Lingemann, M. | bioRxiv Science

bioRxiv2026

Sub-neutralizing concentrations of Zika virus IgM monoclonal antibodies reduce IgG-mediated antibody-dependent enhancement of infectivity.

Zika virus (ZIKV) is an arthropod-borne flavivirus endemic to Latin America and Africa for which IgG-mediated antibody-dependent enhancement of infectivity (ADE) is a phenomenon of concern. The interplay dynamics between flavivirus-specific antibodies of the IgG and IgM isotypes are mostly unknown. Here, we used DH1017.IgM, a previously described human-derived, pentameric, ultrapotent neutralizing ZIKV IgM monoclonal antibody (mAb) and a recombinantly produced IgM version of neutralizing EDE1 mAb C8 (C8.IgM) to assess if IgM antibodies can interfere with IgG-mediated ADE in vitro. Both mAbs consistently reduced IgG-mediated ADE across a panel of ZIKV-binding IgG mAbs in a dose-dependent manner. ADE mitigation was achieved at DH1017.IgM sub-neutralizing concentrations. C8.IgM also mitigated IgG-mediated ADE against the whole panel, demonstrating generalizability. Finally, DH1017.IgM confirmed inhibition of ADE at sub-neutralizing concentrations in sera of ZIKV-infected individuals. In conclusion, mAbs of the IgM isotype may potently counter the adverse effects of IgG-mediated ADE.

immunology↗

bioRxiv2023

Phosphatidylinositol 4-kinase III alpha governs cytoskeletal organization for invasiveness of liver cancer cells

Background and AimsHigh expression of phosphatidylinositol 4-kinase III alpha (PI4KIII) correlates with poor survival rates in patients with hepatocellular carcinoma (HCC). In addition, Hepatitis C virus (HCV) infections activate PI4KIII and contribute to HCC progression. We aimed at mechanistically understanding the impact of PI4KIII on the progression of liver cancer and the potential contribution of HCV in this process. MethodsSeveral hepatic cell culture and mouse models were used to study functional importance of PI4KIII on liver pathogenesis. Antibody arrays, gene silencing and PI4KIII specific inhibitor were applied to identify the involved signaling pathways. The contribution of HCV was examined by using HCV infection or overexpression of its nonstructural protein. ResultsHigh PI4KIII expression and/or activity induced cytoskeletal rearrangements via increased-phosphorylation of paxillin and cofilin. This led to morphological alterations and higher migratory and invasive properties of liver cancer cells. We further identified the liver specific lipid kinase phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2{gamma}) working downstream of PI4KIII in regulation of the cytoskeleton. PIK3C2{gamma} generates plasma membrane (PM) phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]- enriched, invadopodia-like structures which regulate cytoskeletal reorganization by promoting Akt2 phosphorylation. ConclusionsPI4KIII regulates cytoskeleton organization via PIK3C2{gamma}/Akt2/paxillin-cofilin to favor migration and invasion of liver cancer cells. These findings provide mechanistic insight into the contribution of PI4KIII and HCV to progression of liver cancer and identify promising targets for therapeutic intervention. IMPACT AND IMPLICATIONSUnderstanding mechanistically how high PI4KIII expression are associated with poor clinical outcomes of liver cancer is important to develop pharmaceutical interventions. Our study sheds light on the importance of the two lipid kinases PI4KIII and PIK3C2{gamma} as well as the contribution of HCV on liver cancer progression, unraveling the signaling pathway governing this process. This preclinical study contributes to better understanding the complex connection of phospholipids, cytoskeleton and liver cancer and suggests strategies to improve therapeutic outcomes by targeting important signaling molecules. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/541742v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@16ba717org.highwire.dtl.DTLVardef@a6f681org.highwire.dtl.DTLVardef@181c3cdorg.highwire.dtl.DTLVardef@5df6aa_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