Unveiling the Connection: Viral Infections and Genes in dNTP Metabolism.

Deoxynucleoside triphosphates (dNTPs) are crucial for the replication and maintenance of genomic information within cells. The balance of the dNTP pool involves several cellular enzymes, including dihydrofolate reductase (DHFR), ribonucleotide reductase (RNR), and SAM and HD domain-containing protein 1 (SAMHD1), among others. DHFR is vital for the de novo synthesis of purines and deoxythymidine monophosphate, which are necessary for DNA synthesis. SAMHD1, a ubiquitously expressed deoxynucleotide triphosphohydrolase, converts dNTPs into deoxynucleosides and inorganic triphosphates. This process counteracts the de novo dNTP synthesis primarily carried out by RNR and cellular deoxynucleoside kinases, which are most active during the S phase of the cell cycle. The intracellular levels of dNTPs can influence various viral infections. This review provides a concise summary of the interactions between different viruses and the genes involved in dNTP metabolism.

Hydrogen Sulfide: A Versatile Molecule and Therapeutic Target in Health and Diseases.

In recent years, research has unveiled the significant role of hydrogen sulfide (H2S) in many physiological and pathological processes. The role of endogenous H2S, H2S donors, and inhibitors has been the subject of studies that have aimed to investigate this intriguing molecule. The mechanisms by which H2S contributes to different diseases, including inflammatory conditions, cardiovascular disease, viral infections, and neurological disorders, are complex. Despite noteworthy progress, several questions remain unanswered. H2S donors and inhibitors have shown significant therapeutic potential for various diseases. This review summarizes our current understanding of H2S-based therapeutics in inflammatory conditions, cardiovascular diseases, viral infections, and neurological disorders.

Versatility of the Zinc-Finger Antiviral Protein (ZAP) As a Modulator of Viral Infections.

The zinc-finger antiviral protein (ZAP) is a restriction factor that proficiently impedes the replication of a variety of RNA and DNA viruses. In recent years, the affinity of ZAP's zinc-fingers for single-stranded RNA (ssRNA) rich in CpG dinucleotides was uncovered. High frequencies of CpGs in RNA may suggest a non-self origin, which underscores the importance of ZAP as a potential cellular sensor of (viral) RNA. Upon binding viral RNA, ZAP recruits cellular cofactors to orchestrate a finely tuned antiviral response that limits virus replication via distinct mechanisms. These include promoting degradation of viral RNA, inhibiting RNA translation, and synergizing with other immune pathways. Depending on the viral species and experimental set-up, different isoforms and cellular cofactors have been reported to be dominant in shaping the ZAP-mediated antiviral response. Here we review how ZAP differentially affects viral replication depending on distinct interactions with RNA, cellular cofactors, and viral proteins to discuss how these interactions shape the antiviral mechanisms that have thus far been reported for ZAP. Importantly, we zoom in on the unknown aspects of ZAP's antiviral system and its therapeutic potential to be employed in vaccine design.

Crosstalk between Dysfunctional Mitochondria and Proinflammatory Responses during Viral Infections.

Mitochondria play pivotal roles in sustaining various biological functions including energy metabolism, cellular signaling transduction, and innate immune responses. Viruses exploit cellular metabolic synthesis to facilitate viral replication, potentially disrupting mitochondrial functions and subsequently eliciting a cascade of proinflammatory responses in host cells. Additionally, the disruption of mitochondrial membranes is involved in immune regulation. During viral infections, mitochondria orchestrate innate immune responses through the generation of reactive oxygen species (ROS) and the release of mitochondrial DNA, which serves as an effective defense mechanism against virus invasion. The targeting of mitochondrial damage may represent a novel approach to antiviral intervention. This review summarizes the regulatory mechanism underlying proinflammatory response induced by mitochondrial damage during viral infections, providing new insights for antiviral strategies.

The Dual Role of TRIM7 in Viral Infections.

The E3 ubiquitin ligase TRIM7 is known to have dual roles during viral infections. Like other TRIM proteins, TRIM7 can regulate the IFN pathway via the regulation of the cytosolic receptors RIG-I or MDA-5, which promote the production of type I interferons (IFN-I) and antiviral immune responses. Alternatively, under certain infectious conditions, TRIM7 can negatively regulate IFN-I signaling, resulting in increased virus replication. A growing body of evidence has also shown that TRIM7 can, in some cases, ubiquitinate viral proteins to promote viral replication and pathogenesis, while in other cases it can promote degradation of viral proteins through the proteasome, reducing virus infection. TRIM7 can also regulate the host inflammatory response and modulate the production of inflammatory cytokines, which can lead to detrimental inflammation. TRIM7 can also protect the host during infection by reducing cellular apoptosis. Here, we discuss the multiple functions of TRIM7 during viral infections and its potential as a therapeutic target.

