Innate immunity, therapeutic targets and monoclonal antibodies in SARS-CoV-2 infection

Introduction

SARS-CoV-2 is a member of the a/ß-Corona family, characterized by its enclosed, spherical structure. It possesses a non-segmented, positive single-stranded RNA (ssRNA) genome of approximately 30 kilobase pairs (kbp) shielded by the helical capsid made by the nucleocapsid (N) protein and enclosed by an envelope protein (E). The structure of the SARS-CoV-2 protein contains envelope (E) and membrane (M) proteins that help in virus assembly, and spike (S) protein allows the virus to enter the hosts. Among these E, M, and S proteins, the S protein size is too large (180–200 kDa) and appears like a crown (Lan et al., 2020) (Fig. 1A). Among seven viruses (SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1) associated with typical respiratory infections, four (HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1) cause harmless seasonal infections, while the remaining three SARS-CoV, MERS-CoV, and the recently identified SARS-CoV-2 pose a higher risk of lethality. SARS-CoV emerged in China in November 2002 and infected nearly 8,100 individuals, with a mortality rate of 9.6%, resulting in 774 deaths. MERS-CoV, transmitted from camels to humans, appeared a decade later, spreading globally over six years, infecting 2,143 individuals, and resulting in 750 deaths with a mortality of 34.9% (Marschalek, 2023).

In 2019, the SARS-CoV-2 emerged and rapidly spread across the globe. The total confirmed cases of SARS-CoV-2 have surged to a staggering 777.35 million, underscoring the extensive reach of the virus (https://covid19.who.int/). Since the beginning of the COVID-19 pandemic, several new variants of concern have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). These variants are associated with increased transmissibility and virulence. Currently, the World Health Organization (WHO) is tracking various SARS-CoV-2 variants, which include a variant of interest (VOI): JN.1, and variants under monitoring (VUMs): JN.1.18, KP.2, KP.3, KP.3.1.1, LB.1, and XEC. The COVID-19 pandemic and emerging SARS-CoV-2 variants highlight the immense challenges and emphasize the urgent need for ongoing global efforts to mitigate its impact and prevent further losses (Zeyaullah et al., 2021). Many promising strategies demonstrating significant effort in the fight against SARS-CoV-2 are being investigated although challenges remain (Khan et al., 2024; Khan et al., 2021b; Khan et al., 2022; Sharma et al., 2023; Zeyaullah et al., 2023; Zhou et al., 2021). However, SARS-CoV-2 has developed several ways to avoid or circumvent immune mechanisms, allowing it to infect and spread throughout the host successfully (Foxman, 2024; Zaidi & Singh, 2024).

The innate immune response plays a crucial role in defending against SARS-CoV-2. Its primary functions include limiting viral entry, blocking viral translation and replication, and preventing the release of new infectious virions. Additionally, it facilitates the identification and elimination of infected cells while accelerating the development of an adaptive immune response (Hoffmann, Schneider & Rice, 2015; Sievers et al., 2024). However, in severe COVID-19 cases, an overactive immune response can lead to excessive inflammation, significantly impacting disease progression. A key component of this inflammatory response is the interferon cascade, which plays a critical role in SARS-CoV-2 infection (Merad & Martin, 2020). In some individuals, cytokine release syndrome (CRS) occurs, characterized by an overwhelming cytokine surge that leads to acute respiratory distress syndrome (ARDS) and secondary hemophagocytic lymphohistiocytosis (sHLH) (Moore & June, 2020; Quan et al., 2020). To counterbalance this excessive inflammation, the innate immune system employs endogenous feedback mechanisms, utilizing cytokines such as IL-4, IL-10, IL-11, and IL-13 to promote an anti-inflammatory state.

The impact of COVID-19 varies significantly among patient populations, with immunocompromised individuals (cancer patients, organ transplant recipients, individuals with HIV, autoimmune diseases, or immunosuppressive therapy) facing a heightened risk. Among solid organ transplant recipients, lung transplant recipients exhibit the highest fatality rate (Hall et al., 2022). Immunocompromised individuals are at higher risk for severe COVID-19 complications, with mortality rates increasing by 5 to 6% compared to the normal population (Liang et al., 2020; Wu & McGoogan, 2020).

