Noncoding RNAs in the COVID-19 Saga: An Untold Story

CircRNAs

Insufficient research has been conducted on the distinctively expressed (DE) circRNAs in COVID-19. However, this study has the potential to provide useful knowledge about the DEcircRNAs that are found after SARS-CoV-2 infection and their occurrence in different samples from persons with COVID-19. By conducting genome-wide dynamic screening, over five thousand circRNAs were identified in human lung epithelial cells infected with SARS-CoV-2, situated at various positions in the genome (Yang et al., 2021). In addition, DEcircRNAs were identified in the whole-blood sample of individuals experiencing recurrent COVID-19, in comparison to the normal control group (Wu et al., 2021). Previous studies indicate that infection with SARS-CoV-2 has the potential to interfere with the production of circRNAs in the blood. Furthermore, a distinct disruption in the functioning of circRNAs in the cerebrospinal fluid (CSF) has been noted. This is evidenced by a distinctive pattern of circRNA expression in the CSF of COVID-19 patients, which differs from that of both healthy individuals and individuals with neurological disorders (Reinhold et al., 2023). Further work is necessary to determine whether there are similarities or differences in the categories of DEcircRNAs between the brain and red blood cells. Gaining a comprehensive understanding of the broader ramifications of SARS-CoV-2 is essential for furthering our understanding. Techniques such as single-cell RNA sequencing and spatial transcriptomics sequencing are highly useful tools for accomplishing this objective.

LncRNAs

It has been observed that differentially expressed long non-coding RNAs (DElncRNAs) are present in both COVID-19 cases ranging in illness seriousness and people with differing disease seriousness compared with healthy individuals. This depicts that lncRNAs may serve a role in the pathophysiology of this condition (Cheng et al., 2021; Li et al., 2021). The lncRNA expression exhibited changes over time, either within a short period (e.g., from being admitted to 7 days) or a longer duration encompassing treatment, recovery, and rehabilitation (Rombauts et al., 2023; Zheng et al., 2020). Furthermore, DElncRNAs have been found in instances of recurrent COVID-19, as shown by the identification of almost one thousand DElncRNAs in recurrent COVID-19 individuals as opposed to healthy subjects (Wu et al., 2021). However, more studies are necessary to ascertain if there are disparities in the expression of lncRNAs among people with a solitary SARS-CoV-2 infection and those who experience recurrence This is important because multiple infections may heighten the possibility and stress of the illness, indicating the presence of conceivable fundamental variations (Bowe et al., 2022).

Despite the discovery of DElncRNAs at the cellular level, nothing is known about the expression properties of lncRNAs in COVID-19 patients. Single-cell RNA sequencing research demonstrated the presence of DElncRNAs in blood leukocytes from patients with severe COVID-19 compared with healthy persons. This finding suggests that lncRNAs may play a more complex role in the disease’s progression (Aznaourova et al., 2022).

One study established the association between aberrantly expressed lncRNAs and the activation of host responses through innate immune signaling during SARS-CoV infection. This finding raises the possibility of a similar correlation with SARS-CoV-2 infection. Researchers have made several efforts to understand the role of lncRNAs in modulating the interaction between SARS-CoV-2 and the host, aiming to utilize these findings as disease biomarkers or therapeutic interventions. For instance, a study analyzing RNA-seq data from SARS-CoV-2 infected primary normal human bronchial epithelial (NHBE) cells identified 21 differentially expressed lncRNAs and protein-coding genes. Among these, 9 lncRNAs were upregulated, and 12 were downregulated, as detailed in Table 3 (Rai et al., 2024; Turjya et al., 2020).

In addition, among the differentially expressed protein-coding genes, six were found to closely interact with these aberrantly expressed lncRNAs, with the interactions primarily being RNA–RNA and a few involving protein-RNA interactions. By constructing biological networks, researchers identified lncRNA-interacting differentially expressed genes that encode proteins. Moreover, the SARS-CoV-2 protein interactors were associated with pathways that facilitate cell survival, viral proliferation, and immune response. The study also suggested that these dysregulated lncRNAs might act as competing endogenous RNAs to regulate the levels of virus-induced microRNAs [75].

