Lumpy skin disease (LSD), caused by the lumpy skin disease virus (LSDV), is an emerging infectious disease in China that primarily affects cattle. LSDV and goatpox virus (GTPV) belong to the Capripoxvirus genus and exhibit high genomic homology, enabling cross-immunogenicity. Comparative genome analysis revealed that LSDV contains a unique gene, Orf132, whose function remains uncharacterized. In this study, we first confirmed that the recombinant ORF132 protein exhibits immunoreactivity against sera from LSDV-infected cattle. To investigate the biological role of Orf132, we generated an Orf132 deletion strain (LSDV-ΔOrf132). Compared with the wild-type LSDV, the replication capacity of LSDV-ΔOrf132 was reduced approximately tenfold, indicating that Orf132 is critical for viral replication. Transcriptomic analysis of infected MDBK cells revealed significant alterations in endoplasmic reticulum (ER) protein processing and unfolded protein response (UPR) pathways following Orf132 deletion. qRT-PCR validation showed marked upregulation of ER stress markers, including Grp78, Chop, and Gadd34. Subsequent apoptosis assays established that Orf132 deletion triggers CHOP-Caspase-12-mediated apoptotic pathways. This dysregulated stress response cascade culminates in premature apoptotic scenarios, possibly weakening viral replication. We also showed that adding ORF132 protein effectively inhibited ER stress in LSDV-ΔOrf132-infected cells and rescued the attenuation phenotype of LSDV-ΔOrf132. Our findings collectively revealed that Orf132 is a critical gene for LSDV replication and a negative regulator of ER stress. It plays an essential role in the virus's life cycle, and its deletion significantly impairs viral replication while inducing ER stress-related apoptosis.

The silkworm, Bombyx mori, is a crucial model insect in agriculture and biological research. Tetraspanins, known for their effects in regulating cellular functions like cell signalling, adhesion, migration and diffusion, take on a crucial role in viral dynamics, influencing both viral spread and entry into host cells. In this study, a tetraspanin gene called BmTsp.C from the silkworm genome was identified and investigated. Tissue profiles showed that BmTsp.C has the highest transcription level in midgut, with a marked increase following viral infection. The immunofluorescence localization suggested that BmTsp.C is primarily distributed on the cell membrane. Additionally, overexpression of BmTsp.C in BmN cells facilitated the proliferation of BmNPV. Meanwhile, siRNA-mediated knockdown of BmTsp.C could inhibit viral proliferation. In addition, knockdown of BmTsp.C at the individual level further validated the remarkable effect of BmTsp.C during viral infestation. Furthermore, overexpression of BmTsp.C could regulate the expression of apoptosis-related genes. Results from flow cytometry indicated a decrease in the number of apoptotic cells after overexpression of BmTsp.C. Taken together, our results demonstrated that BmTsp.C, as an important factor in the Tetraspanin-enriched microdomains, exerts a significant influence on the proliferation of BmNPV, most likely through the cellular apoptosis pathway.

This study examines the intricate interactions between enterovirus 71 (EV71) and various programmed cell death pathways, specifically apoptosis, necroptosis, and pyroptosis, which collectively shape the pathogenesis and severity of EV71 infections. Primarily affecting children under 5 years of age, EV71 is a leading cause of hand, foot, and mouth disease and has been linked to severe neurological and systemic complications. This paper highlights how EV71 leverages distinct cell death mechanisms to enhance viral replication and amplify disease pathology. Apoptosis, for example, may restrict viral dissemination by systematically eliminating infected cells; however, EV71's activation of necroptosis and pyroptosis induces robust inflammatory responses, potentially resulting in extensive tissue damage and adverse health outcomes. Additionally, this study also summarizes recent advancements in the field, with an emphasis on experimental studies and clinical trials focused on vaccine and antiviral therapy development. Despite substantial progress, challenges persist, notably in achieving reliable vaccine efficacy and formulating safe treatment options specifically for pediatric populations. Moving forward, the review suggests that future research should delve further into understanding EV71-related complications, developing broad-spectrum antiviral agents, and investigating host genetic factors that may influence disease progression and outcomes. Ultimately, this research is essential for the development of targeted interventions capable of reducing severe symptoms without compromising the immune response, underscoring the importance of these efforts for public health and the management of infectious diseases.