Understanding the innate immune response and the pathways that can trigger SARS-CoV-2 viral infections is crucial for precise and targeted therapeutic approaches. The type-I interferon (IFN-1) system plays a critical role in the innate immune response. Dysfunctional early IFN-1 signaling is a key feature of severe COVID-19 and is linked to reduced viral clearance (Hadjadj et al., 2020). A diminished or absent IFN-α response often precedes clinical worsening and the need for intensive care, marking the most severe or critical cases that require invasive ventilation. These cases show significantly lower expression of six interferon-stimulated genes (ISGs), which define the IFN-1 signature, compared to mild to moderate cases with elevated IFN-α levels (Fraser et al., 2023; Zhang et al., 2021a). During the replication and transcription of the coronavirus genome, double-stranded RNA (dsRNA) is produced (Kindler, Thiel & Weber, 2016), which can be identified by RIG-I-like receptors (RLRs) such as retinoic acid-inducible gene I (RIG-I) and/or melanoma differentiation-associated protein 5 (MDA5) in the cytoplasm(Li, Liu & Zhang, 2010; Roth-Cross, Bender & Weiss, 2008). Alternatively, toll-like receptors (TLRs) in endosomes can also recognize dsRNA (Totura et al., 2015). The two-caspase activation and recruitment domains (CARDs) of RIG-I and MDA5 can interact with the mitochondrial antiviral signaling protein (MAVS)(Seth et al., 2005). A study highlights the interaction between SARS-CoV-2 and the host’s innate immune system, revealing how viral proteins play a role in evading immune defences (Lei et al., 2020). Patients with weakened immune systems, such as those with rheumatological conditions or lung transplants, often experience severe COVID-19 symptoms and prolonged hospital stays (Gianfrancesco et al., 2020; Heldman et al., 2021). Individuals with hematologic malignancies, face a heightened risk of SARS-CoV-2-related morbidity and mortality. This is due to immune deficiencies that hinder the prevention, treatment, and elimination of the virus (DeWolf et al., 2022). Data from previous studies suggests that some medications often used to manage immune-mediated inflammatory conditions, such as cytokine inhibitors, could help reduce the severity of COVID-19 (Fagni et al., 2021; Heimfarth et al., 2020). However, treatments like glucocorticoids and those targeting B-cells may negatively impact COVID-19 outcomes (Bruscoli et al., 2022; Fagni et al., 2021). Treatment options include neutralizing mAbs such as regdanvimab, teleseminar, and imdevimab, which specifically target the spike protein of SARS-CoV-2 to inhibit viral replication and reduce disease severity (Miguez-Rey et al., 2022). Among the other factors that manage the progression and severity of SARS-CoV-2 is vitamin D. The BsmI b allele and bb genotype have been linked to an increased likelihood of hospitalization due to SARS-CoV-2 infection, potentially due to the association of the b allele with reduced vitamin D levels (Aci et al., 2024). The insertion/deletion polymorphism of the endothelial growth factor (VEGF) gene, specifically the DD genotype and D allele, has been associated with vitamin D levels in patients with COVID-19 (Yigit et al., 2023). To manage SARS-CoV-2 infection, immunomodulatory therapies, such as corticosteroids and monoclonal antibodies, play a crucial role, especially in severe cases where immune dysregulation drives disease progression. Corticosteroids (e.g., dexamethasone, prednisolone) are particularly beneficial in cases involving hyperinflammation and cytokine storm, helping to reduce excessive immune activation and improve patient outcomes. As research continues, optimizing immunomodulatory interventions for different patient populations, especially those who are immuno-compromised, remains a critical area of focus.

The antibody-based interventions have paved the way for advancements in technology and production methods, ultimately creating more potent and promising therapeutic approaches in the form of mAbs as an important tool for pandemic preparedness. The target audience for this review will be scientists/clinicians/health workers and those interested to know more about the native immune response in SARS-CoV-2 infection and exploring potential treatments that target the viral proteins involved in these immune responses.

Search Methodology

In this review, we searched the literature on PubMed, Google Scholar, ScienceDirect, Google search engine, and Scopus by using the following terms COVID-19 immunity, SARS-CoV-2 immunity, innate immunity/COVID-19, innate immune response to SARS-CoV-2, SARS-CoV-2 protein/immune target, therapeutic strategy/SARS-CoV-2, monoclonal antibody in COVID-19 and COVID-19 therapeutic antibody. We also included reports from the Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO). The search terms were strategically broadened to ensure the inclusion of all relevant studies. Two authors independently screened the literature for reproducibility. Non-COVID-19 and non-English language studies were used as exclusion criteria.

