cells, the injection of type I IFNs may have intense systemic adverse effects. Contrary, the receptor complex of type III IFNs (IFN-λ), which contains IFNLR1 and IL10R2 subunits, is expressed only on epithelial cells and a limited subset of immune cells such as neutrophils. Thus, administration of type III IFNs at an early phase of COVID-19 disease would leads to localized antiviral reactivities with fewer inflammation and adverse effects compare to the systemic immune response of type I IFNs [135].

Early implementation of IFNs has special benefits in lessening virus counts and clinical symptoms of COVID-19. However, it rarely reduces fatality rates [136], [137]. It has also been proposed that IFNs were effective in some patients [138], [139]. Subtype variety could be one of the reason of contradictions among studies. Further details about each type of IFNs are described is separate sections below. Table 2 depicted some principal information about IFNs.

Table 2

Summary of the positive and negative effects of different IFN in treatment of several diseases.

TypeNameCell producerFunctionSide effectsTreatmentCOVID-19 therapy
IIFN-αall immune cells/ infected cells [140]proinflammatory response/ kill infected cells/neutralize the virus [135]significant systemic side effects including flu-like symptoms/nausea/fatigue/weight loss/hematological toxicities/elevated transaminases/psychiatric problems (depression and suicidal ideation) [140]chronic viral infections (e.g. hepatitis) [135][141]relieve symptoms/shorten disease duration/reduce the period of viral flaking [135]
IIFN-βall immune cells/infected cells [140]proinflammatory response/kill infected cells/neutralize the virus [142]significant systemic side effects including hypersensitivity reaction/neuropsychiatric issues/administration-associated problems [140]autoimmune diseases (e.g. multiple sclerosis) [141][143]enhanced ARDS difficulties/augmented discharge rate/inhibit viral replication/upregulate lung antiviral defense/treat LRT illness/improve recovery/declined mortality rate [143]
IIIFN-γall immune cells [132][135]proinflammatory response/kill infected cells/neutralize the virus/immune regulator/induces regulatory T cells and antigen-specific regulatory B cells [142][144]few side effects including flu-like syndrome/headache/fever/abdominal pain [144]a bone disorder/an immune deficiency syndrome/allergic diseases/cancers/infections/chronic granulomatous disease/osteoporosis/tuberculosis/hepatitis/scleroderma [144]stimulates cytokine expression/improves immune response/expands destruction of CTL/restricting virus replication and distribution [145]
IIIIFN-λepithelial cells/limited subset of immune cells like plasmacytoid dendritic cells [140][144]less inflammatory response/reduce viral replication and diffusion/stimulate epithelial barrier stability/inhibit the recruitment of neutrophils [135]few side effects [140]Infection

Interferon α (IFN-α)
IFN-α can decrease the number of viruses in the early phase of COVID-19 leads to relieve symptoms and shorten disease duration.

Clinical studies with IFN-α in treatment of patients with SARS, pneumonia, bronchiolitis, sever URTI, hand foot mouth disease (HFMD), and other viral diseases in children, represented the positive effect of this product.

It is proposed that IFN-α nebulization needs to be administrated 200,000– 400,000 IU/kg or 2–4 μg/kg in 2 mL sterile water, 2 times a day for 5–7 days. The high-risk peoples who are in contact with infected COVID-19 patients or patients in the early stage with only URTI require to use IFN-α2b spray.

IFN-α2b should sprays 1–2 times on each side of the nose, 8–10 times on the throat, with a dosage of 8000 IU per injection, every 1–2 h, for a period of 5–7 days [70], [139]. Interestingly, IFN-α2b therapy could reduce the period of viral flaking. Declining markers of intense inflammation including IL-6 and CRP related to this reduced viral flaking. This finding representing the probability of IFN-α2b in treating COVID-19 disease [148].

In a clinical trial on 446 patients with SARS-CoV-2 infection in Hubei, China has been represented that early usage of IFN-α2b could diminish in-hospital death compare to patients who didn’t received IFN-α2b. However, IFN-α2b administrated in late stage raised mortality.

Among survived patients, early administration of IFN-α2b could not improve CT scan or hospital release, while late IFN-α2b causes postponed recovery. Therefore, IFN-α2b administrated throughout the early phase of COVID-19 disease is associated with promising clinical outcomes [149].

Interferon beta (IFN-β)
Interferon beta-1a (IFN-β-1a)
IFN-β-1a has been demonstrated to be beneficial in treating virus diseases such as hepatitis [150] and SARS-CoV [131], [151], [152], [153]. Because of the high similarity of SARS-CoV with SARS-CoV-2, IFN-β-1a was added to the antiviral drugs using in COVID-19 patients.

SARS-CoV-2 enters the cell by binding to ACE2 receptor, and its expression is begun leads to induction of innate immune system [60], [131], [154]. Generally, IFNs are produced after viral infection to hinder the infection. However, several studies have shown that despite its effectiveness in restraining the SARS-CoV replication, IFNs expression was reduced during infection with SARS-CoV [60].

