Biology subjects

Hernaez, B.

Publications and source records attributed to Hernaez, B..

5 recordsLinked to original sources

bioRxiv2026

Non-cyclic dinucleotide STING agonists abrogate MPXV infection

Mpox has emerged as a global threat to public health following several national and international outbreaks from 2022. Poxviruses deploy multiple strategies to counteract host immune defences including pathways leading to interferon (IFN) production. Here we demonstrate that depleting the viral 23-cGAMP nuclease poxin restores activation of STING and IRF3 during MPXV infection despite the presence of other viral antagonists. We then demonstrate that non-cyclic dinucleotide (non-CDN) STING agonists are resistant to poxin; activate STING and IRF3 during infection; and potently suppress MPXV and orthopoxvirus replication in human primary fibroblasts and differentiated monocytes, where replication is completely abrogated. Mechanistically, non-CDN restriction requires STING, IFNAR and STAT signalling, and induces a unique transcriptional signature over IFN{beta}, enabling expression of additional cytokines. In vivo, non-CDN activity effectively reduces signs of illness and enhances survival in wild-derived castaneous mice inoculated with the virulent clade I MPXV. Our study reveals poxin as an Achilles heel of MPXV, that when bypassed by direct STING agonism, provides a promising novel anti-mpox therapeutic strategy with reduced risk of antiviral resistance.

microbiology↗

bioRxiv2025

Enhanced mouse virulence of mpox virus clade Ib over clade IIb despite genomic changes caused by human-to-human transmission

The recently emerged clade Ib of mpox virus (MPXV) is spreading rapidly across Central and West Africa raising concerns about its potential virulence. Similar to clade IIb lineage B.1, which was responsible for the 2022 global outbreak, clade Ib exhibits sustained human-to-human transmission and a pattern of APOBEC3-associated genomic mutations. Here, we show that clade Ib displays enhanced cell-to-cell dissemination in vitro compared to clade IIb. Additionally, using the CAST mouse model, we show that clade Ib retains a higher level of virulence than that of the markedly attenuated clade IIb. Clade Ib leads to significant weight loss and high mortality in animals following both intraperitoneal and intranasal challenge. Histopathological analysis revealed more severe and extensive lung lesions in clade Ib-infected animals, accompanied by a broader distribution of viral antigens. Moreover, clade Ib, unlike IIb, disseminated efficiently to internal organs. These findings indicate that clade Ib MPXV has not undergone attenuation after human-to-human transmission to the extent observed in clade IIb and underscore the need for surveillance and preparedness against new emerging MPXV lineages.

microbiology↗

bioRxiv2025

Viral soluble decoy receptor as a novel treatment for IFN-I triggered diseases

Besides its antiviral action, type I interferon (IFN-I) plays a key role in triggering the inflammatory response and immunopathology in a group of autoinflammatory disorders known as interferonopathies. Current therapies for these diseases focus on blocking IFN-I signaling at different levels, but with incomplete success. Throughout evolution, to counteract the host immune response, poxviruses have developed decoy receptors, soluble proteins secreted from infected cells during infection that bind and block key host cytokines. One of these, the poxvirus IFN-I binding protein (IFN{beta}BP) is a unique soluble receptor with the ability to block many IFN-I subtypes with broad species specificity. In addition, this protein interacts with glycosaminoglycans on the cell surface while binding IFN-I, which enhances its immunomodulatory potential by allowing the retention of this receptor around the site of infection. In this study, we have deepened into how the poxvirus IFN{beta}BP modulates IFN-I to apply this knowledge to the development of new anti-IFN-I therapeutics. With this purpose, a set of IFN{beta}BP-based recombinant proteins were generated and tested for their ability to neutralize IFN-I and bind to the cell surface in vitro, and their immunomodulatory action was tested in the mousepox model of pathogenesis. Finally, the therapeutic potential of some of these selected viral IFN-I inhibitors was validated in two different murine models of autoinflammatory disease, imiquimod-induced psoriasis and pristane-induced lupus.

immunology↗

bioRxiv2025

Attenuation of the 2022 global outbreak monkeypox virus relative to its clade IIb ancestor

Monkeypox virus (MPXV) is a zoonotic virus endemic to Africa that has recently re-emerged, becoming the first orthopoxvirus with human-to-human transmission since smallpox eradication. The 2022 global epidemic of MPXV was caused by Clade IIb lineage B.1 virus that derives from the Clade IIb lineage A.1, which is endemic to West Africa1-3. Here we compared an early lineage B.1 virus with its closest earlier A.1 ancestor and show that despite only 46 nucleotide differences, lineage B.1 has attenuating phenotypic changes. Both B.1 and A.1 viruses replicated equivalently in cell culture, but B.1 had defects in long-range spread. MPXV B.1 also displayed defects in innate immune control, inducing higher IFN{beta}, innate immune signalling and MAPK gene expression, and a reduced capacity to suppress interleukin-1{beta}-mediated immune responses. Finally, MPXV B.1 had reduced virulence in a mouse model of MPXV infection relative to the ancestral A.1 endemic strain. Our work demonstrates biological differences between human circulating MPXV lineages that correlate with clinical observations documenting reduced in-host viral dissemination and disease severity for lineage B. Our data also reveal that the APOBEC3-like mutational footprint in MPXV is not only a signature of sustained human transmission but can also drive phenotypic changes.

microbiology↗

bioRxiv2020

Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here we demonstrate that the NRF2 anti-oxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, induction of NRF2 by 4-OI and DMF limited host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. One Sentence SummaryNRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

microbiology↗