Receptor-Ligand Interactions in SARS-CoV-2 Infection

SARS-CoV-2 are detected through their pathogen-associated molecular patterns (PAMPS), when bound to host cell pattern recognition receptors (PRRs) and elicit innate immune responses against them (Badia, Garcia-Vidal & Ballana, 2022; Takeuchi & Akira, 2010). PAMPs in viruses primarily include viral nucleic acids, such as ssRNA, dsRNA, unmethylated CpG DNA and viral proteins, which are recognized by the host immune system to trigger an innate immune response. The interaction between PAMPs and PRRs activates the innate immune responses in the form of upregulation of complement proteins, secretion of antimicrobial agents, cytokine signalling, activation, and recruitment of phagocytic cells like, macrophages and natural killer (NK) cells (Tosi & Immunology, 2005).

The S protein of SARS-CoV-2 interacts with ACE2, a critical regulator of the renin-angiotensin system, as a cellular entry receptor for the invasion of virus into human cells. The S1 protein consists of two domains: an N-terminal domain (NTD) and a receptor-binding domain (RBD). The RBD interacts with the peptidase domain of ACE2 using a receptor-binding motif (RBM), while the exact function of the NTD remains unclear, it might be responsible for recognizing specific sugar structures during initial attachment. This recognition could aid the transition of the S protein from perfusion to post-fusion conformation. Antibodies binding to specific epitopes on the NTD have been proven to hinder SARS-CoV-2 infection (Fig. 1B) (Jackson et al., 2022). SARS-CoV-2 activates the innate immune responses through PAMPs (like viral RNAs and oxidized phospholipids) and the infection was restricted to entry gates of the human body (Danladi & Sabir, 2021; Mihaescu et al., 2021). Cells containing NLRP3 (NOD-like receptor family pyrin domain-containing 3) inflammasome like macrophages, epithelial cells and endothelial cells are activated by SARS-CoV-2 through a NOD-like receptor family, helping in caspase-1 activation. Caspase-1 activation leads to the cleavage of proinflammatory cytokine IL-1 into its physiologically active IL-1β and IL-18. Additionally, TLR-3, -7, -8, and -9 receptors respond to viral RNA and trigger the NF-κB pathway that activate the pro-inflammatory cytokine cascade (Khan et al., 2021a; Lee, Channappanavar & Kanneganti, 2020). When SARS-CoV-2 enters the body, it binds to the ACE2 receptor, triggering conformational changes in the S1 subunit (Jackson et al., 2022). This is followed by the cleavage of S2 by cellular proteases such as TMPRSS2 or cathepsin L (Trougakos et al., 2021). This chain of events is detected by various host pattern recognition receptors (PRRs) (Diamond & Kanneganti, 2022). The TLR family, RIG-I-like receptors (RLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are the three main families of PRRs (Kanneganti, 2020). Activation of these receptors through aberrant signalling pathways leads to over-activation of inflammatory cytokines and chemokines. The diversity among the PRRs in the form of extracellular receptors like TLR and dectins, which detect the extracellular PAMPs, and intracellular receptors including RIG-1-like receptors (RLRs), NOD-like receptors (NLRs), AIM2-like receptors (ALRs), which recognize the intracellular PAMPs (Dawoodi, Rizvi & Zaidi, 2024). PAMPs can simultaneously bind to multiple receptors and other signalling pathways to drive extended cellular events including cell death (Franz & Kagan, 2017; Kagan & Barton, 2015). A deeper understanding of the pathophysiological mechanisms involved in innate immunity is crucial for developing effective preventive and therapeutic strategies against COVID-19. The main families of PRRs are summarized below.

