Search Results (187)

Cats represent a susceptible host and a possible translational model for investigating coronavirus pathogenesis and therapeutics. Recent immunohistochemical (IHC) and histopathological studies in both human and feline tissues have demonstrated SARS-CoV-2 nucleocapsid protein (NP) and spike protein expression within pancreatic islet cells, following a classic temporal infection course. Notably, IHC analysis also reveals NP expression within exocrine ductal epithelial cells. Given that ductal epithelium functions as an islet progenitor pool during tissue injury or metabolic stress, pancreotropic coronaviruses may gain access to the endocrine compartment by exploiting this intrinsic cellular differentiation pathway. Although the precise mechanisms governing intra-islet viral entry remain to be elucidated, this review highlights the capacity of SARS-CoV-2 to compromise both the exocrine (digestive) and endocrine functions of the pancreas. Finally, we evaluate the therapeutic potential of direct-acting antivirals—specifically RNA-dependent RNA polymerase (RdRp) and protease inhibitors—as monotherapies and in synergistic combination to limit pancreatic injury and mitigate the diabetogenic effects of coronaviruses across both acute infection and post-acute sequelae, such as human long-COVID syndrome. Full article

Respiratory RNA viruses extensively reprogram host regulatory networks, thereby influencing viral replication, immune evasion, and disease severity. This review examines microRNAs (miRNAs) as regulatory interfaces in host–virus interactions, focusing on influenza A virus as a paradigmatic model while integrating evidence from other respiratory RNA viruses as SARS-CoV-2 and respiratory syncytial virus. After outlining canonical miRNA biogenesis and its manipulation during infection, we discuss how respiratory RNA viruses converge on shared miRNA-regulated pathways, including interferon and NF-κB signaling, apoptosis, autophagy, cellular metabolism, and redox homeostasis. Within these networks, host miRNAs can directly target viral RNAs and modulate antiviral defenses and inflammation, whereas viruses can reshape miRNA expression to facilitate replication, influencing immunopathology. The possibility that RNA viruses encode authentic miRNAs is also critically evaluated; current evidence indicates that manipulating host miRNA biogenesis machinery and remodeling miRNA networks are more prevalent than producing canonical viral miRNAs. Finally, the potential of circulating miRNAs as diagnostic and prognostic biomarkers is considered, as well as the capability of miRNA mimics and antagomiRs to function as host-directed therapeutic strategies. Their clinical translation, however, will require standardized validation, cell- and time-resolved studies, efficient delivery systems, and a careful assessment of specificity, safety, and context-dependent effects. Full article

SARS-CoV-2 relies on a virus-encoded RNA capping pathway to produce 5′ cap structures that are essential for mRNA stability, efficient translation, and evasion of host innate immune surveillance. Within this pathway, nonstructural protein 14 (nsp14) catalyzes N7 methylation of the guanine cap, a key step that converts the cap core into a functional Cap-0 structure and enables subsequent maturation. Owing to its essential role in viral replication and its high conservation across coronaviruses, nsp14 has emerged as an attractive antiviral target. Recent structural and biochemical studies have elucidated the architecture of the nsp14 N7-methyltransferase domain, revealing an S-adenosyl-L-methionine (SAM)-dependent fold with a defined cofactor-binding site and an adjacent cap-binding pocket that orients the RNA substrate for methyl transfer. These insights have guided the development of diverse inhibitor classes, including SAM-competitive analogs, bisubstrate-like compounds, and non-nucleoside inhibitors identified through screening approaches. While early SAM-like inhibitors demonstrated target tractability, their therapeutic potential has been limited by challenges in selectivity and cellular permeability. More recent inhibitors that target the cap-binding pocket or exploit product-assisted ternary complex mechanisms highlight alternative strategies for achieving improved potency and specificity. Despite these advances, current structural models rely on truncated RNA substrates and isolated protein constructs, which may not fully capture the native catalytic environment. Future efforts to resolve nsp14 within the replication–transcription complex and develop novel inhibition strategies will be critical for advancing mechanistic understanding and antiviral development. Full article