Furthermore, transcriptome profiling revealed significant enrichment of differentially expressed genes during SARS-CoV-2 infection. This study utilized primary NHBE cells and the A549 alveolar basal epithelial cell line to investigate the host response to SARS-CoV-2 infection, comparing it with other respiratory viruses. It highlighted the driving force behind the extreme inflammatory state observed during COVID-19. The study demonstrated that SARS-CoV-2 infection induced limited levels of type I and type III interferons, in contrast to the significantly elevated levels of pro-inflammatory cytokines and chemokines such as IL-6, resulting in a reduced innate immune response against the virus [76]. This finding helps explain why elderly individuals or those with compromised immune systems experience severe outcomes upon infection.

Similarly, systemic changes in the host response to SARS-CoV-2 infection were investigated by another research group focusing on lncRNA expression and function. This study utilized NHBE cells and lung tissue samples from SARS-CoV-2-infected subjects, as previously examined by Blanco-Melo et al. [77]. Using various computational methods, the researchers aimed to elucidate virus–host interactions mediated by lncRNAs. Pathway and functional analyses indicated an enhanced interferon-mediated response as the primary defense mechanism against the virus, evidenced by the upregulation of interferon-responsive gene targets, consistent with the findings of Blanco-Melo et al. Key genes such as IRF9, IFIT1, IFIT2, IFIT3, IFITM1, MX1, OAS2, OAS3, IFI44, and IFI44L were significantly elevated in NHBE cells compared with controls, underscoring the pivotal role of interferon signaling in the development of SARS-CoV-2 infection [77].

In addition, network reconstruction through computational analysis revealed biological networks that were both activated and repressed in the NHBE cell model and patient tissue samples. For example, genes involved in type I and III interferon signaling were activated to combat the virus, whereas genes related to p53 binding and cell cycle progression were repressed. The study also demonstrated the expression of several viral proteins both in vitro and ex vivo and identified numerous host-derived lncRNAs that were dysregulated in response to SARS-CoV-2 infection. RNA sequencing of SARS-CoV-2-infected NHBE cells revealed 155 upregulated and 195 downregulated lncRNAs compared with mock-infected cells. Some of these differentially expressed lncRNAs are listed in Table 4 [77]. However, the precise functions of these lncRNAs in modulating the host response to SARS-CoV-2 infection remain to be fully explored.

These lncRNAs offer a new perspective on their role in modulating the antiviral immune response in the host by interacting with chromatin, RNA, or protein molecules [78]. Furthermore, previous studies have highlighted the roles of MALAT1 and NEAT1 in the context of HIV-1 infection and various carcinomas. Investigating their roles in SARS-CoV-2 infection would be valuable for understanding the mechanisms involved in disease pathogenesis and progression. Collectively, such mechanism-centric studies are crucial for determining the effects of dysregulated lncRNAs during SARS-CoV-2 infection and managing the excessive inflammation associated with COVID-19.