The Effects of Viral Infections on the Molecular and Signaling Pathways Involved in the Development of the PAOs.

Cytomegalovirus infection contributes to 10-30% of congenital hearing loss in children. Vertebrate peripheral auditory organs include the outer, middle, and inner ear. Their development is regulated by multiple signaling pathways. However, most ear diseases due to viral infections are due to congenital infections and reactivation and affect healthy adults to a lesser extent. This may be due to the fact that viral infections affect signaling pathways that are important for the development of peripheral hearing organs. Therefore, an in-depth understanding of the relationship between viral infections and the signaling pathways involved in the development of peripheral hearing organs is important for the prevention and treatment of ear diseases. In this review, we summarize the effects of viruses on signaling pathways and signaling molecules in the development of peripheral auditory organs.

Mechanism and complex roles of HSC70/HSPA8 in viral entry.

The process of viruses entering host cells is complex, involving multiple aspects of the molecular organization of the cell membrane, viral proteins, the interaction of receptor molecules, and cellular signaling. Most viruses depend on endocytosis for uptake, when viruses reach the appropriate location, they are released from the vesicles, undergo uncoating, and release their genomes. Heat shock cognate protein 70(HSC70): also known as HSPA8, a protein involved in mediating clathrin-mediated endocytosis (CME), is involved in various viral entry processes. In this mini-review, our goal is to provide a summary of the function of HSC70 in viral entry. Understanding the interaction networks of HSC70 with viral proteins helps to provide new directions for targeted therapeutic strategies against viral infections.

Research progress on the mechanism of exosome-mediated virus infection.

Exosomes are extracelluar vesicles that facilitate intercellular communication and are pivotal in post-transcriptional regulation within cellular gene regulatory networks, impacting pathogen dynamics. These vesicles serve as crucial regulators of immune responses, mediating cellular interactions and enabling the introduction of viral pathogenic regions into host cells. Exosomes released from virus-infected cells harbor diverse microRNAs (miRNAs), which can be transferred to recipient cells, thereby modulating virus infection. This transfer is a critical element in the molecular interplay mediated by exosomes. Additionally, the endosomal sorting complex required for transport (ESCRT) within exosomes plays a vital role in virus infection, with ESCRT components binding to viral proteins to facilitate virus budding. This review elucidates the roles of exosomes and their constituents in the invasion of host cells by viruses, aiming to shed new light on the regulation of viral transmission via exosomes.

Structural insight of cell surface sugars in viral infection and human milk glycans as natural antiviral substance.

Viral infections are caused by the adhesion of viruses to host cell receptors, including sialylated glycans, glycosaminoglycans, and human blood group antigens (HBGAs). Atomic-level structural information on the interactions between viral particles or proteins with glycans can be determined to provide precise targets for designing antiviral drugs. Milk glycans, existing as free oligosaccharides or glycoconjugates, have attracted increasing attention; milk glycans protect infants against infectious diseases, particularly poorly manageable viral infections. Furthermore, several glycans containing structurally distinct sialic acid/fucose/sulfate modifications in human milk acting as a "receptor decoy" and serving as the natural antiviral library, could interrupt virus-receptor interaction in the first line of defense for viral infection. This review highlights the basis of virus-glycan interactions, presents specific glycan receptor binding by gastroenterovirus viruses, including norovirus, enteroviruses, and the breakthroughs in the studies on the antiviral properties of human milk glycans, and also elucidates the role of glycans in respiratory viruses infection. In addition, recent advances in methods for performing virus/viral protein-glycan interactions were reported. Finally, we discuss the prospects and challenges of the studies on the clinical application of human milk glycan for viral interventions.

14-3-3 Family of Proteins: Biological Implications, Molecular Interactions, and Potential Intervention in Cancer, Virus and Neurodegeneration Disorders.

The 14-3-3 family of proteins are highly conserved acidic eukaryotic proteins (25-32 kDa) abundantly present in the body. Through numerous binding partners, the 14-3-3 is responsible for many essential cellular pathways, such as cell cycle regulation and gene transcription control. Hence, its dysregulation has been linked to the onset of critical illnesses such as cancers, neurodegenerative diseases and viral infections. Interestingly, explorative studies have revealed an inverse correlation of 14-3-3 protein in cancer and neurodegenerative diseases, and the direct manipulation of 14-3-3 by virus to enhance infection capacity has dramatically extended its significance. Of these, COVID-19 has been linked to the 14-3-3 proteins by the interference of the SARS-CoV-2 nucleocapsid (N) protein during virion assembly. Given its predisposition towards multiple essential host signalling pathways, it is vital to understand the holistic interactions between the 14-3-3 protein to unravel its potential therapeutic unit in the future. As such, the general structure and properties of the 14-3-3 family of proteins, as well as their known biological functions and implications in cancer, neurodegeneration, and viruses, were covered in this review. Furthermore, the potential therapeutic target of 14-3-3 proteins in the associated diseases was discussed.