Apoptotic cell-death and signaling during SARS-CoV-2 infection

Apoptosis-dependent host cell death is an essential intrinsic antimicrobial process that limits pathogen multiplication and propagation. Inflammatory reactions initiated by SARS-CoV-2 cause apoptosis, which kills host cells (Yuki, Fujiogi & Koutsogiannaki, 2020). Apoptosis is believed to be involved in the pathophysiology of COVID-19 because of severe cell injury and tissue destruction of lung, kidney, liver, pancreas, neurological as well as immunological system. It triggers the process aimed at further halting the infection, but excessive activation may lead to lung damage. The process of apoptosis can be initiated with both intrinsic and extrinsic apoptotic mechanisms. The death-inducing signaling complex (DISC), which contains Fas, Fas-associating protein with a novel death domain (FADD), and procaspase-8, is formed when extracellular ligands, such as Fas ligand (FasL), trigger cell surface death receptors (like Fas) and then activate them and activate caspase-8 (Kaufmann, Strasser & Jost, 2012). After that, it starts to activate caspase-3, which ultimately starts with an extrinsic apoptotic pathway. The intrinsic process (mitochondrial pathway) triggered by outside factors such DNA damage or cellular stress. Bak/Bax (BCL2 antagonist killer/BCL2 associated X protein) is activated in response to external stimuli, leading to the release of cytochrome C from mitochondria and the activation of caspase 9. Cell death of SARS-CoV-2 infected lung epithelial cells occur because of caspase 3 activation, which is initiated by activated caspase 9 (Yuan et al., 2023). Figure 2 illustrates the molecular mechanisms by which SARS-CoV-2 induces apoptosis in lung epithelial cells, leading to pulmonary injury. This process leads to the demise of infected cells, triggering an inflammatory response. A study reported a combination of in vitro, in vivo, and ex vivo models to validate the induction of apoptosis by SARS-CoV-2 and utilized MERS-CoV as a model to investigate the underlying mechanism responsible for virus-induced apoptosis (Chu et al., 2021). They discovered that the MERS-CoV infection’s proapoptotic mediators were tightly controlled by PERK (protein kinase R-like endoplasmic reticulum kinase) signalling. The displacement of PERK from the ER chaperon GRP78 (78 KDa glucose-regulated protein) led to its activation.

ER chaperon GRP78 plays a pivotal role in numerous cellular processes, such as guiding the translocation of newly synthesized polypeptides across the ER membrane, facilitating protein folding and assembly, directing misfolded proteins for ER-associated degradation (ERAD), regulating calcium homeostasis, and acting as a sensor for ER stress. The multifaceted functions of GRP78 underscore its significance in orchestrating diverse cellular activities within the ER (Wang et al., 2009). Additionally, it was found that the PERK signalling converged with the intrinsic or mitochondrial apoptotic pathway. The pathogenesis of both MERS-CoV and SARS-CoV-2 was caused by the inhibition of PERK signalling and the intrinsic apoptotic pathway. Lung damage by the SARS-CoV-2 infection was lessened by PERK signalling modification (Zhou et al., 2020). Studies have shown that SARS-CoV-2 proteins play a significant role in apoptosis induction in several ways (Yuan et al., 2023). It has been established that SARS-CoV-2 ORF3a functions as a viroporin, capable of forming an ion channel on the cell membrane. This disrupts intracellular homeostasis, which plays a role in apoptosis, and facilitates virus release. By cleaving and activating caspase-8 for the extrinsic route and cross-talking to the intrinsic pathway via truncated BH3-interacting domain (tBID), which results in the release of cytochrome c and activation of caspase-9, a different study shown that SARS-CoV-2 ORF3a may efficiently trigger apoptosis (Yuan et al., 2023). In addition, it has been shown that SARS-CoV-2 ORF7b causes TNF-dependent apoptosis in HEK293T cells and Vero E6 cells (Yang et al., 2021). Further investigation revealed that the intrinsic and extrinsic routes caused apoptosis in a variety of cell types, including T cells, vascular endothelial cells (ECs), macrophages, and alveolar type 1 and 2 cells (AT1s and AT2s) in the infected non-human primate lung. The results above are consistent with other research on the SARS-CoV-2-induced apoptosis in respiratory epithelial cells and ECs. In the animal model of SARS-CoV-2 infection, a significant portion of the renal tubular epithelial cells also undergo apoptosis, which results in acute kidney injury (AKI). Another immunological characteristic related to the severity of the SARS-CoV-2 infection is the decreased proportion of dendritic cells (DCs) in COVID-19 patients. DCs and monocyte-derived macrophages (MDMs) were found to harm mitochondria and caspase-3 activation-dependent apoptosis, which could be stopped by anti-IFN therapy (Li et al., 2022). Therefore, a possible treatment for SARS-CoV-2 infection involves blocking TNF- and its receptor. These data not only show how important apoptosis is in the pathogenesis of SARS-CoV-2 but also suggest a treatment strategy that focuses on apoptosis.

