The inhibitory and inactivating effects of visible light on SARS-CoV-2: A narrative update.

Prior to the coronavirus disease-19 (COVID-19) pandemic, the germicidal effects of visible light (λ = 400 - 700 nm) were well known. This review provides an overview of new findings that suggest there are direct inactivating effects of visible light - particularly blue wavelengths (λ = 400 - 500 nm) - on exposed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions, and inhibitory effects on viral replication in infected cells. These findings complement emerging evidence that there may be clinical benefits of orally administered blue light for limiting the severity of COVID-19. Possible mechanisms of action of blue light (e.g., regulation of reactive oxygen species) and important mediators (e.g., melatonin) are discussed.

Glycyrrhizin inhibits swine acute diarrhea syndrome coronavirus infection via the HMGB1/TLR4/JNK signal pathway

Swine acute diarrhea syndrome coronavirus (SADS-CoV), a newly discovered enteric coronavirus, is the etiological agent that causes severe clinical diarrhea and intestinal pathological damage in piglets. In this study, Vero E6 and IPI-2I cells were pretreated with different concentrations of glycyrrhizin (GLY) for 2 hours, and then infected with different concentrations of SADSCoV, aiming to investigate the inhibitory effect of GLY on SADS-CoV. Western blot and TCID50 results revealed a significantly decreased N protein expression and viral titer, indicating that GLY can inhibit the infection of SADS-CoV. Vero E6 and IPI-2I cells were pretreated with different concentrations of GLY for 2 hours and infected with SADS-CoV. Western blot results showed that when the concentration of GLY was 0.8 mmol/L, the expression of N protein decreased significantly, indicating that GLY inhibited the invasion of the virus. At first, cells were treated with 0.4 mmol/L GLY, and cell samples were collected at 2 hours, 6 hours and 12 hours after being infected with SADS-CoV for analysis, and the expression of N protein were found to be significantly reduced at all points, indicating that GLY had a significant inhibitory effect on the replication of the virus. GLY is a competitive inhibitor of high mobility group box 1 (HMGB1), and the receptors of HMGB1 mainly include TLR4 and RAGE. Based on this fact, the mutant plasmid at the key sites of HMGB1 (C45S, C106S, C45/106S) and the siRNA of the RAGE receptor were transfected to Vero E6 cells and infected with SADS-CoV, and the cell supernatant and samples were harvested. The western blot and TCID50 results showed that the expression of N protein and the virus titer were decreased, suggesting that GLY exerts its function by affecting the binding of HMGB1/TLR4/RAGE during SADS-CoV infection. To further explore the signaling pathway through which GLY functions, Vero E6 and IPI-2I cells were inoculated with SADS-CoV, and cell samples were harvested, western blot was used to detect the changes of MAPK proteins. The results showed that the protein expression levels of p-p38, p-JNK and p-ERK were up-regulated in the early and late stages, indicating that the MAPK pathway was activated by SADS-CoV infection. Vero E6 and IPI-2I were pretreated with different concentrations of GLY and TLR4 inhibitor TAK for 2 hours and infected with SADS-CoV. Protein samples were harvested and analysed by western blot which showed a decreased p-JNK and N proteins, while other proteins showed no significant changes. These results indicated that GLY and TAK regulated the phosphorylation of JNK but did not regulate the phosphorylation of p38 and ERK. Also, Vero E6 cells were treated with HMGB1 antibody, the siRNA of HMGB1 and HMGB1 mutants plasmid, and infected with SADS-CoV. Protein samples were harvested, western blot results showed that phosphorylation of JNK decreased, indicating that HMGB1 affected JNK phosphorylation. Finally, Vero E6 and IPI-2I cells were pretreated with different concentrations of JNK inhibitor SP600125 to infect SADS-CoV, western blot, TCID50 and IFA results showed that the expression of N protein and virus titer, as well as virus replication were reduced, indicating that SP600125 inhibited virus replication. In conclusion, our results revealed that GLY can inhibit in vitro replication of SADS- CoV, mainly through the HMGB1/TLR4/JNK signaling pathway. The discovery of this pathway provides theoretical support for the research of novel anti-SADS-CoV drugs.