ZIKV is an emerging mosquito-borne pathogen with the unique capability to cause severe congenital abnormalities. Mosquito-borne viruses are reliant on an optimal temperature within the mosquito host to spread to humans. Few studies explore how day/night temperature variations impact virus replication within the mosquito. Most laboratory studies are conducted at constant temperatures, or with very minimal temperature oscillations. In consequence, ZIKV transmission models and risk maps utilize biological data derived from constant temperature studies. We sought to determine if the use of viral replication data obtained in more biologically relevant, fluctuating temperatures alters the geographic range for ZIKV transmission risk. We used a growing degree day (GDD)-based model to determine ZIKV transmission potential across the US. Replication curves were conducted at eight different average temperatures between 18°C and 32°C with daily fluctuations of either +/−2.5°C or +/−5°C from the baseline. We found that at lower temperatures (18–22°C), fluctuation was beneficial for virus replication, where it had less of an impact at more optimal temperatures (24–30°C). Our transmission potential map exhibited the highest proportion of infected mosquitoes in southeastern United States, with discrete pockets of elevated potential across interior regions, including the southern Great Plains and lower Mississippi Valley. Full article

The receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein remains a central target for antiviral drug development. Recent in silico studies have revealed an expansion of amyloidogenic regions within the RBD of the Omicron variant, raising the possibility that amyloid-prone peptide fragments could modulate Spike function or host–virus interactions. In this study, we combined experimental assays with multiscale computational modeling to systematically characterise two short RBD-derived peptides: Pep-2 (YFPLQSYGFQ) from the ancestral Wuhan strain and Pep-3 (YFPLRSYSFR) from the Omicron BA.1 variant, the latter being predicted to have higher amyloidogenic potential. Cell-based assays demonstrated that neither peptide exhibited intrinsic cytotoxic or cytostatic effects on human lung fibroblasts or A549 lung adenocarcinoma cells at physiologically relevant concentrations, whereas significant cytotoxicity was observed in Vero E6 cells. In infection models with the B.1.1.1 (Wuhan) and BA.1 (Omicron) variants, the peptides unexpectedly enhanced virus-induced cytopathic effects at lower concentrations but inhibited viral infection at higher concentrations, indicating to a dose-dependent modulatory role for these short amyloidogenic RBD fragments. Fluorescence spectroscopy measurements did not detect the formation of stable thioflavin-T-positive amyloid fibrils. Computational analyses revealed that both peptides interact with the Spike RBD via multiple energetically favorable yet spatially heterogeneous modes, mostly outside the ACE2-binding site. Moreover, their predicted binding affinities for the ACE2 receptor were comparable, suggesting an additional route of interaction via the host receptor. Collectively, our findings demonstrate that these short amyloidogenic RBD-derived peptides exert a complex antiviral profile, with their interactions with both viral and host factors potentially shaping infection outcomes. This highlights the importance of spatially targeted and conformationally constrained peptide designs to effectively harness amyloidogenic features for antiviral therapy. Full article

Orthoflaviviruses comprise genetically diverse mosquito-borne viruses responsible for a broad spectrum of human diseases. Although naturally circulating clinical isolates exhibit biological variability, the extent to which they generate distinct early epithelial innate immune responses remains incompletely understood. Here, we characterized five clinical orthoflavivirus isolates obtained in Oaxaca, Mexico, using human HaCaT keratinocytes as an in vitro model of early infection. Productive infection was assessed by immunofluorescence microscopy, immunostained focus appearance under isolate-optimized assay conditions, and infectious virus production, whereas host responses were evaluated by transcriptional profiling and quantitative whole-slide single-cell immunofluorescence. All isolates established productive infection and exhibited different viral replication profiles. Temporal transcriptional analyses revealed variable expression of antiviral (IFNβ, Mx1, OAS1, PKR, IFITM3, Viperin, and RANTES) and inflammatory (TNF-α, IL-8, and MCP-1) genes. Quantitative whole-slide analysis provided complementary evidence of variable STAT1 and NF-κB signaling activation across the analyzed isolates. Within this limited panel, viral replication was not consistently aligned with the selected transcriptional and signaling readouts, although the exploratory nature of these comparisons precludes establishing independence between these variables. Together, the virological, transcriptional, and imaging analyses revealed distinct multidimensional functional profiles across the isolate panel. Overall, these findings demonstrate functional heterogeneity among the analyzed clinical orthoflavivirus isolates and highlight integrated functional phenotyping as a useful framework for examining virus–host interactions beyond viral replication alone. Full article

