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Relationship: 2497
Title
IFN-I response, antagonized leads to SARS-CoV-2 production
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Binding of SARS-CoV-2 to ACE2 leads to viral infection proliferation | adjacent | High | Not Specified | Arthur Author (send email) | Under development: Not open for comment. Do not cite | Under Development |
| Binding of SARS-CoV-2 to ACE2 in enterocytes leads to intestinal barrier disruption | adjacent | Low | Cataia Ives (send email) | Under development: Not open for comment. Do not cite | Under Development | |
| Binding of SARS-CoV-2 to ACE2 receptor leading to acute respiratory distress associated mortality | adjacent | High | Evgeniia Kazymova (send email) | Open for comment. Do not cite | Under Development | |
| Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation | adjacent | Moderate | Moderate | Arthur Author (send email) | Under development: Not open for comment. Do not cite | Under Development |
| Binding of SARS-CoV-2 to ACE2 leads to hyperinflammation (via cell death) | adjacent | High | Moderate | Allie Always (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | Moderate |
Key Event Relationship Description
The normal function of the host’s innate immune response to viruses is the expression of interferons (IFN) which in turn stimulates the expression of many interferon-stimulated gene (ISG) proteins with antiviral functions (Amor et al., 2020; Harrison et al., 2020). ISGs generally function to inhibit viral replication (Yang and Li, 2020). The SARS-CoV-2 antagonism of the IFN-I pathway delays or curtails the expression of IFN-I and ISG proteins. This results in the downstream event, SARS-CoV-2 production, increased. The increase in SARS-CoV-2 viral production can be measured as viral load, which can contribute to both transmission to new hosts and more severe disease. This KER details the specific ISGs that inhibit viral replication, and demonstrates the difference in how SARS-CoV-2 negates the function of these proteins or delays their expression compared to other viruses to successfully increase its numbers.
Evidence Collection Strategy
Evidence collection strategy for this KER uses the same logic as for other events and relationships in this AOP.
Evidence Supporting this KER
See below.
Biological Plausibility
The functional relationships between the upstream IFN-I antagonism and downstream increase in SARS-CoV-2 viral replication is biologically plausible via the suppression of IFN through interaction inhibition of the host pathway proteins by viral proteins. This in turn would lead to suppressing the expression of ISGs that have been demonstrated to inhibit replication. The effects of ISGs on viral replication has been demonstrated for several viruses (Schoggins et al., 2011). SARS-CoV-2 replication may be impacted by different ISGs than other families of viruses. A gain-of-function analysis evaluating the impacts of ISGs on SARS-CoV-2 viral replication (Martin-Sancho et al., 2021) showed that a specific subset of ISGs when stably overexpressed in cultured human cells infected with SARS-CoV-2 controlled viral infection, including RNA binding proteins that suppress viral RNA synthesis and ISGs inhibiting viral assembly and egress. Therefore, the lack of these ISGs due to antagonism of the IFN-I pathway leads to increased viral replication.
Empirical Evidence
Evidence from patients who contracted COVID-19 supports the relationship between IFN antagonism and viral production:
- Busnadiego et al. (2020) found that different IFNs upregulate ACE2 to differing degrees, but all IFNs elevated ISGs and inhibited SARS-CoV-2 replication in a dose-dependent manner. Some people have developed autoimmunity toward their own IFN proteins (Bastard et al., 2021; Lopez et al., 2021). They produce autoantibodies that block even exogenously administered IFN, and this has resulted in more severe COVID-19 disease in these patients. Also, Zhang et al., (2020) note inborn errors (genetic mutations) in IFN-I immunity that result in severe COVID-19.
- Cheemarla et al. (2021) used patient nasopharyngeal samples and airway epithelial organoids. COVID-19 patient samples had upregulated ISG RNAs in the upper respiratory tract. SARS-CoV-2 replicated exponentially when unchecked, doubling in 6 h. ISGs rose with viral replication and peaked as viral load declined. Rhinovirus infection before SARS-CoV-2 exposure caused ISG induction to accelerate and stopped SARS-CoV-2 replication, while blocking ISG induction increased viral replication.
- Hadjadj et al. (2020) report a phenotype in severe COVID-19 patients with no IFNβ, low IFNα, persistent blood viral load and exacerbated inflammatory response.
- Hatton et al. (2021) use human nasal epithelium differentiated at the air-liquid interface (ALI) cultures (organoids) to show delayed induction of IFN-I and -III in SARS-CoV-2 compared to influenza A virus. They found that exogenous IFNs administered pre-exposure or early in infection controlled SARS-CoV-2 replication.
Uncertainties and Inconsistencies
Schuhenn et al. (2022) found that differential immune signatures of IFNα subtypes suppress SARS-CoV-2 infection by treating primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection. The most effective antiviral subtype was IFNα5, against both in vitro and in vivo infected mice, and additive effects with the antiviral drug remdesivir in cell culture.