A Literature Review on the Antiviral Mechanism of Luteolin

Background: Viral infections pose some of the most serious human health concerns worldwide. The infections caused by several viruses, including coronavirus, hepatitis virus, and human immunodeficiency virus, are difficult to treat. Method(s): This review details the findings of a literature search performed on the antiviral properties of luteolin. The keywords engaged in the search are "virus" along with "luteolin." Results: Luteolin possesses antiviral properties, which is the basis for the current review. It is an important natural flavonoid with numerous important biological properties, including anti-inflammatory, immune regulatory, and antitumor effects, and is found in vegetables, fruits, and several medicinal plants. Recent studies have revealed that many traditional Chinese medicines that contain luteolin inhibit the replication of coronaviruses. Conclusion(s): Luteolin effectively inhibits the replication of coronavirus, influenza virus, enterovirus, rotavirus, herpes virus, and respiratory syncytial virus, among others. In particular, it prevents viral infection by improving the body's nonspecific immunity and antioxidation capacity and inhibiting many pathways related to virus infection and replication, such as MAPK, PI3K-AKT, TLR4/8, NF-kappaB, Nrf-2/hemeoxygenase-1, and others. It also regulates the expression of some receptors and factors, including hepatocyte nuclear factor 4alpha, p53, NLRP3, TNF-alpha, and interleukins, thereby interfering with the replication of viruses in cells. Luteolin also promotes the repair of damaged cells induced by proinflammatory factors by regulating the expression of inflammatory molecules. The overall effect of these processes is the reduction in viral replication and, consequently, the viral load. This review summarizes the antiviral effect of luteolin and the mechanism underlying this property.Copyright © The Author(s) 2023.

A review of bioinformatics studies on the function of structural and nonstructural proteins and the level of glycoprotein inhibiting heme metabolism by SARS-CoV-2 virus

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection. Its virus called SARS-COV-2 which is an RNA virus with high homology to the bat coronavirus. In this review study, first the molecular and cellular characteristics and the proliferation and replication of SARS-COV-2 are investigated. Then, by reviewing bioinformatics studies regarding protected domain analysis, homology modeling, and molecular docking, the biological role of some specific SARS-COV-2 proteins are examined. The results showed that the open reading frame 8 (ORF8) and surface glycoprotein could bind to porphyrin. At the same time, ORF1ab, ORF10, and ORF3a can attack the heme part of hemoglobin to dissociate iron and form porphyrin. This attack reduces hemoglobin ability to carry oxygen and carbon dioxide. As a result, lung cells become severely inflamed due to their inability to exchange carbon dioxide and oxygen, which leads to large ground-glass opacities on CT scan images. Based on the bioinformatics results, chloroquine can prevent ORF1ab, ORF3a, and ORF10 from attacking hemoglobin to form porphyrin and avoid the binding of ORF8 and surface glycoprotein to porphyrin, which effectively relieves the symptoms of acute respiratory syndrome. In the current pandemic, bioinformatics studies are of great importance for preventing the spread of COVID-19, developing drugs and vaccines, and clinical practice.

PM10 promotes an inflammatory cytokine response that may impact SARS-CoV-2 replication in vitro.

Introduction: In the last decades, a decrease in air quality has been observed, mainly associated with anthropogenic activities. Air pollutants, including particulate matter (PM), have been associated with adverse effects on human health, such as exacerbation of respiratory diseases and infections. High levels of PM in the air have recently been associated with increased morbidity and mortality of COVID-19 in some regions of the world. Objective: To evaluate the effect of coarse particulate matter (PM10) on the inflammatory response and viral replication triggered by SARS-CoV-2 using in vitro models. Methods: Peripheral blood mononuclear cells (PBMC) from healthy donors were treated with PM10 and subsequently exposed to SARS-CoV-2 (D614G strain, MOI 0.1). The production of pro-inflammatory cytokines and antiviral factors was quantified by qPCR and ELISA. In addition, using the A549 cell line, previously exposed to PM, the viral replication was evaluated by qPCR and plaque assay. Results: SARS-CoV-2 stimulation increased the production of pro-inflammatory cytokines in PBMC, such as IL-1ß, IL-6 and IL-8, but not antiviral factors. Likewise, PM10 induced significant production of IL-6 in PBMCs stimulated with SARS-CoV-2 and decreased the expression of OAS and PKR. Additionally, PM10 induces the release of IL-1ß in PBMC exposed to SARS-CoV-2 as well as in a co-culture of epithelial cells and PBMCs. Finally, increased viral replication of SARS-CoV-2 was shown in response to PM10. Conclusion: Exposure to coarse particulate matter increases the production of pro-inflammatory cytokines, such as IL-1ß and IL-6, and may alter the expression of antiviral factors, which are relevant for the immune response to SARS-CoV-2. These results suggest that pre-exposure to air particulate matter could have a modest role in the higher production of cytokines and viral replication during COVID-19, which eventually could contribute to severe clinical outcomes.