Recent studies represented that IFN-β-1a enhanced ARDS difficulties [15]. Using IFN-β-1a significantly augmented the rate of discharge on day 14 and declined 28-day death. There is no published data regarding to the administration of IFN-β-1a in patients with acute COVID-19.

However, early use of IFN-β-1a, in severely ill instinctively ventilated patients elevated survival rate. Late administration hardly exhibited any benefits. In this randomized clinical trial efficacy and safety of IFN-β-1a has been evaluated in patients with severe COVID-19 [155].

Notably, IFN-β-1a displayed potent antiviral function at dosages that have been accepted in animals due to its safety profiles [143]. The administration route is another critical aspect in treatment of COVID-19 patients with IFN-β-1a. Both intravenous (i.v.) and subcutaneous (s.c.) administration routes are considered to be suitable in therapy. However, because of various bioavailabilities of IFN-β-1a through i.v. and s.c. administrations this feature requires to be taken in to account more seriously, particularly in critically sick patients [156].

Side effects of IFN-β-1a were hypersensitivity reaction, neuropsychiatric issues, and injection-related problems which all were endurable and recovered through the follow-up medical care [155], [157].

On 20th July 2020, Synairgen PLC announced positive results of phase II trial on the novel formulation of IFN-β-1a, called SNG001, in hospitalized 220 COVID-19 patients. SNG001 is a spray to deliver IFN-β-1a to the lungs via nebulization to treat LRTI caused by SARS-CoV-2 viruses. The patients with chronic obstructive pulmonary disease (COPD) or asthma inhaled SNG001 tolerated the drug very well and exhibited improved lung function and recovery rate as well as reduced breathlessness and mortality rate [158].

Interferon beta-1b (IFN-β-1b)
Recent study on IFN-β-1b depicted its potential in vitro to inhibit SARS­CoV and MERS­CoV. In another study, it also hindered SARS­CoV­2 virus effectively. Therefore, some guidelines suggest the subcutaneous administration of IFN-β-1b accompanied by other antiviral drugs.

Recently, the efficacy of IFN-β-1b in COVID­19 patients with moderate to severe pneumonia who hospitalized between 23th February to 4th April 2020 was explored. Patients received 3 to 5 dosages of IFN-β-1b subcutaneously and endpoint of the study was in­hospital fatality. Patients who received IFN-β-1b were also receive lopinavir/ritonavir and hydroxychloroquine.

The total mortality rate was about 20% in patients who received IFN-β-1b compared to 27% of counterparts who did not use this drug. IFN-β-1b administration time in viral disease has been displayed its significance in successful therapy in mouse models.

Although IFN-β-1b therapy reduced in­hospital mortality in patients because of the combination therapy in many patients, it is hard to assign effectiveness to any one drug [159]. In a recent retrospective study on COVD-19 patients with mild or moderate disease treated with IFN-β-1b, despite small number of patients meaningful efficiency and no mortality were observed. Thus, this result confirms that IFN-β-1b is a potential therapeutic agents for SARS-CoV-2 [138].

Early enrolment to organize doses of IFN-β-1b is crucial; however it might be unrealistic as patients hardly present in hospital sooner than 7 days, when disease features usually worsen [160]. It was regularly displayed that IFNβ is more effective than IFNα to hinder COVID-19 [161]. Among IFN-I subtypes, IFNβ-1a and −1b were the greatest effectiveness subtype in preventing COVID-19 patients [143]. This reality can be associated to the defensive function of IFNβ in the lung, preservation of endothelial barrier activity and increasing anti-inflammatory adenosine [141].

Interferon gamma (IFN-γ)
IFN-γ is an immunoregulatory protein with a broad-spectrum antiviral and antimicrobial functions which has influence on multiple cells and cellular activities [162], [163].

It has been demonstrated that IFN-γ initiates its antiviral activity using cellular function at multiple stages [145]. At the beginning, IFN-γ binds to its receptor and subsequently induces several genes resulted in declining virus replication [164].

Otherwise, IFN-γ stimulates cytokine expression by activation of monocytes, macrophages, and T cells. Furthermore, it expands destruction of cytotoxic T lymphocyte (CTL) by inducing major histocompatibility complex (MHC) class I, or granzyme B. In addition, it improves immune response by stimulation of MHC class II receptors [165].

Recent studies on treatment of coronavirus infection with IFN-γ represented its pivotal role in restricting virus replication and distribution inside the retina and protecting host cells throughout a retinal infection [145].

Current experimental studies demonstrate that IFN-γ production by retinal cellular infiltration is a critical function of an immune response accountable for noncytolytic virus clearance from the retina [145]. There are some clinical protocols about dosage and treatment duration of IFN-γ.