MiRNAs

Multiple studies have indicated that the behavior of specific miRNAs is altered in individuals with COVID-19 in comparison to the general population, suggesting a possible role for miRNAs in the development of COVID-19 (Fernández-Pato et al., 2022). Furthermore, the activity of individual miRNAs can be affected by the seriousness of the sickness. This highlights the essential role of miRNAs in differentiating the extent of COVID-19 by revealing the varied profile of miRNAs among individuals with different levels of infection seriousness (Parray et al., 2021). Moreover, the DEmiRNAs profile shows a clear time-dependent responsiveness in relation to COVID-19. The fast alterations become evident within a few days after the commencement of the illness, shifting from the early phase (within 3 days) to the second phase (>7 days), suggesting the ability to promptly anticipate emerging symptoms following SARS-CoV-2 infection (Donyavi et al., 2021; Duecker et al., 2021). When considering the overall timeline of therapy, recovery, and rehabilitative phases, the expression profile of certain miRNAs affected by SARS-CoV-2 also shows distinguishable characteristics (Zheng et al., 2020). In addition, exposure to SARS-CoV-2 could lead to a distinct human miRNA expression pattern different from those observed in people impacted by different pathogens. Three specific miRNAs were identified in the blood of individuals with severe COVID-19, as opposed to those with influenza-induced acute respiratory distress syndrome (ARDS). These small RNA molecules serve a significant part in unraveling the unique progression of SARS-CoV-2 (Garg et al., 2021). Some miRNAs that deviate from the norm have been confirmed by different methods in various scientific circles (Garg et al., 2021; Wilson et al., 2022). In addition, the abundant PCR or sequencing data allowed for a thorough examination of the molecular profile of DEmiRNAs in people affected by COVID-19. Multiple studies have consistently shown that miRNAs, including miR-106b-5p and miR-1246, have distinct levels of expression, suggesting that SARS-CoV-2 has a significant effect on the patient’s miRNA profile (Farr et al., 2021; Fernández-Pato et al., 2022; Gutmann et al., 2022).

miR-21: miR-21 has been shown to modulate the immune response by targeting genes involved in the TLR (Toll-like receptor) signaling pathway. It can downregulate the expression of pro-inflammatory cytokines, thereby preventing excessive inflammation and tissue damage during viral infections. This regulatory role is crucial for maintaining a balanced immune response (Aalaei-andabili and Rezaei, 2013; Qian and Cao, 2013).

miR-29: This miRNA targets the mRNA of IFN-γ (interferon-gamma), a key cytokine in antiviral immunity. By fine-tuning the levels of IFN-γ, miR-29 helps in controlling the extent of the immune response, preventing potential immunopathology due to an overactive immune response while still enabling effective viral clearance (Ma et al., 2011; Schmitt et al., 2013; Schmitt et al., 2012).

miR-155: miR-155 is upregulated in response to viral infections and is involved in the regulation of multiple components of the immune system, including macrophages and dendritic cells. It enhances the production of type I interferons and pro-inflammatory cytokines, crucial for the antiviral state and the activation of adaptive immunity (Mashima, 2015).

miR-223: This miRNA plays a role in modulating the innate immune response by targeting several key molecules involved in inflammation and antiviral defense, such as STAT3 and NLRP3 (Morales et al., 2022; Shi et al., 2023). By regulating these targets, miR-223 contributes to a controlled immune response, reducing the risk of cytokine storm and associated complications in viral infections (Morales et al., 2022; Roffel et al., 2020).

miR-146a: miR-146a is known for its role in the negative regulation of the NF-κB pathway, which is pivotal in the inflammatory response. By targeting TRAF6 and IRAK1, miR-146a reduces the production of pro-inflammatory cytokines, helping to modulate the immune response and prevent excessive inflammation during viral infections (Nahand et al., 2020).

miR-124: This miRNA is involved in the regulation of the JAK/STAT signaling pathway, which is essential for the antiviral response. By targeting STAT3, miR-124 can influence the production of interferons and other cytokines, thereby playing a role in the innate immune response to viral infections (Qin et al., 2016; Sonkoly et al., 2008).

By elucidating the specific mechanisms, we aim to provide a clearer understanding of how the referenced miRNAs contribute to antiviral immunity. Each miRNA discussed plays a distinct and crucial role in regulating the immune response, highlighting their relevance in the context of COVID-19 and other viral infections.

Single-cell RNA sequencing revealing ncRNA dynamics

The importance of ncRNAs (ncRNAs) in diverse physiological processes should be acknowledged, despite the fact that protein-coding sequences have received a lot of attention in genome research. The regulation of the cell cycle, differentiation, imprinting, and other processes and pathways all depend on ncRNAs. The different kinds of ncRNA that have been researched include circRNA, miRNA, tRNA, snoRNA or sdRNA, and lncRNA. tRNAs are essential ncRNAs that are typically 70–100 nucleotides long and are involved in the translation of mRNA into proteins. Owing to their significant impact on translation, mutations in mitochondrial tRNA and issues with the enzymes involved in tRNA processing and modification have been linked to a variety of human illnesses, including cancer, neurological disorders, and mitochondrial diseases. There are variations in the way different diseases impact different tissues, may be due to distinctions in individual cells. Since tRNA expression varies across developing and proliferating cells and is intimately correlated with the translation requirements of distinct tissues, this fluctuation is frequently observed (Cardona-Alberich et al., 2021; Johnsson et al., 2022).

