Antinori, S. | bioRxiv Science

bioRxiv2025

Antigen-agnostic identification of poxvirus broadly neutralizing antibodies targeting OPG153

Recurrent mpox outbreaks caused by the monkeypox virus (MPXV) have prompted the World Health Organization to declare a Public Health Emergency of International Concern and have stimulated the development of medical interventions. Here, antigen-agnostic isolation of neutralizing monoclonal antibodies from convalescent or vaccinated people, AlphaFold 3-based predictive modeling, and cryo-electron microscopy were synergistically combined to identify the protein encoded by orthopoxviral gene (OPG) 153 (MPXV A28) as a target of broadly neutralizing antibodies. OPG153-targeting antibodies neutralized MPXV clade Ib, IIb, and vaccinia virus (VACV), and cross-reacted with OPG153 orthologs from cowpox and variola viruses. Immunization with MPXV OPG153 elicited a potent neutralizing antibody response against MPXV and VACV, substantiating OPG153 as a promising vaccine antigen and a potent target for preventive and therapeutic antibodies.

microbiology↗

bioRxiv2022

The Defenders of the Alveolus Succumb in COVID-19 Pneumonia to SARS-CoV-2, Necroptosis, Pyroptosis and Panoptosis

The alveolar type II (ATII) pneumocyte has been called the defender of the alveolus because, amongst the cells many important roles, repair of lung injury is particularly critical. We investigated the extent to which SARS-CoV-2 infection incapacitates the ATII reparative response in fatal COVID-19 pneumonia, and describe massive infection and destruction of ATI and ATII cells. We show that both type I interferon-negative infected ATII and type I-interferon-positive uninfected ATII cells succumb to TNF-induced necroptosis, BTK-induced pyroptosis and a new PANoptotic hybrid form of inflammatory cell death that combines apoptosis, necroptosis and pyroptosis in the same cell. We locate pathway components of these cell death pathways in a PANoptosomal latticework that mediates emptying and disruption of ATII cells and destruction of cells in blood vessels associated with microthrombi. Early antiviral treatment combined with inhibitors of TNF and BTK could preserve ATII cell populations to restore lung function and reduce hyperinflammation from necroptosis, pyroptosis and panoptosis. Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/503050v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8bf28dorg.highwire.dtl.DTLVardef@1e1335eorg.highwire.dtl.DTLVardef@1f3a0e2org.highwire.dtl.DTLVardef@1c77c62_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIn fatal COVID-19 pneumonia, the initial destruction of Type II alveolar cells by SARS-CoV-2 infection is amplified by infection of the large numbers of spatially contiguous Type II cells supplied by the proliferative reparative response. C_LIO_LIInterferon-negative infected cells and interferon-positive uninfected cells succumb to inflammatory forms of cell death, TNF-induced necroptosis, BTK-induced pyroptosis, and PANoptosis. C_LIO_LIAll of the cell death pathway components, including a recently identified NINJ1 component, are localized in a PANoptosome latticework that empties in distinctive patterns to generate morphologically distinguishable cell remnants. C_LIO_LIEarly combination treatment with inhibitors of SARS-CoV-2 replication, TNF and BTK could reduce the losses of Type II cells and preserve a reparative response to regenerate functional alveoli. C_LI

immunology↗