Epigenetic regulation of the COVID-19 pathogenesis: its impact on the host immune response and disease progression

Coronavirus disease 2019 (COVID-19) is highly infectious and may induce epigenetic alteration of the host immune system. Understanding the role of epigenetic mechanisms in COVID-19 infection is a clinical need to minimize critical illness and widespread transmission. The susceptibility to infection and progression of COVID-19 varies from person to person;pathophysiology substantially depends on epigenetic changes in the immune system and preexisting health conditions. Recent experimental and epidemiological studies have revealed the method of transmission and clinical presentation related to COVID-19 pathogenesis, however, the underlying pathology of variation in the severity of infection remains questionable. Epigenetic changes may also be responsible factors for multisystem association and deadly systemic complications of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected patients. Commonly, epigenetic changes are evoked by alteration of the host's immune response, stress, preexisting condition, oxidative stress response, external behavioral or environmental factors, and age. In addition, the viral infection itself might manipulate the host immune responses associated with inflammation by reprogramming epigenetic processes which are the susceptible factor for disease severity and death. As a result, epigenetic events such as histone modification and DNA methylation are implicated in regulating pro-inflammatory cytokines production by remodeling macrophage and T-cell activity towards inflammation, consequently, may also affect tissue repair and injury resolution process. This review aims to discuss the comprehensive understanding of the epigenetic landscape of COVID-19 disease progression that varies from person to person with supporting interdisciplinary prognosis protocol to overcome systemic impairment.

Antiviral Activity of Acetylsalicylic Acid against Bunyamwera Virus in Cell Culture.

The Bunyavirales order is a large group of RNA viruses that includes important pathogens for humans, animals and plants. With high-throughput screening of clinically tested compounds we have looked for potential inhibitors of the endonuclease domain of a bunyavirus RNA polymerase. From a list of fifteen top candidates, five compounds were selected and their antiviral properties studied with Bunyamwera virus (BUNV), a prototypic bunyavirus widely used for studies about the biology of this group of viruses and to test antivirals. Four compounds (silibinin A, myricetin, L-phenylalanine and p-aminohippuric acid) showed no antiviral activity in BUNV-infected Vero cells. On the contrary, acetylsalicylic acid (ASA) efficiently inhibited BUNV infection with a half maximal inhibitory concentration (IC50) of 2.02 mM. In cell culture supernatants, ASA reduced viral titer up to three logarithmic units. A significant dose-dependent reduction of the expression levels of Gc and N viral proteins was also measured. Immunofluorescence and confocal microscopy showed that ASA protects the Golgi complex from the characteristic BUNV-induced fragmentation in Vero cells. Electron microscopy showed that ASA inhibits the assembly of Golgi-associated BUNV spherules that are the replication organelles of bunyaviruses. As a consequence, the assembly of new viral particles is also significantly reduced. Considering its availability and low cost, the potential usability of ASA to treat bunyavirus infections deserves further investigation.