A role in cellular diversity may be suggested by the complex genomic architecture and varied expression patterns of RNA molecules, which impact the availability of particular anticodon-carrying molecules and, in turn, the rate of protein synthesis. These noncoding, small nucleolar RNAs (snoRNAs) range in length from 60 to 300 base pairs and are mainly responsible for adjusting and adjusting ribosomal RNA (rRNA) (Johnsson et al., 2020). Small nucleolar ribonucleoproteins (snoRNAs) are crucial components that play a role in post-transcriptional modifications of rRNA, such as 2′-O-methylation (2'-O-Methyl) and pseudouridylation. Through the production of proteins, ribosomes are essential for maintaining the functionality of cells. Studies have connected the proliferation of tumor cells to the expression of snoRNA, and several cancer types have been associated with genes that include intronic snoRNA. Different snoRNAs have been linked to neurological disorders such as Prader–Willi syndrome (Isakova et al., 2021; Li et al., 2020). It has been demonstrated that alterations in snoRNA expression lead to oxidative stress traits in cells. It is noteworthy that several findings indicate that snoRNA influences alternative splicing by interacting with lncRNAs. Previously, bulk RNA transcriptomes from several cells were averaged to determine the expression of ncRNA. Numerous ncRNAs are detected at low concentrations, show transient expression, or are linked to other regulating transcription processes. These features make bulk measures less sensitive in identifying the expression of ncRNAs. Examining the effects of ncRNA on differentiation can be challenging when working with expression measurements from distinct cell populations, especially since a small number of cells can result in significant genomic modifications (Zhang et al., 2021).

The evaluation of ncRNAs’ impact in individual cells has prompted recent research to focus on single-cell transcriptome sequencing. A single cell’s transcriptome, which normally consists of 0.2 pg of mRNA and 10 pg of total RNA, can be examined in its entirety using RNA amplification. The amplification of single-cell RNA is facilitated by two primary methods that depend on 3′ poly-A tails to start the process in one or more directions. In vitro transcription techniques and PCR-based approaches are included in these procedures. Being able to remove rRNA, which makes up most RNA, is one benefit of Poly-A priming. Standard single cell RNA sequencing can be used to identify several forms of ncRNAs, such as pri-miRNAs and poly-A tailed annotcRNAs. That being said, poly-A dependent methods cannot be used to study mature miRNAs. In recent times, many techniques have been devised to target single cells’ miRNAs or short RNAs (Huang et al., 2022). Researchers can analyze the transcriptomes of individual cells in a sample and carry out cell-type analysis of gene expression under particular circumstances using single-cell RNA sequencing (scRNA-seq). It has made significant discoveries in a number of disease research investigations. It has been quickly applied to study SARS-CoV-2 infection and immune response at the cellular and molecular levels since the spring of 2020. It is crucial to emphasize that scRNA-seq has effectively unveiled a number of COVID-19 features (Vishnubalaji et al., 2020). Researching the expression of SARS-CoV-2 receptors and infected cells, assessing alterations in cell subpopulations, scrutinizing transcriptomes and immune signaling pathways as the disease advances, comprehending the immune response, and other associated responsibilities have been essential. Finding differences between COVID-19 patients and control groups is the main goal of several research initiatives that use single-cell RNA sequencing for the virus. Further scRNA-seq investigations are needed to investigate the variations in the impact on immunity of the new SARS-CoV-2 variants. As viruses change over time, some strains have shown increased infectivity. Studying how the immune system adjusts in individuals affected by new variants is crucial since antibodies’ capacity to bind and neutralize various variants, such as B.1.351, B.1.617.2, and B.1.1.529 (which includes BA.1, BA.2, BA.3, BA.4, BA.5, and associated lineages), has decreased (Wahiduzzaman et al., 2022; Wang et al., 2020). It is imperative that present and future studies incorporate the most recent dominant variations to uncover their distinct immunological characteristics, as previous research has concentrated on patients infected by earlier variants. Taking into account patients who have not received vaccinations, as well as those who have, offers important insights into how vaccines impact immune cell populations and repertoires in response to novel SARS-CoV-2 variants. scRNA-seq has greatly advanced our ability to study the molecular processes of complex disorders such as COVID-19. Through the investigation of gene expression patterns at the individual cell level made possible by this technique, unique insights into cellular variety and temporal changes can be obtained (Zheng et al., 2020).

