1. Introduction

2. Methods

3. Interferon Types

3.1. Overview to Interferon Cellular Types

Type I IFN proteins are synthesised/secreted by translation from cellular nuclear transcription factors (TFs) resulting in differential anti–viral activity against host pathogens that may vary. Each IFN protein is known as a small molecular weight (MW) molecule in humans; for example, type I IFN–α1/13, IFN–α2, IFN–α8 and IFN–α21 are composed of 187–189 amino–acids, while type III IFN–λ is within the MW range 179–200 amino acids. Chemokines in comparison are smaller MW proteins (e.g., CCL2, 99 amino–acids), with pleiotropic effects directing immune cell migration throughout tissues. Small MW proteins are induced through gene synthesis transcription and subtypes can be differentially modified earlier in response to pathogenic antigens both inside and outside the cell. Interferon subtypes can be synthesised by myeloid cells like plasmacytoid dendritic cells (pDCs) producing higher concentrations of type I IFN (IFN–α/IFN–β), effecting anti–viral responses in hosts; but also, within skin epithelial cell tissues through tumour necrosis factor (TNF) related apoptosis–inducing ligand (TRAIL), and at least 10 intra/extracellular PM and vesicular TLRs [6]. On the other hand, type II IFN–γ is secreted by at least two effector cells (NK/T cells) together with two antigen presenting cells (DCs and Mϕ), each with different phenotypes characterised by cluster of differentiation (CD) marker. Type III IFN subtypes also influence host immune responses within epithelial layers. It is considered through regulating cellular cycle function that each IFN performs roles, with type I IFN–β potentially regulating Mϕ cell cycle (M1ϕ/M2ϕ), and metabolism; while type I IFN–α could be considered similar in the regulation of homeostatic function and observed commonly in health as well as inflammation and AI disorders.

Type I IFNs include IFN–β, IFN–δ, IFN–ε, IFN–κ, IFN–τ, IFN–ω, and IFN–ζ amongst others; whereas type III IFN is composed of IFN–λ (IFN–λ1, IFN–λ2, IFN–λ3, IFN–λ4), known originally as IL29, IL28A, and IL28B with IFN–λ4 discovered in 2014 [7]. Two types of type III IFN (λ2, λ3), are considered to have 96% amino–acid homology [8]. Other classifications of subtype exist and most vary between host animal species encoded by IFN genes. To clarify, human IFN consists of at least 18 subtypes, some others of which are type I IFN–α4, IFN–α7, and IFN–α14; whilst in pigs and bats diversity of IFN–ω is worthy of consideration, with less type I IFN–α described as discussed further [9,10,11]. Amongst type I IFN–α subtypes, a recombinant IFN–α2b therapeutic version in humans is utilised as below [12,13]. However, research studies in 2015 indicate that IFN–α2 is non–glycosylated missing one aspartic acid (D) amino–acid at position 44 in humans without functional change [14]. Furthermore, it is indicated two recombinant type I IFN–α2α / IFN–α2β preparations contain a neutral lysine (L) and alanine (K) substitution at position 23 when observations were that the type I IFN–α2 is conserved and less prone to mutations [15].

Recently, it was shown that type I IFN may contain pro–inflammatory glycans unknown affecting predominant antibody (IgG) binding to immune cell FcγR PM receptors (CD16/CD32/CD64), all of which influence an effective innate system response [15,16]. As a result, this can influence 3 functional branches of the adaptive T cell response (helper (T_H), cytotoxic (T_C), and NK cells). Modulation of sialic acid residues present in other receptors like the specific intercellular adhesion molecule–3 grabbing non–integrin (CD209 or DC–SIGN) or fucose residues may also occur unknown to date. Therefore, the overall homeostatic properties of type I IFN can be considered further.

Before and after 2019, pharmacokinetic properties of recombinant type I IFN–α2 engineering indicated the synthetic IFN production vector could affect pharmacokinetic half–life when glycoengineering indicated Pichia pastoris as an option, together with the purification method of recombinant IFN, whereas all subtypes of type I IFN–β are N–glycosylated [17,18,19]. In comparison, other studies show the addition of a glycosyl group on IFN–λ4 may increase anti–inflammatory actions and anti–viral efficacy [20]. It is notable that glycosylated IFNs vary in stability and display antimicrobial effects with research comparatively unknown [21]. Glycosylated IFN also bind to carbohydrates/ and PM receptors with higher/lower binding affinities to receptors. Respective IFN receptors include type I IFN receptors (IFNAR1/2), type II IFN receptors (IFN–γR1/IFN–γR2), as well as type III IFN receptors (IFN–λR1/IL10R2), each composed of two subunit domains [22,23]. Below is a depiction of 2 type I IFNs (See Figure 1).