Human rhinovirus (HRV) causes the common cold and exacerbates chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Despite its significant impact on public health, there are currently no approved vaccines or antiviral treatments for HRV infection. Apoptosis is the process through which cells eliminate themselves through the systematic activation of intrinsic death pathways in response to various stimuli. It plays an important role in viral infections and serves as a key immune defense mechanism in the interactions between viruses and the host. In the present study, we investigated the antiviral effects of quercetin-3-methyl ether, a flavonoid isolated from Serratula coronata, on human rhinovirus 1B (HRV1B). Quercetin-3-methyl ether significantly inhibited HRV1B replication in HeLa cells in a concentration-dependent manner, thereby reducing cytopathic effects and viral RNA levels. Time-course and time-of-addition analyses confirmed that quercetin-3-methyl ether exhibited antiviral activity during the early stages of viral infection, potentially targeting the replication and translation phases. Gene expression analysis using microarrays revealed that pro-apoptotic genes were upregulated in quercetin-3-methyl ether-treated cells, suggesting that quercetin-3-methyl ether enhances early apoptosis to counteract HRV1B-induced immune evasion. In vivo administration of quercetin-3-methyl ether to HRV1B-infected mice significantly reduced viral RNA levels and inflammatory cytokine production in the lung tissues. Our findings demonstrated the potential of quercetin-3-methyl ether as a novel antiviral agent against HRV1B, thereby providing a promising therapeutic strategy for the management of HRV1B infections and related complications.

Influenza virus is a kind of respiratory pathogen with high morbidity and mortality, which still threatens human health. Existing anti-influenza drugs have various limitations, such as the inability to alleviate body injury and side effects. There remains an urgent need to develop a novel antiviral drug to efficiently inhibit viral infection while avoiding body injury. A series of 2-aminoindole derivatives were synthesized via the TMSOTf-catalyzed reactions of N-arylynamides with sulfilimines and evaluated for their anti-influenza virus activity. The experimental results showed that 2-aminoindole 3h had significant antiviral activity (EC50 = 8.37 ± 0.65 μM) and the lowest cytotoxicity (CC50 = 669.26 ± 11.42 μM) in vitro. 2-Aminoindole 3h could inhibit viral replication by effectively binding to RNA-dependent RNA polymerase (RdRp), and could also directly target host cells to inhibit cytokine storms and apoptosis induced by viral infection, thereby improving host cell survival rate. In addition, viral load and organ injury in the lung tissue of infected mice were effectively reduced by 2-aminoindole 3h with satisfactory biosafety. These findings highlight the potential of a valuable therapeutic option against influenza infection while also laying the foundation for further research and development in this area.

Mitochondria dysfunction is implicated in cell death, inflammation, and autoimmunity. During viral infections, some viruses employ different strategies to disrupt mitochondria-dependent apoptosis, while others, including SARS-CoV-2, induce host cell apoptosis to facilitate replication and immune system modulation. Given mitochondrial DNAs (mtDNA) role as a pro-inflammatory damage-associated molecular pattern in inflammatory diseases, we examined its levels in the serum of COVID-19 patients and found it to be high relative to levels in healthy donors. Furthermore, comparison of serum protein profiles between healthy individuals and SARS-CoV-2-infected patients revealed unique bands in the COVID-19 patients. Using mass spectroscopy, we identified over 15 proteins, whose levels in the serum of COVID-19 patients were 4- to 780-fold higher. As mtDNA release from the mitochondria is mediated by the oligomeric form of the mitochondrial-gatekeeper-the voltage-dependent anion-selective channel 1 (VDAC1)-we investigated whether SARS-CoV-2 protein alters VDAC1 expression. Among the three selected SARS-CoV-2 proteins, small envelope (E), nucleocapsid (N), and accessory 3b proteins, the E-protein induced VDAC1 overexpression, VDAC1 oligomerization, cell death, and mtDNA release. Additionally, this protein led to mitochondrial dysfunction, as evidenced by increased mitochondrial ROS production and cytosolic Ca2+ levels. These findings suggest that SARS-CoV-2 E-protein induces mitochondrial dysfunction, apoptosis, and mtDNA release via VDAC1 modulation. mtDNA that accumulates in the blood activates the cGAS-STING pathway, triggering inflammatory cytokine and chemokine expression that contribute to the cytokine storm and tissue damage seen in cases of severe COVID-19.

The danger theory of immunity, introduced by Polly Matzinger in 1994, posits that tissue stress, damage or infection has a decisive role in determining immune responses. Since then, a growing body of evidence has supported the idea that the capacity to elicit cognate immune responses (immunogenicity) relies on the combination of antigenicity (the ability to be recognized by T cell receptors or antibodies) and adjuvanticity (additional signals arising owing to tissue damage). Here, we discuss the molecular foundations of the danger theory while focusing on immunologically relevant damage-associated molecular patterns, microorganism-associated molecular patterns, and neuroendocrine stress-associated immunomodulatory molecules, as well as on their receptors. We critically evaluate patient-relevant evidence, examining how cancer cells and pathogenic viruses suppress damage-associated molecular patterns to evade immune recognition, how intestinal dysbiosis can reduce immunostimulatory microorganism-associated molecular patterns and compromise immune responses, and which hereditary immune defects support the validity of the danger theory. Furthermore, we incorporate the danger hypothesis into a close-to-fail-safe hierarchy of immunological tolerance mechanisms that also involve the clonal deletion and inactivation of immune cells.

