Alveolar epithelial type 2 cell specific loss of IGFBP2 activates inflammation in COVID-19Pujadas, Chin, Sankpal
et alRespir Res (2025) 26 (1), 111
Abstract: The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines-Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors-Ccr2 and Ccr5-in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines-TNF-α; IL-6 and chemokine receptor-CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.© 2025. The Author(s).
The fusion peptide of the spike protein S2 domain may be a mimetic analog of β-coronaviruses and serve as a novel virus-host membrane fusion inhibitorSafiriyu, Hussain, Dewangan
et alAntiviral Res (2025) 237, 106144
Abstract: Coronavirus has garnered more attention recently, particularly in the aftermath of the 2019 pandemic. The β genus of the coronavirus family has demonstrated a significant threat to humanity. Current mitigation strategies involve the development of vaccines and repurposing drugs for symptomatic management of coronavirus infection, specifically SARS-Cov 2. Fusion inhibitors that are available as antiviral drugs for coronavirus have targeted the heptad repeat (HR) 1 and 2 in the S2 domain of the spike protein. The current study identified a fusion peptide (FP) upstream of HR1 as a potential target for developing membrane fusion inhibitors, and mimetic peptides analogous to the FP segment were tested for antiviral activity. Four mimetic fusion peptides (MFPs) (RSA59PP (MFP633), RSA59P (MFP634), RSMHV2P (MFP635), and RSMHV2PP (MFP636)) that are analogous to the FP of murine β coronavirus mouse hepatitis virus (MHV), MHV-A59/RSA59 (PP) and MHV-2/RSMHV2 (P) with central proline mutations, were tested. Results show the ability of MFPs to reduce cell-to-cell fusion and viral replication in vitro. MFP633, which contains a central double proline, exhibited the most potent inhibitory effect in spike protein-mediated membrane fusion assays. Biophysical experiments also demonstrated the strongest interactions between double-proline containing MFPs (MFP633 and MFP636) with biomimetic liposomes. In vivo studies using a liposome-mediated delivery system in mice confirmed the antiviral activity of MFP633. These findings suggest that targeting FPs could develop effective fusion inhibitors against coronaviruses. MFPs act on the host cell membrane by competing with the viral FP during the early stage of host-viral membrane fusion events. MFP633 is a promising peptide drug candidate that warrants future examination to assess whether this and other dual-proline containing peptides may exert similar anti-viral effects in other coronaviruses with conserved FP structures.Copyright © 2025. Published by Elsevier B.V.
SARS CoV-2 spike adopts distinct conformational ensembles in situGramm, Braet, Srinivasu
et albioRxiv (2025)
Abstract: Engineered recombinant Spike (S) has been invaluable for determining S structure and dynamics and is the basis for the design of most prevalent vaccines. While these vaccines have been highly efficacious for short-term protection from infection, protection waned with the emergence of variants (alpha through omicron). Here we report differences in conformational dynamics between native, membrane-embedded full-length S and recombinant S. Our virus-like particle (VLP) model mimics the native SARS CoV-2 virion by displaying S assembled with auxiliary E, M, and N proteins in a native membrane environment that captures the entirety of quaternary interactions mediated by S. Display of S on VLP obviates the requirement for stabilizing modifications that have been engineered into recombinant S for enhanced expression and solubility. Amide hydrogen/deuterium exchange mass spectrometry (HDXMS) reveals altered interprotomer contacts in VLP S trimers attributable to the presence of auxiliary proteins, membrane anchoring, and lack of engineered modifications. Our results reveal decreased dynamics in the S2 subunit and at sites spanning interprotomer contacts in VLP S with minimal differences in the N-terminal domain (NTD) and receptor binding domain (RBD). This carries implications for display of epitopes beyond NTD and RBD. In summary, despite affording efficient structural characterization, recombinant S distorts the intrinsic conformational ensemble of native S displayed on the virus surface.
Targeting the early life stages of SARS-CoV-2 using a multi-peptide conjugate vaccineMyburgh, Karsjens, Blanas
et alVaccine (2025) 54, 126989
Abstract: The spike glycoprotein is a key factor in the infection cycle of SARS-CoV-2, as it mediates both receptor recognition and membrane fusion by the virus. Therefore, in this study, we aimed to design a multi-peptide conjugate vaccine against SARS-CoV-2, targeting the early stages of the virus's life cycle. We used iBoost technology, which is designed to induce immune responses against low- or non-immunogenic epitopes. We selected six peptide sequences, each representing a key domain of the spike protein (i.e., receptor binding domain (RBM), subdomain 1 (SD1), subdomain 2 (SD2), S1/S2, fusion peptide and the S2' sequences (FP + S2'), heptad repeat 1 (HR1)). Immunization studies in mice displayed targeted humoral and cellular immune responses against specific peptides of the spike protein simultaneously, while inducing cross-protection against the Delta and Omicron coronavirus variants. Moreover, vaccinated hamsters challenged with SARS-CoV-2 elicited high antibody levels against key peptides, induced early neutralizing antibody responses and resulted in less weight loss compared to controls. This highlights the potential for improving viral control and disease outcomes when utilizing this strategy. Therefore, by using iBoost technology in conjunction with our peptide design strategy, we were able to successfully target non-immunodominant regions in the spike protein while activating both arms of the adaptive immune system.Copyright © 2024. Published by Elsevier Ltd.
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