Activation and the secretion of cytokines in SARS-CoV-2 infection

Cytokine markers consist of a group of polypeptides signaling molecules capable of initiating and controlling numerous cellular biological processes through the activation of cell surface receptors. Recent research has demonstrated that SARS-CoV-2 is linked with the activation of innate immunity. Based on their biological effects, the cytokine superfamily can be categorized into several main families, including interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), chemokines, and transforming growth factor (TGF-β). Cytokines can further be classified into pro-inflammatory or anti-inflammatory subclasses. Interleukins such as IL-1, IL-4, IL-6, IL-7, IL-10, IL-12, IL-17, and IL-18 have been demonstrated to play a significant role in the body’s inflammatory response during SARS-CoV-2 infection (Hasanvand, 2022) and its main source are active macrophages and monocytes (Turner et al., 2014). Some important ILs in SARS-CoV-2 infections are described here.

cGAS-STING signaling pathway

The cGAS-STING signaling pathway is a critical component of the innate immune response that helps, detect and defend against viral infections and DNA pathogens (Ahn & Barber, 2019).The innate immune system is the body’s initial defence against invading pathogens (Akira, Uematsu & Takeuchi, 2006). It identifies specific patterns found in pathogens or damaged cells using PPRs, which include TLRs, Nod-like receptors (NLRs), RIG-I-like receptors (RLRs), and the DNA sensor cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Among these receptors, the cGAS-STING pathway, plays a significant role in the innate immune response to viral infections. Multiple lines of evidence have suggested that the cytoplasmic DNA sensor cGAS-STING not only recognizes dsDNA viruses but also plays a crucial role in RNA virus infection, either by directly recognizing virus characteristics or by detecting cellular DNA released from mitochondria or nuclei in response to cellular stress (Li et al., 2021) (Fig. 3). STING has been linked to SARS-CoV-2 infection by triggering the type I IFN response (Chattopadhyay & Hu, 2020; Messaoud-Nacer et al., 2022; Ramanjulu et al., 2018). Although type I IFNs are quickly induced to stop the spread of the virus, a sustained rise in type I IFN levels during the late stages of the infection is linked to aberrant inflammation and a poor clinical outcome (Liu et al., 2021). The cGAS-STING pathway is demonstrated to be a major regulator of aberrant type I IFN responses in COVID-19 (Humphries et al., 2021). Application of a STING inhibitor reduced STING activation, lowering the severe lung inflammation brought on by SARS-CoV-2 and improving the course of the disease (Chattopadhyay & Hu, 2020; Liu et al., 2021). In SARS-CoV-2 infected people and mice, activation of cGAS-STING results in a rise in inflammation and pathogenesis (Liu et al., 2021). STING inhibitors can limit this response, according to Neufeldt et al. (2022) discovery that SARS-CoV-2 infection activates the cGAS-STING route, which causes the production of proinflammatory cytokines mediated by the nuclear factor B (NF-B) pathway (Li et al., 2021). Both Neufeldt et al. (2022) observation of STING colocalization with SARS-CoV-2 N protein in infected cells and Rui et al. (2021) observation of interactions between STING and ORF3a suggest viral proteins have a direct role in modifying the cGAS-STING pathway (Li et al., 2021; Liu et al., 2022). According to data from an earlier investigation, STING activation is a potential therapeutic strategy to manage SARS-CoV-2 (Li et al., 2021) (Table 1). Recent research has demonstrated that STING agonists influence the type I IFN response, which in turn affects SARS-CoV-2 infection (Chattopadhyay & Hu, 2020; Li et al., 2021) and utilization of cGAS-STING pathway agonists holds a promise for a vaccine adjuvants (Tian et al., 2024). Li et al. (2021) performed high-throughput screening to find antiviral innate immune agonists to prevent SARS-CoV-2 infection, and they discovered endogenous STING agonists, cyclic dinucleotides (CDNs), as antiviral drugs against SARS-CoV-2. Strong small molecule STING agonists, including diABZI, have been exploited because of limited potency of CDNs and poor drug quality (Liu et al., 2021; Messaoud-Nacer et al., 2022; Ramanjulu et al., 2018). Li et al. (2021) studied the small chemical STING agonist diABZI and observed that it can successfully prevent SARS-CoV-2 infection of several strains by activating IFN signalling. Notably, diABZI can inhibit viral replication in live mice and primary human bronchial epithelial cells. Consequently, this STING agonist may be applied as a novel treatment approach to combat COVID-19. Like this, Humphries et al. (2021) reported a diamidobenzimidazole drug diABZI-4, which stimulates STING and is particularly effective in limiting SARS-CoV-2 replication in cells and mice. When diABZI-4 was administered intravenously, STING was activated quickly, which helped to temporarily increase the production of proinflammatory cytokines and activate lung lymphocytes and inhibit viral replication (Humphries et al., 2021). There are a number of new cGAS-STING activators, including colloidal manganese salt, CF501, mucoadhesive nanoparticles, and IAPA (indirect-acting pan-antiviral) agents, which offer fresh perspectives on anti-SARS-CoV-2 therapy (Jearanaiwitayakul et al., 2022; Kleandrova, Scotti & Speck-Planche, 2021; Liu et al., 2022; Zhang et al., 2021b). The stability of STING agonists has improved with the development of the biocompatible peptide, protein, and bio membrane platforms (Zheng & Wu, 2022). Few adjuvants have been approved for use in humans thus far, and the only one that is often used is one that contains aluminum (Clapp et al., 2011). Nevertheless, it has been demonstrated that the nanoparticle manganese (nanoMn) adjuvant, also known as STING agonists, promotes antigen presentation, virus-specific memory T-cell generation, and host-adaptive immunity, making it the ideal adjuvant for protein-based COVID-19 subunit vaccines (Wu et al., 2021) (Table 2). The nanoMn adjuvant, according to Zhang et al. (2022) is the most efficient at boosting the immunogenicity or immune responses of SARS-CoV-2 protein-based subunit vaccines. Additionally, the use of a new STING agonist, CDGSF, in combination with the SARS-CoV-2 S protein as an adjuvant result in extraordinarily high antibody titres and a potent T-cell response, outperforming the drawbacks of adjuvants that contain aluminum (Wu et al., 2021). NanoSTING, used as an adjuvant for intranasal vaccination with S protein trimeric or monomeric form, evoked potent serum neutralizing antibodies and T-cell responses (Berthelot & Lioté, 2020). Strong stimulatory effects on antibody responses in the respiratory tract were seen when the S protein and cGAMP were administered (Berthelot & Lioté, 2020; Chauveau et al., 2021).