Rouchka et al., (2021) found that there is not only wide variation in nasopharyngeal viral loads in COVID-19 patients early in infection, but also that viral loads were strongly correlated with host gene expression associated with IFNα-inducible cellular antiviral response genes (ISGs). Also, patients with mild symptoms were often found to have a higher viral load than those with severe disease, indicating lack of correlation between susceptibility to severe disease, and susceptibility to viral replication.
In review articles, Yang and Li (2020) and Samuel (2023) discuss the relationship between the IFN antiviral response and viral replication. Yang et al. focus on ISGs with multiple mechanisms that inhibit viral replication by sensing, degrading, or repressing expression of viral RNA. These ISGs may use a variety of co-factors, which indicates the highly complex nature of the type I IFN response. Samuel et al. report that overall genetic variability of both SARS-CoV-2 and the human host affect the IFN response, and viral replication is in turn sensitive to variation in IFN antiviral action.
These studies point out inconsistencies in quantity and type of IFN expression or administration in patients and COVID-19 disease outcome, but confirming the link between IFN-I response and viral replication. There is uncertainty in the fact that several IFN-I pathway components have been variously implicated. Because many different IFN subtypes and subsequently many different ISGs and cofactors may be involved, not only the specific repertoire of ISGs expressed may differ among individuals, but also the quantity of each ISG may influence viral production.
Known modulating factors
IFN has been the subject of studies for potential therapeutic value to enhance the antiviral response. However, IFN administered too late, in the inflammatory stage (post-symptom onset), led to long-lasting harm and worsened disease outcome (Sodeifian et al., 2021). Therapeutics used in COVID-19 patients tend to target either the ACE2 binding, downstream inflammatory response, or viral replication via inhibition of the viral RNA-dependent, RNA polymerase to block viral genome replication (i.e., Remdesivir) (Narayanan and Parimon, 2022). No other therapeutics were found to be relevant to this KER, i.e., specifically targeted to IFN components or ISGs leading to supressed viral replication (see WHO 2021 and Terracciano et al., 2021).
It is known that per- and poly-fluorinated alkyl substances (PFAS), air pollutants, and other environmental chemicals are implicated in SARS-CoV-2 susceptibility and COVID-19 disease severity (Marques et al., 2022; Nielsen et al., 2021; Xu et al., 2021). However, it is currently unknown whether or how the mechanisms of action are related to blocking IFN components or ISGs, leading to viral replication.
Genetic factors are of importance to this KER: Autoantibodies against IFN, as noted, block even exogenously administered IFN, resulting in more severe disease (Quarleri and Delpino, 2021; Bastard et al., 2021; Busnadiego et al., 2020; Lopez et al., 2021). There are 15 known clinically recessive and inborn errors of type I IFN immunity (Zhang et al., 2022). Four of these including X-linked recessive TLR7 deficiency, and autosomal recessive IFNAR1, STAT2, or TYK2 deficiencies were found in children with moderate to critical pneumonia due to COVID-19. Zhang et al. (2022) also reported enhanced SARS-CoV-2 replication measured as expression of viral nucleocapsid (N-protein) in STAT2- and TYK2-deficient patients’ cells.
Quantitative Understanding of the Linkage
The current quantitative understanding of this relationship is described below.
Response-response Relationship
Busnadiego et al., (2020) found an inverse, linear relationship between IFNβ or IFNλ1 concentration and viral titer, measured as plaque forming units (PFU) in primary human bronchial epithelial cells (BEpCs) differentiated and grown at an air-liquid interface (ALI). However, the upstream event of IFN antagonism is not represented by administered IFN but by antagonism of the IFN response, and does not answer the question of what dose of antagonist results in increased viral replication in a host system, where viral replication is not normal biology. Comparatively, difference in IFN expression between cells infected with influenza A virus vs. SARS-CoV-2 showed significantly higher IFNβ and IFNλ1 for influenza at both 6 and 24 hours post-infection, but this was not tied to relative viral production (Hatton et al., 2021).
The key event of IFN-I response antagonism encompasses a broad range of stressors and targets: 1) viral proteins interacting with pathway proteins leading to IFN expression, 2) the IFN subtypes that induce the expression of ISGs, and 3) the variation in type and amount of ISGs expressed, which also varies with cell/tissue type. Viral replication related to these factors is also dependent on the dose of virus to which the individual host is exposed and the genetic make-up and overall condition of that individual. These factors may explain the variable results in IFN dose-viral production response determination, and why the actual response-response relationship for this KER, between the viral dose resulting in antagonism and viral replication increase, have not been determined. Saheb Sharif-Askari et al., 2022 concluded that more mechanistic studies are needed to quantify the amount of early IFN required to overcome SARS-CoV-2 antagonism and prevent replication. Polyinosinic:polycytidylic acid [poly(I:C)] is a synthetic analog of double-strand RNA (dsRNA) that can stimulate IFN production. The use of poly(I:C) administered before and during SARS-CoV-2 infection in mice increased ISGs and lowered viral loads (Tamir et al., 2022) but was administered at different time points rather than at different dose concentrations. Poly(I:C) dosing may be a potential method to quantify the IFN stimulation needed to overcome SARS-CoV-2 antagonism.