Amid the COVID-19 situation, scRNA-seq has played a crucial role in uncovering the intricacies of ncRNAs and their impact on the development of the disease and immune system reaction. One significant discovery in scRNA-seq research on COVID-19 involves the disruption of different types of ncRNAs, such as miRNAs, lncRNAs, and circRNAs, in various cell types. For instance, miRNAs can regulate the expression of genes related to viral entry, replication, and host immune response. Through ScRNA-seq analysis, specific miRNA signatures linked to COVID-19 severity and immune dysregulation have been identified, indicating their potential as diagnostic and prognostic biomarkers (Bhargava et al., 2023). lncRNAs have been linked to controlling immune cell functions and inflammatory responses in COVID-19. Through ScRNA-seq studies, cell type-specific expression patterns of lncRNAs in lung epithelial cells, immune cells, and endothelial cells have been uncovered, offering valuable insights into their functions in coordinating cellular responses to viral infection. In addition, circRNAs, a type of ncRNAs that have regulatory roles, have been demonstrated to impact gene expression through different mechanisms, such as miRNA sponging and protein binding. Analysis of single-cell RNA sequencing data has revealed disrupted circRNA networks linked to the development of COVID-19, indicating a role in influencing interactions between the host and the virus, as well as inflammatory responses (Emanuel et al., 2021). Furthermore, single-cell RNA sequencing allows for the analysis of immune cell populations and their functional states in individuals with COVID-19, providing insights into the molecular processes responsible for immune dysregulation and cytokine storm syndrome (Fig. 3). Through analyzing immune cells from peripheral blood, bronchoalveolar lavage fluid, and lung tissue, distinct subsets of T cells, B cells, natural killer cells, and myeloid cells with changed gene expression patterns have been discovered in reaction to SARS-CoV-2 infection. By combining scRNA-seq data with bulk RNA-seq and other omics datasets, researchers have been able to pinpoint important ncRNAs and signaling pathways that play a role in immune cell activation, exhaustion, and cytokine production in COVID-19 (Lin et al., 2022).

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FIG. 3.

Visual representation of cytokine storm in COVID-19.

Single-cell RNA sequencing studies have revealed unique reactions of different cell types to antiviral medications and immunomodulatory drugs, offering valuable information on resistance to treatment and mechanisms of therapeutic resistance. Through profiling individual cells before and after treatment, scientists can pinpoint molecular signatures linked to treatment response and resistance, which helps in tailoring personalized therapeutic approaches for COVID-19 patients (Huang et al., 2021).

