Jul 2026· Frontiers in Cellular and Infection Microbiology· Vol 16· 0 citations· 89 references
Medicine
TL;DR
The species specificity and potent immunomodulatory function of E3/49K underscore its role in adenoviral adaptation and highlight its potential for therapeutic immunosuppression and cancer therapy.
Abstract
Human adenoviruses (HAdVs) cause a broad spectrum of diseases, ranging from mild respiratory and gastrointestinal infections to severe, sometimes even fatal illness in immunocompromised individuals. Species D adenoviruses represent the largest group, possibly driven by strong evolutionary pressure, particularly within the highly variable early transcription unit 3 (E3), which encodes immunomodulatory proteins. Among these, E3/49K is unique to species D and utilizes a particularly intriguing immunomodulatory strategy. It is a heavily glycosylated transmembrane protein that undergoes proteolytic shedding to release the soluble ectodomain (sec49K), the only known secreted HAdV protein. Both the membrane-anchored and soluble forms target the leukocyte-specific receptor-like protein tyrosine phosphatase CD45, a key regulator of immune cell activation. E3/49K binds CD45 with high affinity via two domains, inducing dimerization and inhibiting its phosphatase activity, thereby suppressing activation of T, B, and NK cells. The species specificity and potent immunomodulatory function of E3/49K underscore its role in adenoviral adaptation and highlight its potential for therapeutic immunosuppression and cancer therapy.
It is demonstrated that nanobodies targeting the PLpro/ISG15 interface can achieve synergistic antiviral and immunomodulatory effects, providing a proof-of-concept for a novel therapeutic approach to combat SARS-CoV-2 and potentially other emerging coronaviruses.
Guo-Long Liu, Jiantao Chen, Fang Wu et al.· Journal of Virology· 0 citations
Coronavirus disease 2019 (COVID-19) and influenza share key pathogenic mechanisms, including viral invasion, dysregulated innate immune activation, and the development of severe systemic complications. A central mediator of disease progression in both infections is the hyperactivation of the NLRP3 inflammasome, which drives excessive production of pro-inflammatory cytokines, immunothrombosis, multiorgan injury, and increased mortality. Colchicine possesses a unique pharmacokinetic property of preferential accumulation within myeloid cells, where sufficiently high intracellular concentrations inhibit NLRP3 inflammasome activation. This mechanism provides a biological rationale for preventing the cytokine storm and its downstream consequences when colchicine is administered early during infection. Available pharmacokinetic, toxicological, and clinical evidence suggests that loading doses of colchicine up to approximately 0.05 mg/kg body weight can be administered safely in appropriately selected patients, provided that clinically significant drug–drug interactions and hepatic or renal impairment are carefully excluded. The widely accepted belief that total doses of 7–7.5 mg are inherently lethal appears to reflect historical cases complicated by drug interactions and/or hepatic or renal impairment, rather than toxicity attributable to colchicine dose alone. These observations support reconsideration of current guideline recommendations regarding colchicine dosing. In particular, cumulative doses below 0.1 mg/kg appear to be consistently safe, whereas doses between 0.1 and 0.2 mg/kg are associated with only a low risk of toxicity and rarely with severe intoxication. Reassessment of colchicine dosing strategies may therefore be warranted to optimize NLRP3 inflammasome inhibition and improve outcomes in patients with COVID-19 and influenza.
V. Mitev· International Journal of Mol...· 0 citations
MFSD6 is a newly identified receptor that mediates the invasion of respiratory cells by enterovirus D68 (EV-D68), a non-polio enterovirus that causes severe respiratory disease and poliomyelitis-like illness in children. Here, we report near-atomic-resolution cryo-electron microscopy (cryo-EM) structures of historical and contemporary AFM-associated EV-D68 strains, together with their complexes bound to the third extracellular loop of MFSD6 (MFSD6-L3). These structures uncover a previously unrecognized “binary gating switch” mechanism of virus-receptor engagement that differs from the reported model. In this mechanism, the N200-V208 segment of MFSD6, carrying a glycosylated Asn207, inserts into one capsomer, whereas the sialyl-Gal-terminated glycan of MFSD6 engages an adjacent capsomer. Neu5Ac binding induces conformational rearrangements that expel the pocket factor, destabilize the virion, and prime infection. Functional analyses further define the contributions of the receptor-contacting residues and glycans to viral attachment and entry. Together, our findings refine the molecular basis of EV-D68 recognition of MFSD6 and reveal a glycan-mediated dual-lock mechanism that may enhance receptor specificity, prevent premature uncoating, and ensure productive infection only upon engagement of the correct host receptor. These results provide broader insight into enterovirus tropism and establish a framework for structure-guided antiviral design. Liang et al. show how enterovirus D68 uses the respiratory receptor MFSD6 and sugar modifications to enter cells, revealing a checkpoint that primes the virus for infection.