A Review of the Bromodomain and Extraterminal Domain Epigenetic Reader Proteins: Function on Virus Infection and Cancer.

The BET (bromodomain and extraterminal domain) family of proteins, particularly BRD4 (bromodomain-containing protein 4), plays a crucial role in transcription regulation and epigenetic mechanisms, impacting key cellular processes such as proliferation, differentiation, and the DNA damage response. BRD4, the most studied member of this family, binds to acetylated lysines on both histones and non-histone proteins, thereby regulating gene expression and influencing diverse cellular functions such as the cell cycle, tumorigenesis, and immune responses to viral infections. Given BRD4's involvement in these fundamental processes, it is implicated in various diseases, including cancer and inflammation, making it a promising target for therapeutic development. This review comprehensively explores the roles of the BET family in gene transcription, DNA damage response, and viral infection, discussing the potential of targeted small-molecule compounds and highlighting BET proteins as promising candidates for anticancer therapy.

Viral mimicry and endocrine system: Divulging the importance in host-microbial crosstalk.

Host-pathogen interactions are complex associations which evolve over long co-evolutionary histories. Pathogens exhibit different mechanisms to gain advantage over their host. Mimicry of host factors is an influential tool in subverting host mechanisms to ensure pathogenesis. This chapter discusses such molecular mimicry exhibited during viral infections. Understanding the evolutionary relationships, shared identity and functional impact of the virus encoded mimics is critical. With a particular emphasis on viral mimics and their association with cancer and autoimmune diseases, this chapter highlights the importance of molecular mimicry in virus biology.

The Role of the Nrf2 Pathway in Airway Tissue Damage Due to Viral Respiratory Infections.

Respiratory viruses constitute a significant cause of illness and death worldwide. Respiratory virus-associated injuries include oxidative stress, ferroptosis, inflammation, pyroptosis, apoptosis, fibrosis, autoimmunity, and vascular injury. Several studies have demonstrated the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) in the pathophysiology of viral infection and associated complications. It has thus emerged as a pivotal player in cellular defense mechanisms against such damage. Here, we discuss the impact of Nrf2 activation on airway injuries induced by respiratory viruses, including viruses, coronaviruses, rhinoviruses, and respiratory syncytial viruses. The inhibition or deregulation of Nrf2 pathway activation induces airway tissue damage in the presence of viral respiratory infections. In contrast, Nrf2 pathway activation demonstrates protection against tissue and organ injuries. Clinical trials involving Nrf2 agonists are needed to define the effect of Nrf2 therapeutics on airway tissues and organs damaged by viral respiratory infections.

Immunometabolites in viral infections: Action mechanism and function.

The interplay between viral pathogens and host metabolism plays a pivotal role in determining the outcome of viral infections. Upon viral detection, the metabolic landscape of the host cell undergoes significant changes, shifting from oxidative respiration via the tricarboxylic acid (TCA) cycle to increased aerobic glycolysis. This metabolic shift is accompanied by elevated nutrient accessibility, which is vital for cell function, development, and proliferation. Furthermore, depositing metabolites derived from fatty acids, TCA intermediates, and amino acid catabolism accelerates the immunometabolic transition, facilitating pro-inflammatory and antimicrobial responses. Immunometabolites refer to small molecules involved in cellular metabolism regulating the immune response. These molecules include nutrients, such as glucose and amino acids, along with metabolic intermediates and signaling molecules adenosine, lactate, itaconate, succinate, kynurenine, and prostaglandins. Emerging evidence suggests that immunometabolites released by immune cells establish a complex interaction network within local niches, orchestrating and fine-tuning immune responses during viral diseases. However, our current understanding of the immense capacity of metabolites to convey essential cell signals from one cell to another or within cellular compartments remains incomplete. Unraveling these complexities would be crucial for harnessing the potential of immunometabolites in therapeutic interventions. In this review, we discuss specific immunometabolites and their mechanisms of action in viral infections, emphasizing recent findings and future directions in this rapidly evolving field.

STING-NF-κB signaling: Viral infection drives gut aging effects.

Viral infection causes an increase in age-related intestinal pathologies. New research finds that oral viral infection leads to intestinal stem-cell proliferation and a decrease in lifespan in Drosophila melanogaster that depends on Sting-NF-κB signaling.

Virus infection and sphingolipid metabolism.