Cytomegaloviruses, species-specific members of the betaherpesviruses, encode an impressive array of immune evasion strategies committed to the manipulation of the host immune system enabling these viruses to remain for life in a stand-off with host innate and adaptive immune mechanisms. Even though they are species-restricted, cytomegaloviruses are distributed across a wide range of different mammalian species in which they cause systemic infection involving many different cell types. Regulated, or programmed cell death has a recognized potential to eliminate infected cells prior to completion of viral replication and release of progeny. Cell death also naturally terminates replication during the final stages of replication. Over the past two decades, the host defense potential of known programmed cell death pathways (apoptosis, necroptosis, and pyroptosis), as well as a novel mitochondrial serine protease pathway have been defined through studies of cytomegalovirus-encoded cell death suppressors. Such virus-encoded inhibitors prevent virus-induced, cytokine-induced, and stress-induced death of infected cells while also moderating inflammation. By evading cell death and consequent inflammation as well as innate and adaptive immune clearance, cytomegaloviruses represent successful pathogens that become a critical disease threat when the host immune system is compromised. This review will discuss cell death programs acquired for mammalian host defense against cytomegaloviruses and enumerate the range of modulatory strategies this type of virus employs to balance host defense in favor of lifelong persistence.

In contrast to most other rhabdoviruses, which spread by insect vectors, the rabies virus (RABV) is a very unusual member of the Rhabdoviridae family, since it has evolved to be fully adapted to warm-blooded hosts and spread directly between them. There are differences in the immune responses to laboratory-attenuated RABV and wild-type rabies virus infections. Various investigations showed that whilst laboratory-attenuated RABV elicits an innate immune response, wild-type RABV evades detection. Pathogenic RABV infection bypasses immune response by antagonizing interferon induction, which prevents downstream signal activation and impairs antiviral proteins and inflammatory cytokines production that could eliminate the virus. On the contrary, non-pathogenic RABV infection leads to immune activation and suppresses the disease. Apart from that, through recruiting leukocytes into the central nervous system (CNS) and enhancing the blood-brain barrier (BBB) permeability, which are vital factors for viral clearance and protection, cytokines/chemokines released during RABV infection play a critical role in suppressing the disease. Furthermore, early apoptosis of neural cells limit replication and spread of avirulent RABV infection, but street RABV strains infection cause delayed apoptosis that help them spread further to healthy cells and circumvent early immune exposure. Similarly, a cellular regulation mechanism called autophagy eliminates unused or damaged cytoplasmic materials and destroy microbes by delivering them to the lysosomes as part of a nonspecific immune defense mechanism. Infection with laboratory fixed RABV strains lead to complete autophagy and the viruses are eliminated. But incomplete autophagy during pathogenic RABV infection failed to destroy the viruses and might aid the virus in dodging detection by antigen-presenting cells, which could otherwise elicit adaptive immune activation. Pathogenic RABV P and M proteins, as well as high concentration of nitric oxide, which is produced during rabies virus infection, inhibits activities of mitochondrial proteins, which triggers the generation of reactive oxygen species, resulting in oxidative stress, contributing to mitochondrial malfunction and, finally, neuron process degeneration.

The Japanese encephalitis virus (JEV), a zoonotic flavivirus, is Asia's primary cause of viral encephalitis. JEV induces apoptosis in a variety of cells; however, the precise mechanisms underlying this apoptosis resulting from JEV infection remain to be elucidated. Our previous studies showed that the proapoptosis gene BAX may have a role in JEV proliferation. In this study, we constructed a PK-15 cell line (BAX.KO) with a knockout of the BAX gene using CRISPR/Cas9. The knockout of the BAX gene effectively inhibited the proliferation of JEV, resulting in a 39.9% decrease in viral protein levels, while BAX overexpression produced the opposite effect. We confirmed that JEV induces apoptosis of PK-15 using 4',6-diamidino-2-phenylindole (DAPI) staining and Annexin V-FITC/PI staining. Furthermore, we found that the phosphorylation of P53 and the expression levels of BAX, NOXA, PUMA, and cleaved-caspase-3/9 were significantly upregulated after JEV infection. Moreover, we found that JEV infection not only caused mitochondrial damage, the release of mitochondrial cytochrome C (Cyt C), and the downregulation of the apoptosis-inhibiting protein BCL-2 but also reduced the mitochondrial membrane potential (MOMP) and the accumulation of intracellular reactive oxygen species (ROS). These factors collectively encourage the activation of the mitochondrial apoptosis pathway. In contrast, BAX gene knockout significantly reduces the apoptotic changes caused by JEV infection. Treatment with the caspase3 inhibitor attenuated JEV-induced viral proliferation and release, leading to a decrease in viral protein levels of 46% in PK-15 cells and 30% in BAX.KO cells. In conclusion, this study clarified the molecular mechanisms of JEV-induced apoptosis and provided a theoretical basis for revealing the pathogenic mechanisms of JEV infection.