According to the data, STING agonists significantly increased the S protein immunogenicity (Zhang et al., 2021b). These results highlighted the STING agonist adjuvant potential in the SARS-CoV-2 vaccination. STING agonists, which instantly enhance IFNs signalling, can quickly and transiently activate STING (Humphries et al., 2021; Li et al., 2021). Nevertheless, it is important to prevent the progression of the illness brought on by excessive inflammation when using STING vaccination adjuvants that induce long-lasting humoral and cellular immune responses (Liu et al., 2022). As a result, inhibiting STING activation reduces inflammatory responses and pathogenesis, indicating that STING may be exploited as a therapeutic target to prevent SARS-CoV-2-related severe illness symptoms. Incorporating STING activation into antibody therapy for managing SARS-CoV-2 involves designing STING agonist antibodies to enhance type I interferon response within infected cells, strengthening immunity against the virus. Neutralizing antibodies could block viral components that hinder the STING pathway, indirectly promoting STING activation. Combination therapies combining STING-targeting antibodies with antiviral drugs or mAbs could provide a comprehensive. Engineered antibodies might also bolster broader immune responses, such as T cell activation, while others could finely modulate STING-triggered inflammation to prevent excessive reactions. Conjugating antibodies with STING agonists or immune modulators allow targeted delivery to infected cells, enhancing efficacy and minimizing side effects. Personalized antibody therapies, adjusted to individual immune profiles, offer potential for optimized treatment outcomes.