Figure 1. Type I Interferon Receptor/Ligand Binding. Pictures were made using existing PDB files, namely 3SE3 and 3SE4, depicted as ribbon, and ribbon with surfaces of the receptor, with its electrostatic potential.

Figure 1. Type I Interferon Receptor/Ligand Binding. Pictures were made using existing PDB files, namely 3SE3 and 3SE4, depicted as ribbon, and ribbon with surfaces of the receptor, with its electrostatic potential.

As above, the receptor/IFN complex was clarified in 2011, and comparisons of type I IFN–α assays allowed type I IFN–α receptor binding studies to show IFN binding to IFNAR1 occurred with higher (µm) affinity, whilst binding to IFNAR2 was lower affinity in a smaller (nm) range [24]. However, IFN–β and IFN–λ are produced by various cells, with IFN–α generally synthesised by immune cells, but specifically pDCs during infection with receptors throughout the bodily system [25]. Other reviews establish type I IFN downregulation, while research into type III IFNs is in the early stages; however, other authors suggest type III IFNs may have further biological mechanisms [26,27]. Much remains unknown with regard to type III IFN–λ signalling proteins. Specific data on IFN therapy comes through national clinical trials (NCTs) conducted throughout history before/after the first cloning of IFN receptors in 1990 and types of recombinant IFN–α2 (see Supplementary Data S1) [28]. During the recent pandemic, type I IFNs were evidenced to have an effect in reducing SARS–CoV–2 viral genome load requiring further detail [29,30,31,32,33].

3.3. Cellular Signalling Mechanisms of Interferons

Interferon cellular action occurs through transmembrane protein receptors, as above, utilising predominantly janus kinase (JAK), and STAT protein phosphorylation activation pathways. However, seven STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) are described in mammals as central to immune cell regulation with STAT1/STAT2 pertinent to IFN signalling [48,49]. The IFN–λR1/IL–10RB receptors for IFN–λ are notably shared with IL–22 implicated in disease [50]. Less is known about type III IFN. Data (www.proteinatlas.org) implies the IFN–λ receptor (IFN–λR1) is preferentially expressed by both pDCs and B cells, with IFNAR1 by both neutrophils and three phenotypes of monocytes (classical, intermediate and non–classical), whilst IFNAR2 evenly distributed on all immune cells.

During the 1990s, STAT proteins were found to bind to JAK proteins. Various laboratories were known when four scientists including James Darnell, George Stark, as well as Ian Kerr discovered the molecular basis. These were classified into four types (JAK1, JAK2, JAK3) when Muller discovered that the tyrosine kinase (TYK2) enzymes bridged the gap between JAK/STAT proteins to be essential in type I IFN signalling [49]. Thereafter, two pathways are described including initially “canonical” or high–affinity binding of type I IFNs to the IFNAR2 to form a trimer with IFNAR1 [49]. The second pathway described is “non canonical”, referring to three independent kinase enzyme pathways, that include activation of MAP kinase (MAPK), mammalian target of rapamycin (mTOR), but also phosphatidylinositol 3–kinases PI3K, a serine/threonine kinase [49]. In the canonical model, activation and phosphorylation of JAK1/TYK2 occurs by phosphorylation to form a STAT1/STAT2 trimer with other interferon regulator factors (e.g., IRF1/3/7/9), producing interferon stimulating growth factors (e.g., ISGF3) translocating to nuclear interferon sensitive response elements (ISRE) effecting IFN synthesis [51]. However, the original “non–canonical” pathway is considered to be where STAT1 or other proteins, like MAPK or PI3K, homodimerise. Other reviews summarise STAT proteins as containing a conserved DNA binding domain –SH2 recognising phosphotyrosine motifs of cytokine receptors [49]. Below is shown the IFN signalling pathways (see Figure 2).

Figure 2. Systemic Interferon Signalling.

Figure 2. Systemic Interferon Signalling.