SARS-CoV-2 morphology, genome, life cycle and our bodies' immune response: a review Ilyes Zatla, Lamia Boublenza, Hafida Hassaine

A novel coronavirus strain has been testing the capabilities of our modern world and suffocating health care systems, while bringing together scientist's researches and governmental powers, to fight off its robust viral disease. A new zoonotic pathogenic member of the human coronaviruses, that was first documented in Wuhan, China, has crossed the species barrier to infect humans and caused an outbreak of viral pneumonia. In this brief review, we'll discuss the virology of SARS-CoV-2, the virus that causes COVID-19, covering the general structure of the virus, its genetics and its process of replication. SARS-CoV-2 gets into the cell through the recognition of the angiotensin-converting enzyme 2 (ACE2) receptors by the spike glycoprotein, with the aid of the priming protein transmembrane serine protease 2 (TMPRSS2), which is important for its activation, and replicates as a result of a complex process that involves RNA synthesis, proofreading and capping.

COVID-19 Biogenesis and Intracellular Transport.

SARS-CoV-2 is responsible for the COVID-19 pandemic. The structure of SARS-CoV-2 and most of its proteins of have been deciphered. SARS-CoV-2 enters cells through the endocytic pathway and perforates the endosomes' membranes, and its (+) RNA appears in the cytosol. Then, SARS-CoV-2 starts to use the protein machines of host cells and their membranes for its biogenesis. SARS-CoV-2 generates a replication organelle in the reticulo-vesicular network of the zippered endoplasmic reticulum and double membrane vesicles. Then, viral proteins start to oligomerize and are subjected to budding within the ER exit sites, and its virions are passed through the Golgi complex, where the proteins are subjected to glycosylation and appear in post-Golgi carriers. After their fusion with the plasma membrane, glycosylated virions are secreted into the lumen of airways or (seemingly rarely) into the space between epithelial cells. This review focuses on the biology of SARS-CoV-2's interactions with cells and its transport within cells. Our analysis revealed a significant number of unclear points related to intracellular transport in SARS-CoV-2-infected cells.

Effects of natural polymorphisms in SARS-CoV-2 RNA-dependent RNA polymerase on its activity and sensitivity to inhibitors in vitro.

SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is the key enzyme required for viral replication and mRNA synthesis. RdRp is one of the most conserved viral proteins and a promising target for antiviral drugs and inhibitors. At the same time, analysis of public databases reveals multiple variants of SARS-CoV-2 genomes with substitutions in the catalytic RdRp subunit nsp12. Structural mapping of these mutations suggests that some of them may affect the interactions of nsp12 with its cofactors nsp7/nsp8 as well as with RNA substrates. We have obtained several mutations of these types and demonstrated that some of them decrease specific activity of RdRp in vitro, possibly by changing RdRp assembly and/or its interactions with RNA. Therefore, natural polymorphisms in RdRp may potentially affect viral replication. Furthermore, we have synthesized a series of polyphenol and diketoacid derivatives based on previously studied inhibitors of hepatitis C virus RdRp and found that several of them can inhibit SARS-CoV-2 RdRp. Tested mutations in RdRp do not have strong effects on the efficiency of inhibition. Further development of more efficient non-nucleoside inhibitors of SARS-CoV-2 RdRp should take into account the existence of multiple polymorphic variants of RdRp.

Cell Entry and Unusual Replication of SARS-CoV-2.

BACKGROUND: SARS-CoV-2 is the causative virus for the CoVID-19 pandemic that has frequently mutated to continue to infect and resist available vaccines. Emerging new variants of the virus have complicated notions of immunity conferred by vaccines versus immunity that results from infection. While we continue to progress from epidemic to endemic as a result of this collective immunity, the pandemic remains a morbid and mortal problem. OBJECTIVE: The SARS-CoV-2 virus has a very complex manner of replication. The spike protein, one of the four structural proteins of the encapsulated virus, is central to the ability of the virus to penetrate cells to replicate. The objective of this review is to summarize these complex features of viral replication. METHODS: A review of the recent literature was performed on the biology of SARS-CoV-2 infection from published work from PubMed and works reported to preprint servers, e.g., bioRxiv and medRxiv. RESULTS AND CONCLUSION: The complex molecular and cellular biology involved in SARS-CoV-2 replication and the origination of >30 proteins from a single open reading frame (ORF) have been summarized, as well as the structural biology of spike protein, a critical factor in the cellular entry of the virus, which is a necessary feature for it to replicate and cause disease.

Reviewing the Potential Links between Viral Infections and TDP-43 Proteinopathies.