Emerging viral variants can affect both commercial insect production and wild insect populations, highlighting the need to identify molecular features associated with viral host range. TdNV-Korea, isolated from the Korean rhinoceros beetle Allomyrina dichotoma (syn. Trypoxylus dichotomus), represents a Korean isolate within the Oryctes rhinoceros nudivirus (OrNV) lineage associated with infection of a non-Oryctes scarab host. To define candidate features associated with host-range variation, we compared the sequence and predicted structural properties of viral entry factors across OrNV-related isolates using sequence analysis, structural modeling, and electrostatic surface analysis. The major capsid protein VP39 was highly conserved and served as a comparative baseline, whereas the per os infectivity factors GP106 and GP126 showed greater divergence despite their expected constraints during oral entry. GP106 retained an invariant chitin-binding domain, with substitutions restricted to a peripheral C-terminal region, whereas GP126 concentrated most substitutions within a predicted disordered interdomain segment associated with a localized electrostatic shift on a candidate host-interaction surface. Because functional assays were not performed, these findings should be interpreted as a hypothesis-generating model in which two entry factors follow contrasting modes of sequence change. GP126, and secondarily, the GP106 C-terminal region are prioritized for future experimental validation of nudivirus host-range determinants. Full article

Feline panleukopenia virus (FPV) causes severe enteric and systemic disease in cats, with particular importance in shelter environments where susceptible kittens, high population turnover, environmental contamination, and variable vaccination histories increase infection pressure. Recent virome and microbiome studies suggest that FPV-associated enteritis may occur within a broader context of viral co-detection and intestinal microbial disturbance, but direct FPV-specific bacteriome evidence remains limited. This review aims to synthesize current evidence on FPV-associated enteritis in shelter cats by integrating viral pathogenesis, diagnostic interpretation, enteric virome co-detection, gut dysbiosis, recovery dynamics, and intervention-related ecological effects. The literature was organized using an evidence-tier framework that distinguishes direct FPV/feline panleukopenia evidence from feline enteric microbiome proxy evidence and broader comparative or mechanistic microbiome studies. This approach was used to define the limits of inference and to separate evidence-supported conclusions from hypothesis-generating ecological models. Feline panleukopenia in shelter cats should be interpreted not only as an individual viral infection, but also as an ecological process shaped by host susceptibility, shelter exposure, diagnostic complexity, viral co-detection, and microbial community disturbance. Current evidence supports a cautious framework in which virome co-detection and dysbiosis-associated patterns are not treated as direct proof of causation. Future longitudinal, context-controlled, and multi-layer studies integrating validated FPV diagnostics, virome and bacteriome profiling, clinical metadata, treatment records, and functional endpoints are needed to clarify the biological and clinical significance of gut ecosystem disruption in feline panleukopenia. Full article

The concurrent circulation of influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has unveiled complex host–pathogen interactions governed by temporal dynamics of innate immune activation. This narrative review synthesizes evidence from human air–liquid interface (ALI) epithelial models, animal studies (hamster, ferret), clinical cohorts, and randomized controlled trials (2015–2026) to delineate the molecular mechanisms underlying viral interference between these two major respiratory pathogens. Prior IAV infection induces a robust type I/III interferon (IFN) response and broad interferon-stimulated gene (ISG) upregulation that restricts subsequent SARS-CoV-2 replication within a critical 24–72 h temporal window. Conversely, SARS-CoV-2 employs a multi-layered immune evasion strategy that blunts IFN induction, providing minimal heterologous protection. Simultaneous co-infection tends to exacerbate disease severity. Host genetic determinants, including OAS1 and TLR7 variants, modulate interference capacity. Therapeutically, early pegylated IFN-λ shows clinical benefit, while experimental evidence from in vitro and animal models suggests oseltamivir may paradoxically reduce IAV-induced interference. These findings underscore the need for multi-pathogen diagnostics, temporally informed clinical decision-making, and IFN-based therapeutic strategies during co-circulation periods. Full article