Time-scale
The viral entry MIE and early KEs coincide with the time from exposure to symptoms, within which are the latent period, or time from exposure to infectiousness, and the serial interval, or the time interval between the onset of symptoms in the primary (index) and secondary (contact) case. Pre-symptomatic transmission occurs from about 3 days after exposure to symptom onset at about day 5-7, viral load peaks from about day 5-7 to day 9-11, and the host can remain infectious to symptom clearance or death (Byrne et al. 2020). IFN administered prior to exposure or within the latent period window can stop replication (Sodeifian et al., 2021). In a study using a primary nasal cell model (differentiated at air-liquid interface), the virus did not proliferate beyond the limit of assay detection if treated with IFN beta or lambda 16 hours prior to infection, and virus was significantly reduced in cultures treated 6h post-infection compared to untreated cultures. Treatments 24h post infection were not significantly different from untreated controls for either type of IFN (Hatton et al., 2021). This would suggest that viral antagonism of IFN occurring during the first 24h post viral entry allows viral loads to be generated likely concurrently, reaching transmissible levels within 72h post viral entry.
Known Feedforward/Feedback loops influencing this KER
RIG-Like Receptors (RLRs) including MDA5 are Pattern Recognition Receptors (PRRs) that recognize Pathogen-Associated Molecular Patterns (PAMPs) like viral RNA and start signalling cascades to express IFNs. These PRRs and other proteins in the pathway, including STAT1 and STAT2 involved in transcription of the ISGs, are also regulated by IFN, and therefore are themselves ISGs (Yang and Li, 2020). As RNA from most viruses is detected, signalling to express more ISGs increases, and more IFN is expressed (Michalska et al., 2018). However, SARS-CoV-2 inhibits these and other components of the IFN pathway to delay expression of ISGs, and viral production goes unchecked, actually disrupting the normal antiviral positive feedback loop. In fact, SARS-CoV-2 can co-opt another ISG, interferon-induced transmembrane protein 2 (IFITM2), for efficient replication in human lung, heart, and gut cells (Nchioua et al., 2022), which might also be considered a positive feedback loop (i.e., the more IFITM2 is expressed, the more the virus replicates). However, IFITM2 and 3 have also shown antiviral activity toward SARS-CoV-2 (Shi et al., 2021), therefore the conflicting results require more research.
Domain of Applicability
Sex. In a large study modelling URT viral load dynamics drawn from measurements in 605 human subjects, variations over 5 orders of magnitude in URT viral load from the time of symptom onset was not explained by age, sex, or severity of illness. Additionally, these variables did not explain modelling results concerning control of viral load by immune responses in the early (innate) or late (adaptive) phases (Challenger et al. 2022). Other sources also support that rate of infection and measured viral load does not differ by gender (e.g., Arnold et al. 2022; Qi et al. 2021; Cheemarla et al. 2021). This evidence suggests that the components of the early antiviral response are not influenced by gender specific differences such as sex hormone levels or sex chromosomes to the extent of affecting viral load.
Life Stage. To apply to this KER, studies would need to show differences in IFN or ISGs correlated with viral load and differing by age. Saheb Sharif-Askari et al. (2022) reported that children had higher expression of IFN-I and associated ISGs than adults, but did not measure viral loads. Euser et al. (2021) found that SARS-CoV-2 viral loads increase with age, but did not measure IFN or ISGs. Literature that connects the two factors for age in humans was not found.
Taxonomic. No non-mammalian vertebrates have been found to become infected with SARS-CoV-2. Many mammals have tested positive and several are known to shed and transmit the virus, however the prevalent aspects of non-human mammalian infection and transmission found in the literature are ACE2 binding capacity and measures of viral load. For the few species for which IFN is mentioned in the literature (Mostaquil et al., 2020; Rui et al., 2021; Hameedi et al., 2022), the potential IFN antagonism is not linked to resulting increase in viral replication, except in the golden hamster, Mesocricetus auratus (Hoagland et al., 2021). The hamsters were Infected with SARS-CoV-2 resulting in high levels of virus in the upper and lower respiratory tracts and an IFN-I response that was not sufficient to control COVID-19 progression. Direct contact resulted in inoculated hamsters transmitting the virus to naïve hamsters. When intranasal IFN-I was administered to the hamsters, viral replication was reduced and transmission was prevented (Hoagland et al., 2021). For bats, IFN and ISGs are constitutively expressed and therefore may contribute to immune tolerance and lack of replication of SARS-CoV-2 in many bat species (Irving et al., 2021). Differential susceptibility and viral shedding has been found across mammalian species (EFSA/Nielson et al., 2023), and it is likely that differences in IFN-I response may be involved. Therefore, more studies are needed in diverse taxa to assess the tDOA for IFN-I antagonism leading to increase in SARS-CoV-2 replication across the potentially susceptible species.
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