The activity of type I IFN occurs via activation of the nitric oxide synthase (NOS), and inactivation of an enzyme protein kinase R (PKR) that can be regulated by cellular viral DNA/RNA. Further activation of the enzyme oligoadenylate synthetases (OAS) along with peptide presentation by class I/II (MHC–I/II) occurs. Albeit, VP protein fragments are metabolised with short amino–acid peptide chains presented known as epitopes to immune cell receptors (e.g., T cell phenotypes CD4/CD8) [52]. There are four members of OAS enzymes, of which three (OAS1/2/3) produce 2′–5′–linked oligoadenylates and a similar OAS ligand (OASL) binding to RNAase L regulating the degradation of viral or cellular RNA. Activation of adenosine deaminase 1 (ADAR1), a dsRNA binding protein, is known to catalyse the process of deamination of adenosine usually involved in viral RNA replication, but also maturation and development of leukocytes to effect apoptosis of infected [53,54]. Protein kinase R downregulates translation of viral RNA encoding pathogenic protein domains; whereas OAS activation can degrade and lyse RNA with ADAR1 enabling RNA editing Viral NSPs may activate the phosphatidylinositol 3–kinase (PI3K) pathway inhibiting type I IFN synthesis, as well as activating cellular stress–response proteins (e.g., heat–shock proteins) involved in cell proliferation regulation, survival, and differentiation as well as immune cell regulation. Therefore, temporal initial inhibition of regulatory apoptotic pathways can occur while a pathogen replicates, prior to induction of innate immune system host cells [55].

In brief, STAT1 proteins are regulators of cell cyclin–dependent kinase inhibitors (CDKI), P21 and P27, but also caspases (1/3/11) that sense and are activated during cellular apoptosis [49]. However, STAT1 is also involved in antigen presentation as well as B cell development through regulating Fas (CD95), and Bcl–2 affecting granulocyte development [49]. In an immunological context, STAT1 is described to be activated by three cytokines (IL–2, IL–6, TNF), but also interferons. In contrast, STAT2 does not homo–polymerise but can be activated by type I IFN. Thirdly, STAT3 is described to be activated by the IL–6 and IL–10 family of cytokines regulated by CD95 acting as a molecular switch controlling immune cell differentiation, growth and apoptosis as observed in certain cancer types. Transcription of STAT3 is seen to occur constitutively in certain cancer types, like head and neck cancer, as well as haematological tumours amongst others [49,56,57]. However, STAT3 inhibition has been described to affect cytokine receptor, IL–4Rα, expression by naïve CD4 T cells expressing the migration adhesion molecule, CD62L, required to transverse endothelial cell membrane layers [57]. During gene knockout experiments of CD95, it is evidenced that overexpression of STAT1 inhibits STAT3 transcription of the IL17a promoter gene transcript necessary facilitating synthesis of IL–17 from T_H17 cells largely unknown to date [58]. Conversely, in vivo, the role of STAT3 is intertwined with STAT5 where overexpression of STAT5 is suggested with the cytokine GM–CSF to activate the differentiation of both neutrophils while inhibiting myeloid lineages (monocyte/Mϕs) [56]. Overall, viral antagonism is affected by extraneous factors, but also cellular PM as well as vesicular TLRs that could plausibly also have mutations leading to a sensitised and/or delayed immune system response dependent on the homeostatic function of IFN proteins. For example, in this review (n=5/1288) individuals were indicated to have autosomal recessive (AR) disorder. These may result from deficiencies in the genes involved in IFN regulation (OAS1/OAS2/RNASEL), with type II IFN in vitro able to upregulate expression of OAS1/2/3 in the myeloid cell lineage required to synthesise IFN through nuclear transcription of IFN and viral antigen presentation [59,60]. This one project further clarifies, in a subset of multi–inflammatory syndrome associated disorders in children (MIS–C), without COVID–19 pneumonia, but with antibodies to SARS–CoV–2 that mononuclear phagocyte function could rely on IFN signalling during pathological disorders [59].