SARS-CoV-2 proteins and their innate immune targets

SARS-CoV-2 proteins show varying degrees of target tropism and have diverse functions. The role of each SARS-CoV-2 protein in innate immune response was mentioned in details in Table 3 (Minkoff & tenOever, 2023). SARS-CoV-2 proteins nsp-6 and nsp-13 bind TANK binding kinase-1 (TBK-1), leading to inhibition of IRF-3 phosphorylation and subsequent reduction in IFN-beta production. Nuclear translocation of IRF-3 is also abrogated by binding of ORF-6 to importin karyopherin alpha-2 (Lei et al., 2020; Schreiber, 2020) eventually leading to downregulation of type-1 IFN secretion. The abrogation of IRF-3 nuclear translocation and downregulation of type-1 IFN expression can also be from the antagonistic nature of viral proteins ORF3b or due to M protein-dependent ubiquitin-mediated degradation of TBK1 (Konno et al., 2020; Sui et al., 2021). NF-kB and IFN-beta pathway activation is inhibited by ORF6, ORF8, and N proteins of SARS-CoV-2. Moreover, ORF6, ORF8, and nsp-1 abandon the ISRE-driven transcription of ISGs (Li et al., 2020). Researchers identified interactions between ISGs and TLR3 agonists, including poly I:C and imiquimod. This discovery suggests a potential for drug repurposing in the realm of COVID-19, proposing TLR3 agonists as promising candidates for therapeutic exploration. ISGs, such as IFIT and IFITM, ISG15, IFIH1, MX1, IRF7, OAS 1-3, and STAT1 are recognized for enhancing IFN signaling, thereby contributing to antiviral activity, emerge as potential candidates for drug targets in COVID-19 treatment (Prasad et al., 2020). Some other proteins involved in the downregulation of type-1 IFN expression are ORF-96, nsp13, nsp-1, and M proteins, and the target of these viral proteins are RIG-1/MDA-5/MAVS signaling cascade (Jiang et al., 2020; Ricci et al., 2021).

The phosphorylation of STAT-1 and STAT-3 is inhibited by SARS-CoV-2 viral proteins including nsp-6, nsp-13, ORF-39, and ORF-7b, so these proteins have an antagonistic impact on the type-1 IFN signaling pathway (Li et al., 2020). In addition, the prevention of STAT phosphorylation and their nuclear translocation is suppressed by other SARS-CoV2 proteins like N, ORF-6, and M proteins (Fig. 4) (Ricci et al., 2021; Schultze & Aschenbrenner, 2021). A study shows that patients with inborn errors in TLR-3 and IRF-3 dependent type-1 IFN immune response presented with severe SARS-CoV-2 infection, concluding the vital role of type-1 IFN in combating the viral infection (Zhang et al., 2020b). In another study, 3.5% of patients with autosomal recessive deficiencies in IRF-7 and IFNAR1 genes and autosomal dominant deficiencies in genes encoding TLR-3, unc-93 homolog B1, TLR adaptor molecule 1, TBK1, IRF-3, IRF-7, IFNAR1, and IFNAR2 showed severe COVID-19 pneumonia (Gao et al., 2020). The role of type-1 IFN is demonstrated by a study where the anti- type1 IFN autoantibodies have been observed in severe COVID-19 infections (Bastard et al., 2020). The nonstructural protein 16 (nsp16) derived from SARS-CoV-2 diminishes the splicing of overall mRNA and hinders the identification of viral RNA by intracellular helicase receptors. Additionally, nsp-1 disrupts mRNA translation by attaching to 18s ribosomal RNA within the mRNA entry channel, while both NSP-8 and NSP-9 impede protein trafficking to the cell membrane. These three distinct mechanisms collectively exert detrimental effects on the production of type-1 interferon by the infected cells (Banerjee et al., 2020).