Cellular sphingolipids have vital roles in human virus replication and spread as they are exploited by viruses for cell entry, membrane fusion, genome replication, assembly, budding, and propagation. Intracellular sphingolipid biosynthesis triggers conformational changes in viral receptors and facilitates endosomal escape. However, our current understanding of how sphingolipids precisely regulate viral replication is limited, and further research is required to comprehensively understand the relationships between viral replication and endogenous sphingolipid species. Emerging evidence now suggests that targeting and manipulating sphingolipid metabolism enzymes in host cells is a promising strategy to effectively combat viral infections. Additionally, serum sphingolipid species and concentrations could function as potential serum biomarkers to help monitor viral infection status in different patients. In this work, we comprehensively review the literature to clarify how viruses exploit host sphingolipid metabolism to accommodate viral replication and disrupt host innate immune responses. We also provide valuable insights on the development and use of antiviral drugs in this area.

Cortactin: A major cellular target of viral, protozoal, and fungal pathogens.

Many viral, protozoal, and fungal pathogens represent major human and animal health problems due to their great potential of causing infectious diseases. Research on these pathogens has contributed substantially to our current understanding of both microbial virulence determinants and host key factors during infection. Countless studies have also shed light on the molecular mechanisms of host-pathogen interactions that are employed by these microbes. For example, actin cytoskeletal dynamics play critical roles in effective adhesion, host cell entry, and intracellular movements of intruding pathogens. Cortactin is an eminent host cell protein that stimulates actin polymerization and signal transduction, and recently emerged as fundamental player during host-pathogen crosstalk. Here we review the important role of cortactin as major target for various prominent viral, protozoal and fungal pathogens in humans, and its role in human disease development and cancer progression. Most if not all of these important classes of pathogens have been reported to hijack cortactin during infection through mediating up- or downregulation of cortactin mRNA and protein expression as well as signaling. In particular, pathogen-induced changes in tyrosine and serine phosphorylation status of cortactin at its major phospho-sites (Y-421, Y-470, Y-486, S-113, S-298, S-405, and S-418) are addressed. As has been reported for various Gram-negative and Gram-positive bacteria, many pathogenic viruses, protozoa, and fungi also control these regulatory phospho-sites, for example, by activating kinases such as Src, PAK, ERK1/2, and PKD, which are known to phosphorylate cortactin. In addition, the recruitment of cortactin and its interaction partners, like the Arp2/3 complex and F-actin, to the contact sites between pathogens and host cells is highlighted, as this plays an important role in the infection process and internalization of several pathogens. However, there are also other ways in which the pathogens can exploit the function of cortactin for their needs, as the cortactin-mediated regulation of cellular processes is complex and involves numerous different interaction partners. Here, the current state of knowledge is summarized.

Ubiquitination in viral entry and replication: Mechanisms and implications.

The ubiquitination process is a reversible posttranslational modification involved in many essential cellular functions, such as innate immunity, cell signaling, trafficking, protein stability, and protein degradation. Viruses can use the ubiquitin system to efficiently enter host cells, replicate and evade host immunity, ultimately enhancing viral pathogenesis. Emerging evidence indicates that enveloped viruses can carry free (unanchored) ubiquitin or covalently ubiquitinated viral structural proteins that can increase the efficiency of viral entry into host cells. Furthermore, viruses continuously evolve and adapt to take advantage of the host ubiquitin machinery, highlighting its importance during virus infection. This review discusses the battle between viruses and hosts, focusing on how viruses hijack the ubiquitination process at different steps of the replication cycle, with a specific emphasis on viral entry. We discuss how ubiquitination of viral proteins may affect tropism and explore emerging therapeutics strategies targeting the ubiquitin system for antiviral drug discovery.

A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections.

Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.

Exploring the role of brain-derived extracellular vesicles in viral infections: from pathological insights to biomarker potential.

Extracellular vesicles (EVs) are membrane-bound vesicles secreted by all cell types that play a central role in cell-to-cell communication. Since these vesicles serve as vehicles of cellular content (nucleic acids, proteins and lipids) with the potential to cross biological barriers, they represent a novel attractive window into an otherwise inaccessible organ, such as the brain. The composition of EVs is cell-type specific and mirrors the physiological condition of the cell-of-origin. Consequently, during viral infection, EVs undergo significant changes in their content and morphology, thereby reflecting alterations in the cellular state. Here, we briefly summarize the potential of brain-derived EVs as a lens into viral infection in the central nervous system, thereby: 1) uncovering underlying pathophysiological processes at play and 2) serving as liquid biopsies of the brain, representing a non-invasive source of biomarkers for monitoring disease activity. Although translating the potential of EVs from research to diagnosis poses complexities, characterizing brain-derived EVs in the context of viral infections holds promise to enhance diagnostic and therapeutic strategies, offering new avenues for managing infectious neurological diseases.