The last key protein to be considered, ISG15, derived through the translation of the IFN–stimulated gene 15 (ISG15), is an intracellular/extracellular protein described as ”ubiquitin–like” [61]. The protein, ISG15 has only been found in vertebrates and is induced by a range of cellular–associated injury or infection (bacterial/viral) factors and can initiate cytokine release (e.g., IL–1β, retinoic acid), during hypoxia or DNA damage induced by each of the type I/II/III IFNs [61]. The function of ISG15 in relation to immune cells was described some years ago to direct 3 cellular factors. Firstly, it can increase stimulation of monocyte cytotoxicity, secondly stimulate type II IFN synthesis, thirdly, induce NK cell maturation and finally DC maturation. This variability in function remains largely unknown as to the mechanism of ISG15 exocytosis; although it is also considered that ISG15 is localised in neutrophil vesicle exosomes in TLR3–activated endothelial cells during apoptosis [61]. Other authors ascertain that ISG15 can bind to the leukocyte function antigen (LFA–1,) and can induce IL–10 known to affect both NK and T cell differentiation, but also is induced by type I IFNs. The gene ISG15 has two IFN–stimulated response elements (ISREs) in its promoter area that bind to IRF3/9 ISRE. Of these, IRF9 interacts with STAT1/2 to form the ISGF3 complex that induces ISG nuclear transcription, although IRF3 also complexes, however, the other IRFs (e.g., IRF4) can also induce ISG15 translation [61,62].

3.5. Errors in Interferon STAT Pathway Signalling

Initially, four errors in STAT1 signalling were defined to be genetic factors affecting protein production and immune system function. These were defined as follows: “AR complete” STAT1 deficiency, along with “autosomal dominant (AD)”, but also “partial”, along with “gain of function (GOF)” and observed in pathological reports (n=6) in children [85].

During 2006, errors in TYK signalling emerged when one patient was observed to have recurrent viral and mycobacterial infections along with increased levels of IgE susceptible to bacterial staphylococcal infections. In 2015, other cases emerged (n=7) indicating the IFNAR1 could be downregulated, but that 2 key cytokine receptors (IL–10R2 and IL–12Rβ1) were affected, with reduced expression of the IFNLR subunit affecting both IL–12 and IL–23 receptors during mycobacterial infection [90,91]. Conversely, isolated reports from 2015 into chronic mucocutaneous candidiasis (CMC), evidenced mutations in STAT1 to be independent of STAT3 affecting T_H17 cell differentiation producing IL–17 [92]. During 2020, only the second report of an individual case reported from a family with a heterozygous deficiency for the type I IFN receptor (IFNAR2) during a similar clinical pathology to haemophagocytic lymphohistiocytosis (HLH) occurred. This indicates that type I IFN–α does affect NK degranulation and function as well as controlling inhibition of type II IFN. Interestingly, the same donor cells were used in vitro to confirm that STAT1 phosphorylation is required for IFN signalling. This project noted that IFN signalling did not occur in monocytes by flow cytometry with type I IFN gene transcripts abrogated nearly completely (RSAD2, IFI44, ISG15, SIGLEC1, CXCL10, IFI27), with type II IFN regulated genes observed [93]. Therefore, it could be considered given the scarcity of reports prior that further research would be needed. Summary reviews in 2020 detail the complexity of errors in IFN signalling occurring affecting type I/II IFN signalling through gamma activated sequences (GAS) causal in delivering an effective immune response to infections and cell cycle regulation in cancer through adaptive T cell phenotypes [94]. The role of type II IFN cannot equally be understated as 3 types of IFN regulate and signal through STAT proteins.

More recently, reports indicate that TLR3 deficiencies in people may occur as an AR disorder found during Influenza infection [95]. Moreover, in 2020, it was seen that the function of STAT1 in monocytes could display a dual role of abrogating or reducing type II IFN–γ and type I IFN–α function during infections. These can result in serious complications immunologically, by LOF of monocytes, with recurrent infections independent of type III IFN–λ [96]. More recently, within the Shigella bacterial species outer surface protein C (OspC) member, OspC2 inhibition of type III IFN–λ1 synthesis was observed during infection [97]. In 2021, one report discovered through Enterovirus infection that deficiencies in cytoplasmic TLR3 together with a RIG–I like receptor, named Melanoma differentiation–associated protein 5 (MDA5), may explain that activation of TLR3 is required for endosomal sensing type I/III IFN and MDA5 is required for cytoplasmic pattern recognition independently [98]. These were interesting observations.