Epitranscriptomic modifications of ncRNAs

Studying chemical modifications of RNA molecules has revealed a new way to control protein expression, prompting a reevaluation of certain aspects of cellular biology. Studying epitranscriptomic modifications is crucial for understanding RNA metabolism, influencing various processes such as transcription, translation, splicing, subcellular localization, and stability. They have a significant influence on the transcriptome, offering a quick and efficient method to alter its composition and function in reaction to different stimuli. One method to achieve this decidable task is by modulating RNA interactions with RNA-binding proteins (RBPs) (Huang et al., 2021; Jusic et al., 2022). An approximate number of over 3,000 RBPs are present in human cells. Even though the purpose of most of them remains a mystery, it is evident that numerous RBPs are involved in various stages of post-transcriptional RNA processing. Three primary RBPs linked to RNA epitranscriptomic modifications have been identified as follows: enzymes responsible for depositing, removing, and recognizing specific chemical groups. Nevertheless, not all RNA chemical groups have designated erasers or readers. Therefore, there is a need for targeted proteomic methods to comprehensively identify and quantify epitranscriptomic regulators and effectors (Atlante et al., 2020; Yahaya et al., 2021). When RBPs interact with RNA targets, it can happen in two ways as follows: either directly by recognizing the RNA modification or indirectly by influencing the RNA’s secondary structure, which in turn affects RBPs. Both coding and ncRNAs interact regularly with different RBPs. Part of the 'house-keeping' category RBPs can be active all the time and everywhere, whereas some RBPs show specific expression patterns or their RBPs could be controlled. Natural RNAs frequently contain alterations to RNA, sometimes known as epitranscriptomic changes of RNA. It has been determined that approximately 140 post-transcriptional changes are critical for the structural variety and metabolism of RNAs. At the cellular level, messenger RNA (mRNA), rRNA, and tRNAs undergo chemical changes. Studies have indicated the importance of RNA epigenetic modifications in viral infection (Arzumanian et al., 2022; Atlante et al., 2020). A-to-I editing and pseudouridine are examples of noncanonical nucleotides that have significant modifications in the virus genome, along with methylation of adenine and cytidine residues like N6-methyladenosine (m6A), or 7-methylguanosine, as well as 2'-O-Methyl. These alterations in methylation are often caused by cellular enzymes, although virus-encoded methyltransferases have also been linked to distinct consequences. Determining the impact of epigenetic modifications on viral RNA metabolism or virus infection is challenging since these modifications are dynamic and reversible during viral infection and are aided by enzymes (Stamatopoulou and Zaravinos, 2021). Despite the rapid advancements in RNA research, scientists have identified numerous RNA modifications in various virus genomes that could influence virus infection. When a virus infects the body, the immune system’s initial response is usually to activate innate antiviral defenses. TLRs, PRRs, Myeloid Differentiation Factor-88, TIR-domain-containing adaptor protein inducing interferon-beta, and other cytoplasmic receptors/adapters are activated when they recognize external nucleic acids, such as virus-derived RNAs or DNAs. This process also activates TNF receptor-associated factors (TRAFs) (Song et al., 2023). Activation of TRAFs triggers the activation of IRF3/7 and NF-κB signaling pathways, leading to the production of type I interferons and pro-inflammatory cytokines. Apart from the TLR pathway, another family of Pattern recognition receptors (PRRs) known as the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family has been found to be essential cytosolic sensors of viral nucleic acids. The RLR signaling pathway’s receptor protein is recognized as the mitochondrial antiviral-signaling protein, which can be found in the endoplasmic reticulum or mitochondria. When a virus infects, this route makes it possible for IFN-β to express itself quickly. Strong antiviral effects are shown by IFNs and pro-inflammatory cytokines (Hussain et al., 2024d; Jiang et al., 2023).