ABSTRACT Influenza B virus (IBV) exhibits antigenic diversity and significantly contributes to the annual burden of influenza-related disease, posing substantial impacts on global public health and the economy. In this study, we focused on the neuraminidase (NA) of IBV, immunized an alpaca with tetrameric IBV NA, and identified a series of nanobodies with a common feature of the “DYR” motif in CDR3, exhibiting broad inhibitory activity against diverse NAs of IBV. Among these, the most potent VHH5 broadly inhibits NA from multiple representative strains across ancestral, B/Yamagata/16/88-like, and B/Victoria/2/87-like lineages. Moreover, fusing VHH5 to a human immunoglobulin G1 Fc domain significantly increased its antiviral potency in vitro, with the 50% inhibitory concentration in the low nanomolar range. Structural modeling and molecular dynamics simulations revealed that the “DYR” motif within the elongated CDR3 loop of VHH5 penetrates the catalytic pocket and engages the highly conserved catalytic site of IBV NA. Experimental mutagenesis analysis of the predicted interface further supported this binding model. Furthermore, the VHH5-Fc protects mice from the lethal challenge with a high dose of the IBV-2024 virus in both prophylactic and therapeutic settings. Our findings highlight the potential of the Fc-fused VHH5 antibody in controlling influenza B virus infections. IMPORTANCE Although influenza B viruses (IBVs) account for a substantial proportion of seasonal influenza virus infections, they have received comparatively less research attention. The small size and flexible binding modes of nanobodies enable them to access cryptic or recessed epitopes, supporting their development as potent clinical therapeutics. Here, we report the identification of VHH5, a nanobody targeting conserved residues within the neuraminidase active site of the influenza B virus, conferring broad inhibitory activity. Moreover, Fc-fused VHH5 enhanced antiviral potency in vitro and provided robust protection against lethal IBV challenge in mice. Together, these findings establish VHH5-Fc as a promising therapeutic candidate with potent and broad-spectrum activity against antigenically diverse IBV strains. Although influenza B viruses (IBVs) account for a substantial proportion of seasonal influenza virus infections, they have received comparatively less research attention. The small size and flexible binding modes of nanobodies enable them to access cryptic or recessed epitopes, supporting their development as potent clinical therapeutics. Here, we report the identification of VHH5, a nanobody targeting conserved residues within the neuraminidase active site of the influenza B virus, conferring broad inhibitory activity. Moreover, Fc-fused VHH5 enhanced antiviral potency in vitro and provided robust protection against lethal IBV challenge in mice. Together, these findings establish VHH5-Fc as a promising therapeutic candidate with potent and broad-spectrum activity against antigenically diverse IBV strains.
Hang Jia, Chaohui Lin, Yinghao Guo et al.· Journal of Virology· 0 citations
Influenza A viruses (IAVs), particularly highly pathogenic avian influenza (HPAI) strains like H5N1 and H7N9, cause severe pneumonia and acute respiratory distress syndrome (ARDS) driven by dysregulated cytokine storms. A key mediator of this immunopathology is the excessive activation of the NLRP3 inflammasome, which governs the maturation of IL-1β. Galectin-3 (Gal3), a β-galactoside-binding lectin, is upregulated during infection; however, its specific regulatory role in coordinating NLRP3 inflammasome activation across distinct viral hemagglutinin (HA) subtypes remains to be elucidated. In this study, we demonstrate that Gal3 functions as a critical amplifier of influenza pathogenesis through a distinct dual-stage mechanism. Results from viral binding and internalization assays indicate that extracellular Gal3 promotes viral entry by interacting with viral HA, an effect that is strictly strain-dependent (H5N1 > H1N1 > H7N9). This enhanced entry consequently amplifies the initial signal for inflammasome activation. Intracellularly, Gal3 regulates the NLRP3 cascade by sustaining NF-κB activation (priming) to upregulate NLRP3 and pro-IL-1β transcription and acting as a facilitator to strengthen the NLRP3-ASC-pro-caspase-1 interaction, promoting ASC oligomerization (activation). Consistently, in vivo studies demonstrate that Gal3-deficient mice exhibit significantly improved survival, reduced weight loss, and attenuated pulmonary inflammation and IL-1β release following infection, with the most pronounced protective effects observed against H5N1. Collectively, these findings identify Gal3 as a potent host factor that orchestrates excessive inflammation by simultaneously facilitating viral entry and driving the assembly of the NLRP3 inflammasome, highlighting the Gal3-NLRP3 axis as a promising therapeutic target to mitigate severe influenza-induced lung injury.
Zih-Syuan Yang, A. Thitithanyanont, Jason C. Huang et al.· International Journal of Bio...· 0 citations
In vitro studies show that SLC15A4 inhibition results in the intracellular degradation of the TASL adapter protein and blockade of inflammatory cytokine production in response to TLR7/8/9 agonists, and these results highlight the early progress developing novel, drug-like inhibitors of SLC15A4.
J. McElwee, Ana Antić, A. Basavapathruni et al.· Journal of Immunology· 0 citations