Deficiencies in many STAT proteins affect all aspects of an effective immunological response. Through single–cell RNA sequencing (scRNA) experiments, the STAT2 deficiency recently (n=23) was quantified further elucidating the relationship between IFNAR2 and STAT1/STAT2 IFN signalling. There were indications STAT2 deficiency results in loss of sensitivity to type I IFN. Gene transcripts at a single cell level showed that STAT2 deficiency affects effector memory (T_EM) cells with reduced gene transcripts (MX1, IRF9, USP18 and ISG15), observed concurrently with three others (STAT1/IRF1/ICAM1), that could affect classical monocyte response IFN signalling and adhesion during viral inflammatory disorders like severe Influenza, SARS–CoV–2, Enterovirus, but also Herpes Simplex virus (HSV–1) [80,99]. On the other hand, STAT3 deficiencies were also initially described as hyper–immunoglobulinaemia E in 1966. The protein, STAT3, was suggested as a factor during sporadic cases in individuals (n=98) of another rare AD disorder (Job’s syndrome) characterised by dermatitis and increased serum IgE. In this instance, IL–6 stimulation resulted in less CCL2 synthesis by leukocytes was suggested [100]. Therefore, below is shown the role of STAT3 in the immune system (see Figure 3).

Figure 3. STAT3 Protein role in immune system and cancer. Depicted are positive (green half of the circle) and negative (red half of the circle) effects exerted in the shown immune cells.

Figure 3. STAT3 Protein role in immune system and cancer. Depicted are positive (green half of the circle) and negative (red half of the circle) effects exerted in the shown immune cells.

Therefore, STAT1 signalling was examined in individuals with GOF or overactive STAT1 signalling to examine the role in diagnosed CMC individuals (n=8) [92]. Fungal and T_H17 cell immune response during recurrent infection remains unknown with clarification on DCs examined further. In 2023 DC analysis, through comparison of monocyte–derived DCs (moDCs) to tolerogenic DCs (tDCs), it is surmised that tDCs may express less immune cell checkpoint regulatory proteins (CD80, CD83, CD40); whilst moDC phenotypes expressed other inhibitory receptors like programmed death–ligand, PD–L1 [101]. However, the dual activity action of PD–L1 with the T cell immunoglobulin (Ig) and mucin domain–containing protein (TIM3) was characterised as a receptor expressed on both T cell types (CD4 ⁺/CD8⁺) producing type II IFN with both considered checkpoint proteins remaining a target of cancer therapeutic development [102,103].

3.6. Other Types of Interferon Regulation Pathways

The other 3 crucial STAT proteins (STAT4/5/6) remain comparatively recently investigated. As recently as 2021, other authors concur that STAT4 has not been extensively examined and remains comparatively unknown. The considered role of STAT4 is that it is expressed constitutively by haematopoietic cells (HSPCs), including both NK/T cells and is consistent in health and disease [104]. In 2020, STAT4 was clarified to be encoded by a further two gene transcripts (α/β), with the STAT4α subunit able to induce cellular production of more type II IFN; whereas the STAT4β subunit could better respond to IL–12 stimulation [105]. Other reviews ascertain that STAT4 is a pertinent protein as well as a relevant potential modulator of tumour suppression during hepatocellular carcinoma (HCC), but also correlates with serum hepatitis B antigen levels (HBsAg). An additional role in AI diseases (Sjögren’s syndrome (SS), Systemic Lupus Erythematosus (SLE), Psoriasis, Type 1 Diabetes 1 (T1D), Rheumatoid Arthritis (RA)), as well as both asthma and atherosclerosis, is suggested but discussed elsewhere [105,106,107]. Of the last two STAT proteins (STAT5), conversely is essential for NK cell development and has two types of protein domains [49]. This was shown comparatively recently utilising mouse cytomegalovirus (MCMV) infection in vitro of human cells. Expression of STAT5 was observed as upregulated on memory NK cells rather than naïve NK cells [108]. Furthermore, this was induced by IL–12 dependent on two cytokines (IL–2/IL–15) to produce granzyme A, with the possibility that the apoptotic PI3K pathway could be affected [108,109]. However, 2 subunit proteins of STAT5 possess varying functions. Overexpression of STAT5A in vitro with type I IFN–β stimulation of CD4⁺ T cells was seen to suppress PD–1 induction, in effect regulating other coinhibitory receptors [110]. In comparison, STAT5B deficiency has been observed to produce reduced counts of T_REG cells with STAT5A unchanged [111]. Furthermore, STAT5B deficiencies could manifest during lymphopenia together with reduced γδ T cells, as well as NK cells [111]. Deficiency of STAT5B in individuals has been associated with other AI diseases, like idiopathic arthritis, thyroiditis, and thrombocytic purpura, with the role of T_REG cells unknown [108,109]. Lastly, the dimer STAT6 can be activated by phosphorylation and is considered to transduce signals from Mϕ maturation factors, (IL–4/IL–13), alongside B cell–driven maturation, and Ig subtype maturation in germinal centres [49]. STAT6 can be activated independently by viruses, but also recruits APCs and T cells playing a part in innate immunity during allergic conditions, and immunity to helminthic parasites during TH2 cell–driven responses [112]. The relevance of other genes translated into extracellular cytokine–like proteins induced by type I IFN, like ISG15, is of consideration. During deficiency, it could be seen that the encoded protein appears to play a role in regulating type II IFN mycobacterial immune responses and is expressed in acute arthritic conditions [86]. The overall role of STAT proteins is shown below (see Figure 4).