Transactive response DNA binding protein 43 kDa (TDP-43) was discovered in 2001 as a cellular factor capable to inhibit HIV-1 gene expression. Successively, it was brought to new life as the most prevalent RNA-binding protein involved in several neurological disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the fact that these two research areas could be considered very distant from each other, in recent years an increasing number of publications pointed out the existence of a potentially important connection. Indeed, the ability of TDP-43 to act as an important regulator of all aspects of RNA metabolism makes this protein also a critical factor during expression of viral RNAs. Here, we summarize all recent observations regarding the involvement of TDP-43 in viral entry, replication and latency in several viruses that include enteroviruses (EVs), Theiler's murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). In particular, in this work, we aimed to highlight the presence of similarities with the most commonly studied TDP-43 related neuronal dysfunctions.

Mouse-Adapted SARS-CoV-2 MA10 Strain Displays Differential Pulmonary Tropism and Accelerated Viral Replication, Neurodissemination, and Pulmonary Host Responses in K18-hACE2 Mice.

Several models were developed to study the pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as the in vivo efficacy of vaccines and therapeutics. Since wild-type mice are naturally resistant to infection by ancestral SARS-CoV-2 strains, several transgenic mouse models expressing human angiotensin-converting enzyme 2 (hACE2) were developed. An alternative approach has been to develop mouse-adapted SARS-CoV-2 strains. Here, we compared the clinical progression, viral replication kinetics and dissemination, pulmonary tropism, and host innate immune response dynamics between the mouse-adapted MA10 strain and its parental strain (USA-WA1/2020) following intranasal inoculation of K18-hACE2 mice, a widely used model. Compared to its parental counterpart, the MA10 strain induced earlier clinical decline with significantly higher viral replication and earlier neurodissemination. Importantly, the MA10 strain also showed a wider tropism, with infection of bronchiolar epithelia. While both SARS-CoV-2 strains induced comparable pulmonary cytokine/chemokine responses, many proinflammatory and monocyte-recruitment chemokines, such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10/CXCL10, and MCP-1/CCL2, showed an earlier peak in MA10-infected mice. Furthermore, both strains induced a similar downregulation of murine Ace2, with only a transient downregulation of Tmprss2 and no alterations in hACE2 expression. Overall, these data demonstrate that in K18-hACE2 mice, the MA10 strain has a pulmonary tropism that more closely resembles SARS-CoV-2 tropism in humans (airways and pneumocytes) than its parental strain. Its rapid replication and neurodissemination and early host pulmonary responses can have a significant impact on the clinical outcomes of infection and are, therefore, critical features to consider for study designs using these strains and mouse model. IMPORTANCE The COVID-19 pandemic, caused by SARS-CoV-2, is still significantly impacting health care systems around the globe. Refined animal models are needed to study SARS-CoV-2 pathogenicity as well as efficacy of vaccines and therapeutics. In line with this, thorough evaluation of animal models and virus strains/variants are paramount for standardization and meaningful comparisons. Here, we demonstrated differences in replication dynamics between the Wuhan-like USA-WA1/2020 strain and the derivative mouse-adapted MA10 strain in K18-hACE2 mice. The MA10 strain showed accelerated viral replication and neurodissemination, differential pulmonary tropism, and earlier pulmonary innate immune responses. The observed differences allow us to better refine experimental designs when considering the use of the MA10 strain in the widely utilized K18-hACE2 murine model.

Effect of SARS-CoV-2 digital droplet RT-PCR assay sensitivity on COVID-19 wastewater based epidemiology