Hopefully, few adverse effects are detected for this available and cheap therapeutic. The safety of IFN-γ has already been approved but its efficacy needs to be confirmed. IFN-γ is recently suggested to be used in virus pandemics, particularly for endangered patients when exact therapeutics are not obtainable [144].

Interferon lambda (IFN-λ)
IFN-λ mainly stimulates epithelial cells and decreases the macrophage-mediated activity of IFN-α and β [166]. Furthermore, IFN-λ prohibit the employment of neutrophils to the location of inflammation [167]. MERS-CoV and SARS-CoV principally invade to alveolar epithelial cells (AEC). As IFN-λ induces several antiviral genes in epithelial cells, leading to antiviral activities, it can be a proper candidate for an effective treatment.

To date, the only available therapeutic IFN-λ in the market is pegylated IFN-λ1 (peg-IFN-λ1). In vitro, IFN-λ therapy represented efficacy against different viruses, including MERS-CoV and SARS-CoV-2 [140]. The key activity of IFN-λ is to hinder viral infection by inducing an antiviral response and, if infected, to reduce viral production and diffusion. In treatment of COVID-19, the lack of proinflammatory activity in the lungs is one of the significant benefits of IFN-λ compare to type I IFNs [140], [166].

However, it needs to be determined if immune system is reactive to IFN-λ in COVID-19, as the immune cells impair inflammation. Additionally, it needs to be investigated that if antiproliferative effect of IFN-λ could hamper recovery procedures of epithelial cells and virus-induced apoptotic cell death [140].

Indeed, IFN-λ can induce an antiviral effect in cells with IFN-λ receptor 1 (IFNLR1). For COVID-19, it is uncertain whether alveolar endothelial cells or macrophages are effectively infected and supported viruses to not be available to IFN-λ antiviral function for absence of IFNLR1. Although IFN-λ may be more suitable than type I IFNs in anti-COVID-19 therapy, more studies are required to analyze probable negative effects of IFN-λ.

Even though not yet administrated in active COVID-19 infection, no improved lung infections have appeared in 3,000 patients who were preserved for 48 weeks with peg-IFN-λ1. Probable side effects might also be diminished by shorter treatment period [140].

There are many outstanding questions in relation to COVID-19 and IFN-λs, however it could be beneficial in this pandemic outbreak.

Potential combination therapy and clinical trials for COVID-19
A combination of IFN-α-2a with ribavirin postponed mortality rate [136] and displayed efficient outcomes in the rhesus macaque, but was questionable in human [141]. In China, the administration of 5 million U of IFNα twice a day accompanied with ribavirin in COVID-19 patients is recommended [141].

Administration of IFNβ with lopinavir/ritonavir enhanced pulmonary function without declining virus production or lung injury in COVID-19 infection [168]. In general, the combination of type I IFN with remdesivir, ribavirin, or lopinavir/ritonavir could elevate its efficacy in COVID-19 [168]. It might also be applicable to treat COVID-19 patients with type III IFN due to its shielding property in the pulmonary tract [169].

In clinical trials performed on 4th May 2020 on COVID-19 patients, treating with the combination of opinavir/ritonavir, chloroquine/hydroxychloroquine, and plasma therapy were evaluated. Although protein and cell therapies have been shown promising results in different diseases, were not effective in COVID-19.

The antiviral medications like remdesivir applies in moderate level in the therapeutic community. Outcomes of the effectiveness of remdesivir are discontinued by the manufacturer. Treatment with lopinavir/ritonavir hardly showed promising remedial effects. More investigations are still required to be able to clarify inconsistent data about the merits of using chloroquine and hydroxychloroquine in COVID-19 [170].

IFN-β-1 may consider as a safe and effective treatment against SARS-CoV-2 in the early phases of the disease [141]. Furthermore, combination therapy with IFN-γ and a type I IFN might stimulate synergistic effects. However, more comprehensive studies are required to demonstrate the ideal timing and dosage to avoid undesired outcomes.

The azithromycin-hydroxychloroquine combination was also exhibited positive results in clinical trials against COVID-19; however further studies with more patients may be needed to approve these results.

In a randomised phase 2 clinical trial in COVID-19 patients, a triple combination of an injectable IFN-β-1b, with an oral nucleoside (ribavirin) and protease suppressor (lopinavir–ritonavir), administrated in 7 days of symptom beginning, was inhibited the flaking of SARS-CoV-2 [171].

Overall SARS-CoV-2 is more delicate to type I IFNs than other therapeutics. The data of IFN therapy against COVID-19 executed in China will be published in a near future. This data should reveal more accurate information about this therapy [141].

In conclusion, combination therapy with various drugs in different stages of this pandemic could be more efficient than monotherapy [172]. We hope the ongoing clinical trials scheduled to be finished in 2020, may assist us to find the most effective therapeutics to treat COVID-19 in this year.

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608019/


More information: Anthony T. Tan et al. Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients, Cell Reports (2021). DOI: 10.1016/j.celrep.2021.108728

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