Figure 4. Protein and Cytokine STAT Protein Interactions Summary known today.

Figure 4. Protein and Cytokine STAT Protein Interactions Summary known today.

4. The Role of Type I/II/III Interferon Signalling Since Discovery

4.4. Interferon and Immunotherapy Regulation in Cancer

Interferons play roles in many pathologies. Both type I/II IFNs have long been considered to be immune cell regulatory affecting both cell cycle and cancer cell proliferation, with partial protective roles during tumorigenesis through expression of PD–L1, whilst tissue cells produce a suppressive cytokine IL–10, but also a metabolite indoleamine–pyrrole 2,3–dioxygenase (IDO1/2). The regulatory effects of IFN rely on complex interactions with metabolic and cytokine factors affecting immune cell function (see Figure 5).

Figure 5. The Role of Type I Interferon in the Immune System.

Figure 5. The Role of Type I Interferon in the Immune System.

Some of these include tryptophan and kynurenine regulating cellular metabolism differentially in immune cells like Mϕ (M1ϕ/M2ϕ), as well as activating killer cytotoxic T cells expressing CD8⁺. Effector immune cell function relies on the production of perforin, granzymes and other cytolytic enzymes from both T_C/NK cells in the tumour microenvironment (TME) where other cell cycle proteins are factors [43]. Other reviews ascertain categories of therapeutics undergoing clinical trials targeting type I IFN pathways as TLR agonists, STING agonists, chemotherapeutics, oncolytic viruses and cancer–targeted drugs [133]. In contrast, overexpression of IRF7 proteins also affects cancer and acute myeloid leukaemia (AML) progression [134]. Similarly, inhibition of other vascular endothelial cell adhesion molecules (VCAM1/VLA–4) may reduce intracerebral invasion during AML in vivo [134]. Before 2020, it was known that type II IFN–γ affected an immune cell regulation checkpoint, PD–L1, as well as IDO1/2 and may inhibit T cell activity in tumours through STAT1 with upregulation of IRF1, as well as degradation of tryptophan and NK cell suppression. It is considered that the T cell response is determined by the concentration of type II IFN–γ, within the TME, aside from Mϕ phenotypes and tumour–associated antigens (TAAs), as well as type I/III IFNs unknown to date [43]. But also, that escape from type II IFN immune cell detection can regulate tumorigenesis [43,133,135].

5. The Role of Interferon during SARS–CoV–2 induced COVID–19 in 2023

5.1. Introduction to SARS–CoV–2 Structure and Interferon Regulation

The SARS–CoV–2 viral protein domains consist of protein domains that include spike (S1/S2), membrane (M), nucleocapsid (N) and envelope (E) protein domains encoded by and 16 non–structural proteins (NSP1–NSP16) with differing detailed host roles. The first encompasses a receptor binding domain (RBD) that has an affinity to the human cell receptor angiotensin–converting enzyme (ACE2) receptor. These are depicted below (see Figure 6).

Figure 6. SARS–COV–2 Genome Structure.

Figure 6. SARS–COV–2 Genome Structure.

