Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(6)

Published: March 20, 2025

Autoantibodies neutralizing type I interferons (IFN-Is; IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by autoantibody–containing plasmas from aged individuals with HIV-1 and COVID-19. These overlap regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, efficiently block interaction of both receptor subunits in vitro. In contrast, non-neutralizing limit only one subunit display relatively low IFN-I–binding avidities, thus likely hindering function. Iterative engineering signaling-inert mutant IFN-Is (simIFN-Is) retaining autoantibody targets created potent decoys that prevent neutralization autoantibody-containing restore IFN-I–mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting autoantibodies plasmas, leaving antibodies unaffected. Our study reveals mechanisms action demonstrates a proof-of-concept strategy to alleviate pathogenic effects.

Language: Английский

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Powassan and other emerging neuroinvasive arboviruses in North America

Current Opinion in Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: March 30, 2025

Purpose of review Arthropod-borne viruses (arboviruses) represent a group pathogens with increasing global relevance, some which cause neuroinvasive disease. Transmitted by arthropod vectors and maintained variety primary amplifying hosts, epidemics are dependent on numerous environmental anthropogenic factors. This serves to highlight several important arboviruses relevant North America discuss the neurologic presentations, diagnosis, outcomes, future trends. Recent findings shifts in epidemiology ecology include divergence such as dengue chikungunya from dependence enzootic cycles, geographical expansion Oropouche virus, incidence established American Powassan virus. Accurate identification factors contributing arboviral outbreaks is critical improve preventive public health measures. Similarly, further elucidating pathogen host that determine neuroinvasiveness, neurotropism, neurovirulence will be key development successful vaccines targeted therapeutics. Summary Arboviruses an human Familiarity diagnostic workup, treatment strategies, expected course for clinicians caring these patients.

Language: Английский

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Human type I interferons protect Vero E6 and ARPE-19 cells against West Nile virus and are neutralized by pathogenic autoantibodies

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 2, 2025

Auto-antibodies (auto-Abs) that neutralize type I interferons (IFNs) have been implicated in severe viral infections, including ~ 40% of cases West Nile virus (WNV) neuroinvasive disease (WNND). Developing robust vitro models to evaluate the protective effects IFNs against infection, as well disruptive auto-Abs, is essential for understanding pathogenesis and identifying patients at risk. In this study, we used Vero E6 ARPE-19 cell lines investigate ability (IFN-α, IFN-β, IFN-ω), II (IFN-γ), III (IFN-λ1) restrict WNV infection. Our results demonstrate IFN-α, IFN-ω effectively protect cells from with IFN-β exhibiting strongest antiviral effect. contrast, required higher concentrations achieve comparable protection. Neither IFN-γ nor IFN-λ1 conferred protection either line. We further screened serum samples WNV-infected auto-Abs neutralizing IFNs. findings confirm ARPE-19-based assay consistent other established methods detecting This simple reliable offers a valuable tool assessing activity both research clinical settings. Future studies should aim validate utility ARPE-19-WNV infection model on larger scale.

Language: Английский

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Deciphering the autoreactome: Massively parallelized methods for autoantibody detection in humans

Journal of Immunological Methods, Journal Year: 2025, Volume and Issue: unknown, P. 113876 - 113876

Published: May 1, 2025

Language: Английский

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