RNA alterations are becoming more and more important in controlling antiviral innate immune responses, according to recent study. Exploring modifications of ncRNAs has unveiled significant insights into the progression of COVID-19, exposing the intricate molecular mechanisms at play in viral infection, host immune response, and disease progression. Exploring epitranscriptomics entails analyzing the dynamic chemical modifications of RNA molecules that affect their structure, stability, and function. In the context of COVID-19, these modifications play a crucial role in controlling the interactions between the virus and host cells, as well as shaping the immune response to infection. One of the extensively studied epitranscriptomic modifications involves the addition of a methyl group to the adenosine nucleotide in RNA molecules, known as m6A (Courtney, 2021). Studies have demonstrated that m6A modifications are involved in regulating the stability, translation, and splicing of coding and ncRNAs. COVID-19 observations indicate that the m6A modification process is disturbed, leading to alterations in the expression of ncRNAs associated with viral replication, host immune response, and inflammatory signaling pathways. Modifications to viral RNA may influence its stability and translation efficiency, which could in turn impact viral replication and pathogenesis. Modifications in m6A patterns of host ncRNAs, such as miRNA and lncRNAs, could impact their connections with target mRNAs and regulatory proteins, ultimately altering gene expression patterns in response to viral infection (Ruiz Ramírez and Prado Montes de Oca, 2022). One of the epitranscriptomic changes linked to COVID-19 pathogenesis is 5-methylcytosine (m5C), where cytosine residues within RNA molecules are methylated. Modifications of m5C impact RNA stability, structure, and RBPs, thus altering RNA processing, translation, and function. There may be a disruption in m5C modification machinery in COVID-19, potentially causing changes in the expression and function of ncRNAs related to antiviral defense, immune regulation, and tissue balance. Furthermore, additional epitranscriptomic changes, like pseudouridylation and adenosine-to-inosine (A-to-I) editing, have been linked to COVID-19 pathogenesis (Zheng et al., 2024). Changing uridine to pseudouridine can affect RNA structure, stability, and interactions with proteins. When adenosine deaminases acting on RNA catalyze A-to-I editing, it causes nucleotide modifications in RNA molecules, which can impact RNA splicing, stability, and translation. When these epitranscriptomic modifications are disrupted, it can lead to abnormal expression and functioning of ncRNAs that play a role in viral–host interactions, immune evasion, and inflammatory signaling pathways.

Interaction networks between ncRNAs and viral genomes

Recent findings in virology indicate that ncRNAs are essential in various stages of viral infection, including controlling virus growth, replication, and cell death. Based on research findings, it is evident that viral ncRNAs can influence cellular and viral gene expression to create a favorable environment for the viral life cycle. Just as medical researchers have discovered, numerous cellular ncRNAs have the ability to impact viral replication and target viral genomes, either directly or indirectly. The complex functional interaction network is formed by the interaction of viral and cellular ncRNAs with their viral and cellular targets. Understanding intricate interactions is crucial for comprehending viral infection and creating novel antiviral treatments (Enguita et al., 2022; Suga et al., 2023). Severe viral infections are caused by intricate interactions between two organisms, where the infectious agent relies on the infected cell’s molecular and metabolic functions for both growth and replication. Viral components and cellular structures establish crucial molecular linkages as the virus penetrates the host’s cellular machinery. These interactions are necessary to alter cellular metabolism, help viruses enter cells more easily, and circumvent certain defense mechanisms. Studying the molecular components of cells and viruses during infection primarily centers on proteins. Studying viral polypeptides that facilitate infection or evade the immune system, along with their cellular counterparts, is a key aspect of this research (Enguita et al., 2022; Liu et al., 2019).

It is critical to understand the role that viral and cellular RNAs play as critical components during an infection. The past 10 years have seen the beginning of research into the roles of lncRNAs in viral infections. Research has demonstrated the critical function of lncRNA mediators in controlling the inflammatory and immunological reactions to viral infections. These particular instances show how some lncRNAs control the spread of RNA viruses. The ability of the human norovirus to strongly activate a lncRNA-mediated response in host cells that regulates the interferon reaction is one important element in the development of viral gastroenteritis. By lowering lncPINT expression, human HCV strains can withstand interferon defense and the innate immune response, allowing them to survive for prolonged periods of time (Serpeloni et al., 2021). The recently identified lncRNA AP000253 illustrates how HBV might go unreported in the host for extended periods of time using a similar technique. Research from experimental models has connected a complicated system of RBPs with lncRNA regulators of infection by looking at various cases. A respiratory RNA(+) virus known as SARS-CoV-2 quickly spread throughout the world, causing the pandemic that began in late 2019. Acknowledged as a member of the coronaviridae family, SARS-CoV-2 enters cells by attaching itself particularly to the host’s ACE2 receptor. Once inside the cell, infection causes alterations in the pattern of gene and protein expression, exhibiting an increase in genes linked to the synthesis of interleukin and the interferon response (Cheng et al., 2022; Serpeloni et al., 2021).