Influenza A virus (IAV) poses a global threat worldwide causing pandemics, epidemics, and seasonal outbreaks. Annual modification of vaccines is costly due to continual shifts in circulating genotypes, leading to inadequate coverage in low- and middle-income countries like India. Additionally, IAVs are evolving resistance to approved antivirals, necessitating a search for alternative treatments. In this study, the antiviral role of the FDA-approved antibiotic minocycline against IAV strains was evaluated in vitro and in vivo by quantifying viral gene expression by qRT-PCR, viral protein levels by Western blotting, and viral titers. Our findings demonstrate that minocycline at a non-toxic dose effectively inhibits IAV replication, regardless of viral strain or cell line. Its antiviral mechanism operates independently of interferon signaling by targeting the MEK/ERK signaling pathway, which is crucial for the export of viral ribonucleoproteins (vRNPs). Minocycline prevents the assembly and release of infectious viral particles by causing the accumulation of vRNPs within the nucleus. Moreover, minocycline also inhibits IAV-induced late-stage apoptosis, further suppressing viral propagation. The antiviral activity of minocycline against IAVs could offer a promising solution amidst the challenges posed by influenza and the limitations of current treatments.

The controlled release of mitochondrial content into the cytosol has emerged as one of the key steps in mitochondrial signaling. In particular, the release of mitochondrial DNA (mtDNA) into the cytosol has been shown to activate interferon beta (IFN-β) gene expression to execute the innate immune response. In this report, we show that human adenovirus type 5 (HAdV-C5) infection induces the release of mtDNA into the cytosol. The release of mtDNA is mediated by the viral minor capsid protein VI (pVI), which localizes to mitochondria. The presence of the mitochondrial membrane proteins Bak and Bax are needed for the mtDNA release, whereas the viral E1B-19K protein blocked pVI-mediated mtDNA release. Surprisingly, the pVI-mediated mtDNA release did not increase but inhibited the IFN-β gene expression. Notably, the pVI expression caused mitochondrial leakage of the HSP60 protein. The latter prevented specific phosphorylation of the interferon regulatory factor 3 (IRF3) needed for IFN-β gene expression. Overall, we assign a new mitochondria and IFN-β signaling-modulating function to the HAdV-C5 minor capsid protein VI.

Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, including conjunctivitis and the common cold. HAdVs need to interfere with multiple cellular signaling pathways during the infection to gain control over the host cell. In this study, we identified human adenovirus type 5 (HAdV-C5) minor capsid protein VI as a factor modulating mitochondrial membrane integrity and mitochondrial signaling. We show that pVI-altered mitochondrial signaling impedes the cell's innate immune response, which may benefit HAdV growth. Overall, our study provides new detailed insights into the HAdV-mitochondria interactions and signaling. This knowledge is helpful when developing new anti-viral treatments against pathogenic HAdV infections and improving HAdV-based therapeutics.

During oxidative phosphorylation, mitochondria continuously produce reactive oxygen species (ROS), and untimely ROS clearance can subject mitochondria to oxidative stress, ultimately resulting in mitochondrial damage. Mitophagy is essential for maintaining cellular mitochondrial quality control and homeostasis, with activation involving both ubiquitin-dependent and ubiquitin-independent pathways. Over the past decade, numerous studies have indicated that different forms of regulated cell death (RCD) are connected with mitophagy. These diverse forms of RCD have been shown to be regulated by mitophagy and are implicated in the pathogenesis of a variety of diseases, such as tumors, degenerative diseases, and ischemia‒reperfusion injury (IRI). Importantly, targeting mitophagy to regulate RCD has shown excellent therapeutic potential in preclinical trials, and is expected to be an effective strategy for the treatment of related diseases. Here, we present a summary of the role of mitophagy in different forms of RCD, with a focus on potential molecular mechanisms by which mitophagy regulates RCD. We also discuss the implications of mitophagy-related RCD in the context of various diseases.

Adenovirus (HAdV) can cause severe respiratory infections in children and immunocompromised patients. There is a lack of specific therapeutic drugs for HAdV infection, and the study of anti-adenoviral drugs has far-reaching clinical implications. Elemental selenium can play a specific role as an antioxidant in the human immune cycle by non-specifically binding to the amino acid methionine in body proteins. Methods: The antiviral mechanism of selenomethionine was explored by measuring cell membrane status, intracellular DNA status, cytokine secretion, mitochondrial membrane potential, and ROS production. Conclusions: Selenomethionine improved the regulation of ROS-mediated apoptosis by modulating the expression of Jak1/2, STAT3, and BCL-XL, which led to the inhibition of apoptosis. It is anticipated that selenomethionine will offer a new anti-adenoviral therapeutic alternative.