Retroviruses induce immunosuppression in their infected hosts. This phenomenon is well described for the immunodeficiency viruses, with human immunodeficiency virus type 1 (HIV-1) representing the best-studied example, but it also occurs in other retroviral infections. Immunosuppressive properties were first characterized in murine leukemia viruses (MuLV). Additional well-studied examples include feline leukemia virus (FeLV) and koala retrovirus (KoRV). Investigations into the mechanisms underlying retrovirus-induced immunosuppression revealed that not only inactivated viral particles but also their purified transmembrane (TM) envelope proteins exhibit immunosuppressive activity. However, in certain retroviral infections, additional viral proteins contribute to the immunosuppression in vivo. Within the TM envelope proteins, a highly conserved region—designated the immunosuppressive (isu) domain—was identified. Synthetic peptides corresponding to this domain suppress a wide range of in vitro immune responses, possibly by regulating Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR pathways. They modulate cytokine release and alter gene expression in immune cells, mirroring the activity of the corresponding TM envelope protein. Mutations in the sequence abrogate the effect. Numerous TM envelope proteins have demonstrated immunosuppressive activity in vivo in a tumor rejection model, and mutations within the isu domain also abrogate this function. These studies have important implications for reproduction, particularly through the immunosuppressive syncytins in the placenta, for tumor development, where similar mechanisms may protect cancer cells from the host immune system, and for vaccine development and xenotransplantation. Notably, immunization with TM envelope proteins carrying mutations in the isu domain elicits stronger immune responses compared with the wild-type proteins. Finally, the potential of retroviral TM envelope proteins to protect xenotransplants from immune rejection will be discussed. Full article

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma endemic in children in regions of sub-Saharan Africa, where its incidence geographically overlaps holoendemic Plasmodium falciparum malaria and poorly controlled childhood Epstein–Barr virus (EBV) infection. Despite decades of research, the precise mechanistic synergy between these two pathogens remains incompletely defined. This review synthesizes current epidemiological, immunological, and molecular evidence to propose an integrated model for the etiology of endemic BL. We outline a paradoxical, dual-edged relationship wherein EBV infection during infancy may provide a short-term child survival advantage against severe malaria while simultaneously increasing the long-term oncogenic risk in B-cells infected by EBV. P. falciparum infection triggers polyclonal B-cell activation, increasing the probability of an activation-induced cytidine deaminase (AID)-mediated c-MYC translocation in proportion to the recurrent parasite burden. Concurrently, EBV expands within this B-cell pool and modulates the host immune response, potentially through viral interleukin-10 (vIL-10), to prevent lethal malarial inflammation. At the cellular level, EBV provides a critical “second hit” when it establishes latency I infection that rescues c-MYC-translocated B-cells from apoptosis. This framework explains why BL manifests as a “tumor of malaria survivors,” peaking in incidence years after the highest-risk period for malaria mortality. Ultimately, this model underscores that malaria control is a critical form of cancer control and highlights key future directions for validating these pathways in prospective clinical studies. Full article

Bats are important reservoirs of zoonotic pathogens and valuable models for studying antiviral tolerance and neuroinflammation within a One Health framework. However, chiropteran neural 2D-in vitro models remain limited. Here, we established and characterized the first chiropteran primary (CpBCs) and immortalized (CiBCs) cell lines from Hypsugo savii species. To overcome the limited lifespan of CpBCs, immortalization strategies based on human telomerase reverse transcriptase (hTERT) and Simian virus 40 large T antigen (SV40) were evaluated. Electroporation-mediated transfection with SV40 successfully generated CiBCs, whereas liposome-mediated and hTERT-based approaches were unsuccessful. RNA sequencing revealed marked transcriptional changes comparing CiBCs with CpCBs, such as the upregulation of pathways related to cell cycle progression, DNA replication, and proliferation in CiBCs, together with the downregulation of apoptosis, inflammatory signaling, and immune-related pathways. Immortalized cells also exhibited enrichment of neural stem cell-like and cancer-associated signatures, suggesting partial dedifferentiation induced by SV40-mediated immortalization. Overall, this study provides a novel chiropteran brain-derived 2D-in vitro platform for investigating bat neurobiology, host–pathogen interactions, viral tolerance, and neurotropic infectious diseases relevant to emerging zoonoses. Full article