Addressing deficiencies in immune genes through therapeutic antibodies offers potential for patients with autosomal recessive or dominant deficiencies in vital genes like IRF-7, IFNAR1, TLR-3. The identification of IFIT1, IFITM1, IRF7, ISG15, MX1, and OAS2 as pivotal components suggested their viability as potential drug targets for COVID-19 (Prasad et al., 2020). Similarly, targeting anti-type 1 IFN autoantibodies via antibody therapy can restore natural defenses, aiding controlling severe COVID-19. Counteracting inhibitory viral proteins (nsp16, nsp-1, NSP-8, NSP-9) through antibody design could restore effective type-1 IFN production by impeding their interaction with cellular components (Beyer & Forero, 2022). Engineering antibodies to enhance type-1 IFN production by targeting specific cellular factors presents a strategy for boosting antiviral immunity. Given the complexities, combining antibodies targeting distinct aspects of immune response, viral inhibition, and IFN production could offer a comprehensive treatment approach. Moreover, personalized antibody therapies tailored to individual genetic, immunological variations, and viral interactions could optimize specificity and efficacy in managing severe cases.

Monoclonal antibodies and Innate immune targets

Monoclonal antibodies (mAbs) have shown promising results for the effective management of COVID-19. These laboratory-engineered antibodies are designed to mimic the natural immune system response to infections. In the early COVID-19 pandemic, IgG mAbs directed against the spike protein of SARS-CoV-2, as single or in the form of mAb cocktails garnered substantial attention as a effective therapeutic solution for COVID-19 (Focosi et al., 2022). The Coronavirus Antibody Database (CoV-Ab Dab), managed by the University of Oxford, is a comprehensive repository containing 12,916 antibodies and nanobodies (as of the latest update on February 8, 2024) specifically designed to target SARS-CoV, MERS-CoV, and SARS-CoV-2 (Raybould et al., 2021). mAbs have also emerged as a promising class of therapeutics for targeting the innate immune response. These antibodies were developed with the goal of reducing the aberrant immune response observed in severe COVID-19 cases and target innate immune system components. These mAbs can block key pro-inflammatory cytokines such as IL-6 and TNF-α and several others, thereby weakening the cytokine storm associated with disease severity (Abbasifard & Khorramdelazad, 2020). Additionally, some mAbs directly target viral components, preventing the virus from evading innate immune detection and mounting a robust response (Znaidia et al., 2022). Several mAbs that may act upon the innate immune response are highlighted in Table 4. A recent study by Sele et al. (2024) highlight the pivotal role of SARS-CoV-2 non-structural protein 10 (nsp10) in enhancing the enzymatic activities of nsp14 and nsp16, crucial for the virus evasion of innate immunity. The research emphasizes the importance of the C-terminal region of nsp10 in its interaction with nsp14, highlighting the necessity of both N- and C-termini for optimal binding. Targeting these sites with mAbs could offer a promising strategy for combating SARS-CoV-2. The research and development of mAbs for COVID-19 should continue to evolve and explore as novel therapeutics. A deeper understanding of mAbs for fine-tuning the innate immune response can lead to the development of tailored therapeutics against SARS-CoV-2 and future variants.

Conclusion and prospects

The innate immune response is the host first line of defense for viral infection including SARS-CoV-2. A comprehensive study of this response in SARS-CoV-2 is crucial for developing effective strategies against SARS-CoV-2 variants. This knowledge will aid scientists and innovators in designing novel antibodies, enhancing preparedness for future outbreaks. Utilizing mAbs to rectify innate immune responses and counteract inhibitory viral proteins like nsp16, nsp-1, nsp-8, and nsp-9 offers innovative strategies to bolster anti-SARS-CoV-2 immunity and can be neutralized via the strategic design of antibodies that disrupt their interactions. Targeting anti-type 1 interferon (IFN) autoantibodies in severe cases allows for the restoration of the body natural defences, providing a tailored approach to control viral replication. The strategic design of antibodies not only neutralizes the inhibitory impact of viral proteins but also opens avenues for engineering antibodies capable of enhancing type-1 IFN production. This dual functionality contributes to a robust antiviral defence’s mechanism. Considering the intricacies involved, a comprehensive strategy involving combination therapies, tailored to individual profiles, emerges as a promising frontier for treatment precision. Additionally, rectifying immune gene deficiencies such as IRF-7, IFNAR1, and TLR-3 can be accomplished by employing therapeutic antibodies as substitutes. Moreover, the integration of these approaches with the unique recognition capability of RIG-1, triggering interferon production in response to specific viral RNA structures, holds considerable promise for advancing targeted and efficient antibody-based therapies against COVID-19 disease. Understanding innate immune response and targeted therapy in the form of mAbs will be instrumental in addressing future outbreaks.

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