Apoptosis is a physiological cell death phenomenon, representing one of the fundamental physiological mechanisms for maintaining homeostasis in living organisms. Previous studies have observed typical apoptotic features in Carassius auratus gibelio caudal fin cell (GiCF) infected with Cyprinid herpesvirus 2 (CyHV-2), and found a significant up-regulation of ccBAX expression in these infected cells. However, the specific apoptotic mechanism involved remains unclear. In this study, we utilized the GiCF cell line to investigate the apoptotic mechanism during CyHV-2 infection. Immunofluorescence staining revealed translocation of ccBAX into mitochondria upon CyHV-2 infection. Flow cytometry analysis demonstrated that overexpression of ccBAX expedited virus-induced apoptosis, characterized by heightened mitochondrial depolarization, increased transcriptional levels of Cytochrome c (Cyto c) in both the cytoplasm and mitochondria, and augmented Caspase 3/7 enzyme activity. Bax inhibitor peptide V5 (BIP-V5), an inhibitor interfering with the function of Bax proteins, inhibited Bax-mediated apoptotic events through the mitochondrial pathway and attenuated apoptosis induced by CyHV-2. In this study, it was identified for the first time that CyHV-2 induces apoptosis via the mitochondrial pathway in GiCF cells, bridging an important gap in our understanding regarding cell death mechanisms induced by herpesvirus infections in fish species. These findings provide a theoretical basis for comprehending viral apoptotic regulation mechanisms and the prevention and control of cellular pathologies caused by CyHV-2 infection.

Viruses target mitochondria to promote their replication, and infection-induced stress during the progression of infection leads to the regulation of antiviral defenses and mitochondrial metabolism which are opposed by counteracting viral factors. The precise structural and functional changes that underlie how mitochondria react to the infection remain largely unclear. Here we show extensive transcriptional remodeling of protein-encoding host genes involved in the respiratory chain, apoptosis, and structural organization of mitochondria as herpes simplex virus type 1 lytic infection proceeds from early to late stages of infection. High-resolution microscopy and interaction analyses unveiled infection-induced emergence of rough, thin, and elongated mitochondria relocalized to the perinuclear area, a significant increase in the number and clustering of endoplasmic reticulum-mitochondria contact sites, and thickening and shortening of mitochondrial cristae. Finally, metabolic analyses demonstrated that reactivation of ATP production is accompanied by increased mitochondrial Ca2+ content and proton leakage as the infection proceeds. Overall, the significant structural and functional changes in the mitochondria triggered by the viral invasion are tightly connected to the progression of the virus infection.

Epidemic diseases that arise from infectious RNA viruses, particularly influenza viruses, pose a constant threat to the global economy and public health. Viral evolution has undermined the efficacy of acquired immunity from vaccines and the antiviral effects of FDA-approved drugs. As such, there is an urgent need to develop new antiviral lead agents. Natural compounds, owing to their historical validation of application and safety, have become a promising solution. In this light, a novel marine bacterium, Pseudomonas sp. M20A4R8, has been found to exhibit significant antiviral activity [half maximal inhibitory concentration (IC50) = 1.3 µg/mL, selectivity index (SI) = 919.4] against influenza virus A/Puerto Rico/8/34, surpassing the activity of chloroquine. The antiviral response via M20A4R8 extract was induced during post-entry stages of the influenza virus, indicating suitability for post-application after the establishment of viral infection. Furthermore, post-treatment with M20A4R8 extract protected the host from virus-induced apoptosis, suggesting its potential use in acute respiratory disease complexes resulting from immune effectors' overstimulation and autophagy-mediated self-apoptosis. The extract demonstrated an outstanding therapeutic index against influenza virus A/Wisconsin/15/2009 (IC50 = 8.1 µg/mL, SI = 146.2) and B/Florida/78/2015 Victoria lineage (IC50 = 3.5 µg/mL, SI = 343.8), indicating a broad anti-influenza virus activity with guaranteed safety and effectiveness. This study provides a new perspective on mechanisms for preventing a broad spectrum of viral infections through antiviral agents from novel and natural origins. Future studies on a single or combined compound from the extract hold promise, encouraging its use in preclinical challenge tests with various influenza virus strains.