We developed and implemented a framework for examining how molecular assay sensitivity for a viral RNA genome target affects its utility for wastewater-based epidemiology. We applied this framework to digital droplet RT-PCR measurements of SARS-CoV-2 and Pepper Mild Mottle Virus genes in wastewater. Measurements were made using 10 replicate wells which allowed for high assay sensitivity, and therefore enabled detection of SARS-CoV-2 RNA even when COVID-19 incidence rates were relatively low (~10−5). We then used a computational downsampling approach to determine how using fewer replicate wells to measure the wastewater concentration reduced assay sensitivity and how the resultant reduction affected the ability to detect SARS-CoV-2 RNA at various COVID-19 incidence rates. When percent of positive droplets was between 0.024% and 0.5% (as was the case for SARS-CoV-2 genes during the Delta surge), measurements obtained with 3 or more wells were similar to those obtained using 10. When percent of positive droplets was less than 0.024% (as was the case prior to the Delta surge), then 6 or more wells were needed to obtain similar results as those obtained using 10 wells. When COVID-19 incidence rate is low (~ 10−5), as it was before the Delta surge and SARS-CoV-2 gene concentrations are <104 cp/g, using 6 wells will yield a detectable concentration 90% of the time. Overall, results support an adaptive approach where assay sensitivity is increased by running 6 or more wells during periods of low SARS-CoV-2 gene concentrations, and 3 or more wells during periods of high SARS-CoV-2 gene concentrations.

Fidelity of Ribonucleotide Incorporation by the SARS-CoV-2 Replication Complex.

The SARS-CoV-2 coronavirus has caused a global pandemic. Despite the initial success of vaccines at preventing infection, genomic variation has led to the proliferation of variants capable of higher infectivity. Mutations in the SARS-CoV-2 genome are the consequence of replication errors, highlighting the importance of understanding the determinants of SARS-CoV-2 replication fidelity. The RNA-dependent RNA polymerase (RdRp) is the central catalytic subunit for SARS-CoV-2 RNA replication and genome transcription. Here, we report the fidelity of ribonucleotide incorporation by SARS-CoV-2 RdRp (nsp12), along with its co-factors nsp7/nsp8, using steady-state kinetic analysis. Our analysis suggests that in the absence of the proofreading subunit (nsp14), the nsp12/7/8 complex has a surprisingly low base substitution fidelity (10-1-10-3). This is orders of magnitude lower than the fidelity reported for other coronaviruses (10-6-10-7), highlighting the importance of proofreading for faithful SARS-CoV-2 replication. We performed a mutational analysis of all reported SARS-CoV-2 genomes and identified mutations in both nsp12 and nsp14 that appear likely to lower viral replication fidelity through mechanisms that include impairing the nsp14 exonuclease activity or its association with the RdRp. Our observations provide novel insight into the mechanistic basis of replication fidelity in SARS-CoV-2 and the potential effect of nsp12 and nsp14 mutations on replication fidelity, informing the development of future antiviral agents and SARS-CoV-2 vaccines.

Virtual Screening of Cyanobacterial Metabolites as Inhibitors of SARS-CoV-2 Host Cell Entry, Viral Replication, and Host Immunity Modulation Infective Mechanisms

Despite the global effort to recover from the COVID-19 pandemic through vaccine procurements and the development of new treatments, the unpredictable fluctuations of symptomatic cases due to the increase in COVID-19 variants still demand the discovery of additional efficacious antiviral drugs. Cyanobacteria generate a wide array of biologically active secondary metabolites, establishing the domain of cyanotherapeutics. However, the therapeutic applications of cyanobacteria against SARS-CoV-2 are yet to be explored. In this study, 56 cyanobacterial secondary metabolites were screened for in silico inhibitory potential against five main target sites of SARS-CoV-2 involved in viral attachment and replication mechanisms. Top-ranked ligands were then subjected to molecular dynamics (MD) simulation. Pharmacokinetic properties and toxicity predictions were also performed. Of the 56 secondary metabolites molecularly docked, compounds 1-7 showed favorable binding energy ranging from -8.0 to -11.2 kcal/mol against the spike's ACE2 (angiotensin-converting enzyme 2) and GRP 78 (glucose-related protein 78) receptor-binding domains, 3CLPRO (3-chymotrypsin-like protease), PLPRO (papain-like protease), and RdRp (RNA-dependent RNA-polymerase). Three compounds -- scytonemin (1), a bisindole alkaloid dimer;enterobactin (2), and agardhipeptin A (3) -- exhibited the highest binding affinities with BEs ranging from -8.2 to -11.2 kcal/mol. Through MD simulations, scytonemin (1) complexed with the spike RBD, 3CLPRO, and RdRp, as well as enterobactin (2) complexed with PLPRO demonstrated dynamic stability. Among the three top-scoring lead papaincompounds, scytonemin (1) exhibited drug-like and favorable ADME properties. Hence, the topscoring compounds from cyanobacteria present as favorable drug prototypes for optimization and in vitro testing against SARS-CoV-2. [ FROM AUTHOR]

IFN-stimulated metabolite transporter ENT3 facilitates viral genome release.