Avian orthoreovirus (ARV) has re-emerged as one of the most important viral pathogens affecting modern poultry production worldwide. In China, the epidemiological landscape of ARV has undergone a substantial transformation over the past decade, characterized by increasing genotypic diversity, frequent genome reassortment, an expanding host range, and recurrent vaccine-breakthrough outbreaks. Growing evidence indicates that contemporary ARV populations evolve within a dynamic multispecies transmission network shaped by intensive poultry production, host adaptation, and vaccine-associated selective pressures. Recent molecular studies have revealed extensive genetic heterogeneity among circulating strains and highlighted the limitations of conventional σC-based classification systems for accurately describing viral evolution, pathogenicity, and antigenic diversity. Whole-genome analyses further demonstrate that reassortment among chicken-origin, duck-origin, and goose-origin orthoreoviruses plays a pivotal role in generating novel viral variants with altered biological properties. In parallel, accumulating evidence suggests that ARV exerts broad immunomodulatory effects through the disruption of innate antiviral signaling, impairment of lymphoid organ function, interference with vaccine responsiveness, and the enhancement of susceptibility to secondary infections. These findings indicate that ARV should be regarded not only as an arthrotropic pathogen but also as an important immunopathological agent influencing flock health and productivity. This review summarizes current knowledge of ARV in China, with an emphasis on molecular epidemiology, genomic evolution, reassortment mechanisms, transmission ecology, immune interference, vaccine escape, and integrated prevention strategies. Particular attention is given to the increasing importance of whole-genome surveillance, phylodynamic analysis, and multispecies epidemiological monitoring for understanding contemporary ARV evolution. Future perspectives involving structural vaccinology, precision immunization, metagenomics-assisted surveillance, and predictive evolutionary modeling are also discussed. Collectively, sustainable ARV control will likely require genome-informed and adaptive prevention frameworks integrating virology, immunology, epidemiology, and precision poultry management. Full article

Background/Objectives: Respiratory tract symptoms, urinary symptoms, and acute fevers frequently prompt emergency urgent care visits. Distinguishing bacterial from viral or non-bacterial etiology remains difficult because clinical features overlap and laboratory microbiological tests are often non-specific or delayed. The MeMed BV^® test is a rapid host-response assay that combines TRAIL, IP-10, and CRP into a composite score to differentiate between bacterial and viral/non-bacterial infections within 15 min. The objective of this systematic review and meta-analysis was to evaluate the diagnostic accuracy and clinical utility of the MeMed BV test in adults and children with suspected respiratory tract infections, urinary tract infections, and undifferentiated fever. Methods: The review followed PRISMA-DTA guidelines. Medline, Embase, CINAHL, and the Cochrane Library databases were searched. The risk of bias was assessed using the QUADAS-2, Cochrane RoB 2.0, ROBINS-I, and JBI tools. Where appropriate, meta-analyses were performed using a bivariate random-effects or HSROC model. Results: Sixteen studies (12 diagnostic test accuracy (DTA) studies and four non-DTA studies) were included. The pooled sensitivity was 91% (95% CI: 86–94%), and specificity was 92% (95% CI: 91–93%), with consistent accuracy in adults (Sensitivity 93%/Specificity 91%) and children (Sensitivity 88%/Specificity 93%). The non-DTA studies demonstrated that MeMed BV-guided management improved antibiotic stewardship: antibiotics were prescribed in 20.6% of viral versus 73.2% of bacterial cases, and clinician adherence to MeMed BV results reached 75–80%. Conclusions: The MeMed BV test demonstrates consistently high diagnostic accuracy and is associated with improved antibiotic decision-making, supporting its integration into clinical workflows. Full article

Essential host functions are often maintained by conserved molecular systems, but in biological contexts shaped by evolutionary conflict, the genes that execute such functions may be unstable, replaceable, or repeatedly recruited from different evolutionary sources. Mammalian placentation provides a striking example of this principle. Trophoblast cell fusion is essential for placental development, yet this function is mediated in different mammalian lineages by distinct endogenous retrovirus-derived envelope proteins, including syncytin-1, syncytin-2, and other lineage-specific Env-derived fusogens. Here, I propose the Baton Pass model as a conceptual framework for explaining how host-level biological functions can be maintained despite turnover of the molecular agents that execute them. This model differs from conventional examples of antagonistic coevolution, which often emphasize recurrent mutations within the same interacting genes, and from non-orthologous gene displacement, which generally concerns replacement among cellular genes. In the syncytin paradigm, the molecular executors are repeatedly supplied by exogenous retroviral env genes that become endogenized, domesticated, and incorporated into host developmental programs. I further discuss how receptor compatibility, placental expression control, and host–virus evolutionary conflict may together destabilize individual Env–receptor systems while allowing the host-level function of trophoblast fusion to persist. Analogous functional reassignment is also observed in primate lentiviruses, where antagonism of BST-2 shifts among distinct viral genes. The Baton Pass model therefore describes a testable evolutionary principle: essential host functions can be preserved not only through conservation of specific genes, but also through dynamic succession of genes of distinct evolutionary origins. Full article