The first NSP (NSP1), lyses host mRNA affecting type I IFN signalling through STAT proteins. The last NSP (NSP16), towards the 3’ end of viral RNA is followed by a variety of structural/accessory proteins encoded by open reading frames (ORFs). Many NSPs are defined and end with a cleaving methyltransferase enzyme at NSP16 (2ʹ–O–MTase) [136]. The latter enzyme is conserved in a viral pocket known as the S–Adenosyl–L–Methionine complex, activated by joining NSP10, forming the 2’–O–Methyltransferase enzyme complex. The resulting methyl group (–CH3) transfer occurs to the 5’ end of the +ssRNA VP upon activation. Moreover, specific ORFs (e.g., ORF6) encode other proteins affecting IFN signalling through STAT1/STAT2 and other membrane proteins as above [137,138,139]. The –CH3 group is transported from S–adenosyl–L–methionine pocket formed after reacting with the S–adenosyl molecule and L–methionine amino–acids to NSP13/NSP14 before binding to an NSP16 effector protein. Each of NSP13–16 as well as ORF6 were indicated to suppress IFN production through STAT1 [138,140,141,142]. Below is shown the NSP and ORF function characterised for SARS–CoV–2 (see Figure 7 and Table 1).

Figure 7. SARS–CoV–2 Non–Structural Protein (NSP) Function.

Figure 7. SARS–CoV–2 Non–Structural Protein (NSP) Function.

Table 1. SARS-CoV-2 Open Reading Frames (ORF).

Table 1. SARS-CoV-2 Open Reading Frames (ORF).

These can have implications upon adaptive immune responses with lesser or greater incidence of moderate to severe disease [143]. The effective regulation by IFN products play a major role in anti–viral defence [144]. As above, SARS–CoV–2 proteins (e.g., ORF3a, ORF9b and ORF10) perform a role in modulating type I/III IFN mediated immune responses through inhibiting nuclear transport of IRF3, NF–κB and STAT polymers, leading to downregulated expression of a variety of IFI genes [145]. Type I IFN is described as critical to regulating the activation and recruitment of neutrophils [146]. Indeed, neutrophils may reduce IFIT3 translation leading to a reduction in IRF3 phosphorylation [147,148]. Similar events occur in RSV and other infections [149]. Each virus synthesises NSP1 inhibiting translation of type I and type III IFN–encoding genes leading to stimulation or inhibition of IFN receptor activity (e.g., IFNAR2); whilst RSV translates NSP2 to suppress responses as such [150]. As above, RSV activates Rab5a host cell proteins to downregulate the activation of type III IFN signalling cascades [151].

As above, SARS–CoV–2 ORF9b impairs type I IFN responses specifically through receptors but also intracellular enzymes (e.g., IκB kinase (IKK)–related kinases (IKKα/β/γ), as well as nuclear transcription factors (e.g., TFs, NF–κB). These can activate PRR proteins localised near mitochondria, namely, RIG–I and MAVS, usually resulting in robust IFN expression [152,153]. Other signalling pathways affected through type I IFN–α and IFNAR1/2 can result in homeostatic signal transduction through STAT proteins including cytokines (e.g., transforming growth factor (TGF–β) and TNF–α).

During chronic COVID–19, the rate of increase in cytokine synthesis can therefore affect cytolytic/cytotoxic NK/T cell function alongside T_H cell recognition of peptide antigens [1,154,155,156]. Moreover, chronic viral, bacterial, fungal or oncological pathology can involve the inhibition of both innate or adaptive type II IFN–γ synthesis together with significant inhibition of the lesser understood β2 integrin (CD18) by NK cells around vascular endothelial cells [1,43,157]. Sixteen NSPs are translated that can directly suppress the immune–stimulatory action of type I IFN and type III IFNs through ISGs [158,159].