An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of equilibrative nucleoside transporter 3 (ENT3, encoded by solute carrier family 29 member 3, Slc29a3) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon-induced signaling, demonstrating that this metabolite transporter is an interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV-2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses to gain a survival advantage.

COVID-19, Influenza, and Other Acute Respiratory Viral Infections: Etiology, Immunopathogenesis, Diagnosis, and Treatment. Part 2. Other Acute Respiratory Viral Infections.

The first part of this paper presented the current knowledge on two very significant respiratory diseases with high pandemic potential, COVID-19 and influenza. The second part reviews other pathogens that cause acute respiratory viral infections, ARVI, including parainfluenza viruses, adenoviruses, pneumoviruses and specifically respiratory syncytial virus, enteroviruses, rhinoviruses, bocaviruses, and seasonal coronaviruses. The review presents modern data on the structure and replication of viruses, epidemiology and immunopathogenesis of diseases, diagnostics, preventive vaccination, and antiviral drugs. Topical issues regarding ARVI vaccination and the search for new broad-spectrum antiviral drugs are discussed.

Blue light irradiation exerts anti-viral and anti-inflammatory properties against herpes simplex virus type 1 infection.

The aim of this study was to investigate the antiviral and anti-inflammatory functions of blue light (BL) in cutaneous viral infections. Previously, we examined the photo-biogoverning role of 450 nm BL in SARS-CoV-2-infected cells, which showed that photo-energy could inhibit viral activation depending on the number of photons. However, the communication network between photo-energy irradiation and immune cells involved in viral infections has not been clarified. We verified viral activation, inflammatory responses, and relevant downstream cascades caused by human simplex virus type I (HSV-1) after BL irradiation. To examine the antiviral effect of BL, we further tested whether BL could disturb viral absorption or entry into host cells. The results showed that BL irradiation, but not green light (GL) exposure, specifically decreased plaque-forming activity and viral copy numbers in HSV-1-infected cells. Accumulated BL irradiation inhibited the localization of viral proteins and the RNA expression of characteristic viral genes such as UL19, UL27, and US6, thus exerting to an anti-viral effect. The results also showed that BL exposure during viral absorption interfered with viral entry or destroyed the virus, as assessed by plaque formation and quantitative PCR assays. The levels of the pro-inflammatory mediators interleukin (IL)-18 and IL-1ß in M1-polarized macrophages were increased by HSV-1 infection. However, these increases were attenuated by BL irradiation. Importantly, BL irradiation decreased cGAS and STING expression, as well as downstream NF-κB p65, in M1-polarized HSV-1-infected macrophages, demonstrating anti-viral and anti-inflammatory properties. These findings suggest that BL could serve as an anti-viral and anti-inflammatory therapeutic candidate to treat HSV-1 infections.

Defective Interfering Particles of Influenza Virus and Their Characteristics, Impacts, and Use in Vaccines and Antiviral Strategies: A Systematic Review.

Defective interfering particles (DIPs) are particles containing defective viral genomes (DVGs) generated during viral replication. DIPs have been found in various RNA viruses, especially in influenza viruses. Evidence indicates that DIPs interfere with the replication and encapsulation of wild-type viruses, namely standard viruses (STVs) that contain full-length viral genomes. DIPs may also activate the innate immune response by stimulating interferon synthesis. In this review, the underlying generation mechanisms and characteristics of influenza virus DIPs are summarized. We also discuss the potential impact of DIPs on the immunogenicity of live attenuated influenza vaccines (LAIVs) and development of influenza vaccines based on NS1 gene-defective DIPs. Finally, we review the antiviral strategies based on influenza virus DIPs that have been used against both influenza virus and SARS-CoV-2. This review provides systematic insights into the theory and application of influenza virus DIPs.