Grass carp reovirus (GCRV), particularly the highly prevalent type II GCRV (GCRV-II), causes huge losses in the aquaculture industry. However, little is known about the mechanisms by which GCRV-II invades grass carp and further disseminates among tissues. In the present study, monocytes/macrophages (Mo/Mφs) were isolated from the peripheral blood of grass carp and infected with GCRV-II. The results of indirect immunofluorescent microscopy, transmission electron microscopy, real-time quantitative RT-PCR (qRT-PCR), western blot (WB), and flow cytometry analysis collectively demonstrated that GCRV-II invaded Mo/Mφs and replicated in them. Additionally, we observed that GCRV-II induced different types (M1 and M2) of polarization of Mo/Mφs in multiple tissues, especially in the brain, head kidney, and intestine. To assess the impact of different types of polarization on GCRV-II replication, we recombinantly expressed and purified the intact cytokines CiIFN-γ2, CiIL-4/13A, and CiIL-4/13B and successfully induced M1 and M2 type polarization of macrophages using these cytokines through in vitro experiments. qRT-PCR, WB, and flow cytometry analyses showed that M2 macrophages had higher susceptibility to GCRV-II infection than other types of Mo/Mφs. In addition, we found GCRV-II induced apoptosis of Mo/Mφs to facilitate virus replication and dissemination and also detected the presence of GCRV-II virus in plasma. Collectively, our findings indicated that GCRV-II could invade immune cells Mo/Mφs and induce apoptosis and polarization of Mo/Mφs for efficient infection and dissemination, emphasizing the crucial role of Mo/Mφs as a vector for GCRV-II infection.IMPORTANCEType II grass carp reovirus (GCRV) is a prevalent viral strain and causes huge losses in aquaculture. However, the related dissemination pathway and mechanism remain largely unclear. Here, our study focused on phagocytic immune cells, monocytes/macrophages (Mo/Mφs) in blood and tissues, and explored whether GCRV-II can invade Mo/Mφs and replicate and disseminate via Mo/Mφs with their differentiated type M1 and M2 macrophages. Our findings demonstrated that GCRV-II infected Mo/Mφs and replicated in them. Furthermore, GCRV-II infection induces an increased number of M1 and M2 macrophages in grass carp tissues and a higher viral load in M2 macrophages. Furthermore, GCRV-II induced Mo/Mφs apoptosis to release viruses, eventually infecting more cells. Our study identified Mo/Mφs as crucial components in the pathway of GCRV-II dissemination and provides a solid foundation for the development of treatment strategies for GCRV-II infection.

The dual-specificity phosphatase (DUSP) family plays key roles in the maintenance of cellular homeostasis and apoptosis etc. In this study, the DUSP member DUSP1 of Epinephelus coioides was characterized: the length was 2371 bp including 281 bp 5' UTR, 911 bp 3' UTR, and a 1125 bp open reading frame encoding 374 amino acids. E. coioides DUSP1 has two conserved domains, a ROHD and DSPc along with a p38 MAPK phosphorylation site, localized at Ser308. E. coioides DUSP1 mRNA can be detected in all of the tissues examined, and the subcellular localization showed that DUSP1 was mainly distributed in the nucleus. Singapore grouper iridovirus (SGIV) infection could induce the differential expression of E. coioides DUSP1. Overexpression of DUSP1 could inhibit SGIV-induced cytopathic effect (CPE), the expressions of SGIV key genes, and the viral titers. Overexpression of DUSP1 could also regulate SGIV-induced apoptosis, and the expression of apoptosis-related factor caspase 3. The results would be helpful to further study the role of DUSP1 in viral infection.

Long noncoding RNA (lncRNA) is a potential regulator of biological processes, including immunity, reproduction, and development. Although several transcriptome studies have focused on responses of viral infections in several organisms, the role of lncRNAs in viral responses in shrimp is still unclear. Therefore, this work aimed to identify putative lncRNAs and study their role in white spot syndrome virus (WSSV) infection in white shrimp. The hepatopancreas transcriptome from WSSV infected shrimp was analyzed in silico to identify putative lncRNAs. Among 221,347 unigenes of the de novo assembled transcriptome, 44,539 putative lncRNAs were identified, 32 of which were differentially expressed between WSSV-infected and control shrimp. Five candidate lncRNAs were validated for their expressions in shrimp tissues and in response to WSSV infection. Lnc164 was chosen for further investigation of its role in WSSV infection. Knockdown of lnc164 prolonged survival of shrimp when challenged with WSSV, suggesting a role in shrimp immunity. In addition, lnc164 was not directly involved in the control of total hemocytes and viral loads in hemolymph of WSSV-infected shrimp. A set of lnc164-regulated genes was obtained by RNA sequencing among which 251 transcripts were differentially expressed between lnc164 knockdown and control shrimp. Six immune-related genes were validated for their expression profiles. Our work sheds light on lncRNA profiles in L. vannamei in response to WSSV infection and paves the way to a functional study of lnc164 in host antiviral response.

Although FeHV-1 is a primary feline pathogen, little is known about its interactions with host cells. Its relationship with several cellular pathways has recently been described, whereas its interplay with the apoptotic process, unlike other herpesviruses, has not yet been clarified. The aim of this work was to evaluate whether FeHV-1 induces apoptosis in its permissive cells, as well as the pathway involved and the effects of induction and inhibition of apoptosis on viral replication.