In severe instances of SARS-CoV-2 infection, there is typically a significant acute inflammatory reaction associated with an overproduction of cytokines, referred to as a “cytokine storm.” Researchers discovered that certain proteins are engaged by genomic SARS-CoV-2 RNA and its RNA transcripts, influencing cellular responses to the infection, through high-throughput proteomic analysis (Zhang et al., 2019a). Studying the intricate networks between ncRNAs and viral genomes reveals a multifaceted relationship that impacts different facets of viral infection, replication, and pathogenesis. It is essential to comprehend these networks to uncover the molecular mechanisms behind viral–host interactions and pinpoint potential therapeutic targets for fighting viral diseases like COVID-19. One of the key connections between ncRNAs and viral genomes is through miRNAs (Wang, 2018; Zhang et al., 2019a). Exploiting host cellular machinery, viruses can encode viral miRNAs that regulate both viral and host gene expression. Examining viral miRNAs reveals their ability to impact different phases of the viral life cycle, such as viral entry, replication, and avoidance of host immune reactions (Lanjanian et al., 2021). In contrast, cellular miRNAs from the host can target viral genomes, either by directly stopping viral replication or by adjusting host immune responses to control viral spread. For instance, within the realm of COVID-19, researchers have pinpointed various host miRNAs that could potentially control SARS-CoV-2 replication and pathogenesis. These miRNAs focus on viral RNA sequences or host factors related to viral entry and replication, like transmembrane protease serine 2 (TMPRSS2) and ACE2, which serve a crucial role in viral entry into host cells. Moreover, viral-encoded miRNAs play a role in controlling host immune responses and adjusting viral gene expression to enhance viral persistence and pathogenesis. lncRNAs play a role in interaction networks with viral genomes, influencing viral replication, host immune responses, and inflammatory processes (Arora et al., 2020; Lanjanian et al., 2021). lncRNAs have the ability to function as molecular scaffolds, decoys, or competitive endogenous RNAs to regulate the expression of viral and host genes. Through interactions with viral RNA or proteins, lncRNAs have the ability to impact viral replication and assembly, along with host antiviral defense mechanisms. When it comes to COVID-19, the disruption of host lncRNAs has been linked to changes in immune responses, cytokine production, and disease severity. For instance, specific lncRNAs have been demonstrated to control the expression of pro-inflammatory cytokines and chemokines, which play a role in the cytokine storm syndrome seen in severe instances of COVID-19. Furthermore, alterations in lncRNA expression profiles caused by viruses can help viruses evade the immune system and remain in host cells for longer periods (Madhry et al., 2021; Withers et al., 2019). CircRNAs have also been linked to interaction networks with viral genomes. These circRNAs can act as molecular sponges for miRNA or RBPs, influencing gene expression and signaling pathways related to viral replication and host immune responses. Changes in circRNA expression profiles caused by viral infection can disrupt cellular processes and immune evasion mechanisms (Pan et al., 2021).

During the COVID-19 situation, increasing evidence suggests the important role circRNAs play in regulating viral replication and host immune responses. One illustration is how circRNAs are involved in regulating the expression of crucial host factors related to viral entry and replication, along with inflammatory signaling pathways linked to COVID-19 development. In addition, circRNAs encoded by viruses can function as competitive inhibitors of host circRNAs or miRNAs, interfering with cellular processes and enhancing viral survival. Studying the dynamic and context-dependent interaction networks between ncRNAs and viral genomes involves considering factors like viral strain, host cell type, and immune status. To comprehend these intricate networks, a combination of high-throughput sequencing technologies, bioinformatics analyses, and experimental validation is essential. Through understanding the molecular mechanisms involved in viral–host interactions, scientists can discover new targets for antiviral treatments and create plans to fight against viral diseases like COVID-19 (Jafarinejad-Farsangi et al., 2020; Pan et al., 2021; Sun and Chen, 2020).