6. The Four Types of Type III Interferon during Health and Disease

6.4. Other Factors in IFN Signalling

Above, many of the relevant protein factors that can be stimulated by IFN have been outlined. However, other proteins transcribed and translated also play a role. These include IFI27, encoding IFI27 proteins (122 amino–acid hydrophobic protein, MW 12kDa), next to IFI6, both present within the mitochondrial membrane. These may contribute towards cellular IFN sensitization and organelle permeability through modulation of RIG–I. For example, IFI27 was observed elevated in peripheral serum (Influenza, SARS–CoV–2 and RSV) during infection [228,229]. The proposed mechanism is that IFI27 can impair RIG–I before binding to MAVS [229]. Remarkably, the same research group showed an RNA analogue, poly (I:C), bound to IFI6 localising with RIG–I protein. In this case, it was shown in cell line deficiency in vitro that two type III IFN gene transcripts (IFN–λ2, IFN–λ3) were upregulated with STAT gene transcripts and ISGs (IFIT/IFITM and OAS). Each of these gene classes is required to be transcribed and translated for IFN synthesis and secretion to occur [228]. Cell lines infected by either SARS–CoV–2/Influenza in cells without IFI6, in comparison to controls, could be observed to reduce viral replication with other type I IFN gene transcripts (ISG15/IFIT1) silenced [228]. The role of ISG15 protein remains unclear. In ISG15 deficiency some individuals show enhanced anti–viral immune responses or similarities with other disorders. It can be considered that ISG15 is a regulatory protein [58]. As an ubiquitin–like protein (Ubl), ISG15 can be covalently linked to substrates either intracellularly, via a cascade of E1, E2, and E3 enzymes, or secreted, so termed “ISGylation”. However, another endogenously produced metabolite, retinoic acid A metabolised from Vitamin A, and found at high levels in the gastrointestinal (GI) tract may play an as yet unknown role in IFN subtypes regulation. Retinoic acid was seen to induce IL–10 from T_REG cells in the gastrointestinal (GI) tract where it is present at higher concentrations [230]. Research in vivo in 2014, indicated that stimulation of naïve T cells (T_N) can produce IL–10; but also in vivo, retinoic acid primes DCs in the lamina propria (LP) to express CD103 and synthesise retinoic acid [230].

Table 2. Genetic Regulation during Interferon Signalling.

Table 2. Genetic Regulation during Interferon Signalling.

6.4. Interferon from Early Clinical Trials to Licensing as a Therapeutic

Early research, during and published towards the end of the 1969 Influenza (H2N2) pandemic investigated the efficacy of a nasal spray (n=14,000), based on a small concentration of human leukocyte–produced IFN, with a calculated efficacy rate range (56.3%–69.2%), with age–group variations, in prevention of symptomatic disease (see Supplementary Materials). In the 20th century, other clinical trials evaluating the administration of PEG IFN–α therapies (n=168) indicate a restriction of HIV replication in individuals (n=168) with PEG thought to increase serum availability of IFN [231].

Currently, synthetic type I IFN–β derivatives (IFN–1β, IFNβ–1a, peg–IFN–β1a) are approved and licensed by the FDA and some also the EMA. These are used, and monitored, as therapeutics for relapsing–remitting multiple sclerosis (MS), considered to reduce inflammation and promote the repair of damaged neurons [232]. Type II IFN–γ is approved for the treatment of chronic granulomatous disease (CGD) [233]. Below are the current synthetic IFN therapeutics licensed for therapeutic use (see Table 3).

Fifty years later, during the 2009 Influenza (swine flu, H1N1) pandemic, the effects of type I IFN lozenges were examined (n=200) appearing to reduce severity and fever [234]. It was assessed then that IFN–based therapeutics may reduce Influenza severity significantly. Furthermore, prior Influenza (H2N2) exhibited different strains that could be equally divided into IFN–positive and IFN–negative evoking strains (see Supplementary Materials). Therefore, SARS–CoV–2 variants may also differentially affect type I IFN (IFN–α/IFN–β) expression [235,236].

The scientific rationale could plausibly be IFN subtype specificity, with as yet unknown effects of type III IFN subtypes or others. Some results recommended synthetic IFN–α2b therapy for the treatment of COVID–19 disease [237]. Type I IFN–α2b was also observed to result in an early reduction of viral load in the upper respiratory tract [237,238]. Whilst a clinical trial in Iran indicated IFN–α treatment had encouraging results reducing COVID–19 mortality rate by more than 50% with early intervention reducing mortality [239]. In 2020, the University of Western Australia signified low–dose oral type I IFN (nose drops/mouth spray/ lozenges) may prevent severe COVID–19 (see Supplementary Materials). Furthermore, a clinical trial (n=2944) in China examined prophylactic administration of low–dose recombinant IFN–α2b also demonstrating similar protection of individuals during COVID–19 outbreaks [240,241]. With regards to type III IFN, an experiment in NHP involving a dosage of IFN–λ2 in vivo has so far denoted positive results in mitigating viral–induced disease [242].

Table 3. Current FDA licensed Interferon Therapeutics, adapted from, Deckers et al. [13]. Accessed on 16^th August 2023

Table 3. Current FDA licensed Interferon Therapeutics, adapted from, Deckers et al. [13]. Accessed on 16^th August 2023

Discussion

Limitations

Conclusion

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