Monolayers of CRFK cells were infected at different times with different viral doses. A cytofluorimetric approach allowed the quantification of cells in early and late apoptosis. All infections and related controls were also subjected to Western blot analysis to assess the expression of apoptotic markers (caspase 3-8-9, Bcl-2, Bcl-xL, NF-κB). An inhibitor (Z-VAD-FMK) and an inducer (ionomycin) were used to evaluate the role of apoptosis in viral replication. Finally, the expression of autophagy markers during the apoptosis inhibition/induction and the expression of apoptosis markers during autophagy inhibition/induction were evaluated to highlight any crosstalk between the two pathways.

FeHV-1 triggered apoptosis in a time- and dose-dependent manner. Caspase 3 cleavage was evident 48 h after infection, indicating the completeness of the process at this stage. While caspase 8 was not involved, caspase 9 cleavage started 24 h post-infection. The expression of other mitochondrial damage markers also changed, suggesting that apoptosis was induced via the intrinsic pathway. NF- κB was up-regulated at 12 h, followed by a gradual decrease in levels up to 72 h. The effects of apoptosis inhibitors and inducers on viral replication and autophagy were also investigated. Inhibition of caspases resulted in an increase in viral glycoprotein expression, higher titers, and enhanced autophagy, whereas induction of apoptosis resulted in a decrease in viral protein expression, lower viral titer, and attenuated autophagy. On the other hand, the induction of autophagy reduced the cleavage of caspase 3.

In this study, we established how FeHV-1 induces the apoptotic process, contributing to the understanding of the relationship between FeHV-1 and this pathway.

Duck Tembusu virus (DTMUV) is an emerging pathogenic flavivirus that replicates well in mosquito, bird, and mammalian cells. An in vivo study revealed that BALB/c mice and Kunming mice were susceptible to DTMUV after intracerebral inoculation. Moreover, there are no reports about DTMUV-related human disease, but antibodies against DTMUV and viral RNA were detected in the serum samples of duck industry workers. This information implies that DTMUV has expanded its host range and poses a threat to mammalian health. Thus, understanding the pathogenic mechanism of DTMUV is crucial for identifying potential antiviral targets. In this study, we discovered that NS3 can induce the mitochondria-mediated apoptotic pathway through the PERK/PKR pathway; it can also interact with voltage-dependent anion channel 2 to induce apoptosis. Our findings provide a theoretical basis for understanding the pathogenic mechanism of DTMUV infection and identifying potential antiviral targets and may also serve as a reference for exploring the pathogenesis of other flaviviruses.

The COVID-19 pandemic has highlighted the importance of identifying new potent antiviral agents. Nutrients as well as plant-derived substances are promising candidates because they are usually well tolerated by the human body and readily available in nature, and consequently mostly cheap to produce. A variety of antiviral effects have recently been described for the hop chalcone xanthohumol (XN), and to a lesser extent for its derivatives, making these hop compounds particularly attractive for further investigation. Noteworthy, mounting evidence indicated that XN can suppress a wide range of viruses belonging to several virus families, all of which share a common reproductive cycle. As a result, the purpose of this review is to summarize the most recent research on the antiviral properties of XN and its derivatives, with a particular emphasis on the positive-sense RNA viruses human hepatitis C virus (HCV), porcine reproductive and respiratory syndrome virus (PRRSV), and severe acute respiratory syndrome corona virus (SARS-CoV-2).

Apoptotic inhibition and immune evasion have particular importance to efficient viral infection, while a dilemma often faced by viruses is that inhibiting apoptosis can up-regulate antiviral immune signaling. Herein, we uncovered that in addition to inhibiting caspase-8/extrinsic apoptosis, human cytomegalovirus (HCMV)-encoded UL36 suppresses interferon regulatory factor 3 (IRF3)-dependent immune signaling by directly targeting IRF3 to abrogate IRF3 interaction with stimulator of interferon genes or TANK-binding kinase 1 and inhibit IRF3 phosphorylation/activation. Although UL36-mediated caspase-8/extrinsic apoptosis inhibition enhances immune signaling, the immunosuppressing activity of UL36 counterbalances this immunoenhancing "side effect" undesirable for virus. Furthermore, we used mutational analyses to show that only the wild-type, but not the UL36 mutant losing either inhibitory activity, is sufficient to support effective HCMV replication in cells, showing the functional importance of the dual inhibition by UL36 for the HCMV life cycle. Together, our findings demonstrate a sophisticated mechanism by which HCMV tightly controls innate immune signaling and extrinsic apoptosis for efficient infection.

Avian infectious bronchitis virus (IBV), a coronavirus, causes a huge economic loss to the poultry industry. Andrographolide (APL) is a compound with a variety of pharmacological properties, including antiviral and anti-inflammatory effects. In this study, APL was evaluated for antiviral activity by its anti-apoptotic, anti-pyroptosis, and anti-inflammatory effects.

The cytotoxicity of APL was determined by the MTT method. We investigated the therapeutic impact of APL on IBV through a plate assay. We explored that APL inhibited IBV-induced apoptosis, pyroptosis, and inflammation in HD11 cells by RT-qPCR and immunofluorescence. Also, it was verified in the clinical chicken embryo trial.

We found that APL down-regulated apoptosis-related genes Caspase-3, Caspase-8, Caspase-9, Bax, Bid, and Bak, down-regulated pyroptosis gene DFNA5, and down-regulated inflammation-related genes (NF-κB, NLRP3, iNOS, TNF-α, and IL-1β). In addition, APL reduced the reactive oxygen species (ROS) production in cells. Finally, clinical trials showed that APL inhibited IBV-induced apoptosis, pyroptosis, and inflammation, as well as reduced the mortality and malformation of chicken embryos.

In this study, we delved into the antiviral properties of APL in the context of chicken macrophage (HD11) infection with IBV. Our findings confirm that andrographolide effectively inhibits apoptosis, pyroptosis, and inflammation by IBV infection. Furthermore, this inhibition was verified on chicken embryos in vivo. This inhibition suggests a substantial potential for APL as a therapeutic agent to mitigate the harmful effects of IBV on host cells.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has seriously threatened global public health and caused huge economic losses. Omics studies of SARS-CoV-2 can help understand the interaction between the virus and host, thereby providing a new perspective in guiding the intervention and treatment of the SARS-CoV-2 infection. Since large amount of SARS-CoV-2 omics data have been accumulated in public databases, this study aimed to identify key host factors involved in SARS-CoV-2 infection through systematic integration of transcriptome and interactome data. By manually curating published studies, we obtained a comprehensive SARS-CoV-2-human protein-protein interactions (PPIs) network, comprising 3591 human proteins interacting with 31 SARS-CoV-2 viral proteins. Using the RobustRankAggregation method, we identified 123 multiple cell line common genes (CLCGs), of which 115 up-regulated CLCGs showed host enhanced innate immunity and chemotactic response signatures. Combined with network analysis, co-expression and functional enrichment analysis, we discovered four key host factors involved in SARS-CoV-2 infection: IFITM1, SERPINE1, DDX60, and TNFAIP2. Furthermore, SERPINE1 was found to facilitate SARS-CoV-2 replication, and can alleviate the endoplasmic reticulum (ER) stress induced by ORF8 protein through interaction with ORF8. Our findings highlight the importance of systematic integration analysis in understanding SARS-CoV-2-human interactions and provide valuable insights for future research on potential therapeutic targets against SARS-CoV-2 infection.

The regulation of mitochondria structure and function is at the core of numerous viral infections. Acting in support of the host or of virus replication, mitochondria regulation facilitates control of energy metabolism, apoptosis, and immune signaling. Accumulating studies have pointed to post-translational modification (PTM) of mitochondrial proteins as a critical component of such regulatory mechanisms. Mitochondrial PTMs have been implicated in the pathology of several diseases and emerging evidence is starting to highlight essential roles in the context of viral infections. Here, we provide an overview of the growing arsenal of PTMs decorating mitochondrial proteins and their possible contribution to the infection-induced modulation of bioenergetics, apoptosis, and immune responses. We further consider links between PTM changes and mitochondrial structure remodeling, as well as the enzymatic and non-enzymatic mechanisms underlying mitochondrial PTM regulation. Finally, we highlight some of the methods, including mass spectrometry-based analyses, available for the identification, prioritization, and mechanistic interrogation of PTMs.

Nosema ceranae infects midgut epithelial cells of the Apis species and has jumped from its original host A. cerana to A. mellifera worldwide, raising questions about the response of the new host. We compared the responses of these two species to N. ceranae isolates from A. cerana, A. mellifera from Thailand and A. mellifera from France. Proteomics and transcriptomics results were combined to better understand the impact on the immunity of the two species. This is the first combination of omics analyses to evaluate the impact of N. ceranae spores from different origins and provides new insights into the differential immune responses in honeybees inoculated with N. ceranae from original A. cerana. No difference in the antimicrobial peptides (AMPs) was observed in A. mellifera, whereas these peptides were altered in A. cerana compared to controls. Inoculation of A. mellifera or A. cerana with N. ceranae upregulated AMP genes and cellular-mediated immune genes but did not significantly alter apoptosis-related gene expression. A. cerana showed a stronger immune response than A. mellifera after inoculation with different N. ceranae isolates. N. ceranae from A. cerana had a strong negative impact on the health of A. mellifera and A. cerana compared to other Nosema isolates.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.