Biology subjects

Binder, P.

Publications and source records attributed to Binder, P..

5 recordsLinked to original sources

bioRxiv2026

Dual-Antigen CCHFV Vaccine Induces Neutralizing Immunity and Protection Against Lethal Challenge

Crimean-Congo hemorrhagic fever virus (CCHFV) is a WHO-priority pathogen with high mortality and wide global distribution. A major challenge in CCHFV vaccine development is identifying antigens that induce functional cellular and humoral immunity. We previously showed that the CCHF nucleoprotein (NP) elicits protective responses in mice and non-human primates but does not induce neutralizing antibodies. We therefore systematically screened six chimeric DNA vaccines expressing different CCHF glycoproteins combined with NP. A construct comprising the ectodomain of the glycoprotein Gc and NP elicited robust antibody and T-cell responses to both antigens. The Gc-NP gene was subsequently developed as a lipid nanoparticle-formulated mRNA vaccine using a scalable manufacturing pipeline. Gc-NP mRNA-LNP induced robust antigen-specific humoral and cellular responses comparable to those elicited by the corresponding DNA vaccine, despite the substantially lower dose. Both vaccine approaches generated Gc-directed neutralizing antibody responses against CCHFV pseudovirus and protected mice against homologous Hoti and heterologous IbAr10200 strain challenge. These findings demonstrate that systematic antigen screening combined with genetic vaccine platforms can identify a potent multi-antigen CCHF vaccine candidate.

immunology↗

bioRxiv2025

Eukaryotic translation initiation factor 3d regulates stress granule assembly via its RNA binding domain

Stress granules are cytoplasmic mRNA-protein complexes that form by liquid-liquid phase separation in response to a variety of stresses. Their assembly is contingent upon the inhibition of mRNA translation. Depending on the type of stress and severity, they can promote stress resistance or act to reduce cellular fitness. As such, stress granules are implicated in ageing and a range of related pathologies. Many translation factors are components of stress granules, but it is unclear how they contribute to granule assembly. Here we show that the eIF3d component of the eIF3 translation initiation complex is recruited to stress granules in human cells and is required for stress granule assembly in response to specific stresses. The RNA-binding domain of eIF3d mediates its recruitment to stress granules and deletion of this domain blocks granule formation and decreases cell viability. Furthermore, the exogenous expression of just the eIF3d RNA-binding domain can rescue stress granule assembly in eIF3d-depleted cells. We confirmed the importance of eIF3d for robust stress granule assembly in vivo using the nematode worm C. elegans. This study demonstrates that eIF3d is a critical evolutionary conserved stress granule assembly factor, rather than simply coalescing passively into stress granules following the inhibition of translation initiation.

cell biology↗

bioRxiv2025

Competitive resource allocation drives asynchronous and rapid nuclear multiplication in the malaria parasite

The unicellular malaria parasite Plasmodium falciparum proliferates within the red blood cells of its human host, where it generates approximately 20 new parasites within an infection cycle of two days. Proliferation proceeds by nuclear divisions in a shared cytoplasm, followed by cellularization. In stark contrast to the highly synchronized nuclear division cycles in many eukaryotes, Plasmodium nuclear cycles desynchronize rapidly. Here, we elucidate the mechanism of desynchronization and study its impact on parasite fitness by combining live-cell imaging of DNA replication with biophysical modeling. We find that the standard model of independent nuclear cycles with transgenerational inheritance cannot account for the experimental data, and therefore desynchronization requires nuclear coupling. Competition for a limiting pool of a replication resource explains the data, provided that the resource is allocated sequentially to individual nuclei. Sequential allocation can be achieved by stable but reversible loading of a replication component to DNA, for example proliferating cell nuclear antigen (PCNA). Remarkably, the resultant asynchronous nuclear cycles accelerate parasite proliferation by minimizing idling times of resources. Indeed, we predict theoretically that this mechanism maximizes overall proliferation rate with limited resource availability. Thus, our findings identify nuclear cycle asynchrony as a resource-efficient means to achieve rapid proliferation.

biophysics↗

bioRxiv2023

Malaria parasite proliferation implicates a resource-dependent counter mechanism

Malaria is caused by the rapid proliferation of Plasmodium parasites in patients and disease severity correlates with the number of infected red blood cells in circulation. Parasite multiplication within red blood cells is called schizogony and occurs through an atypical multinucleated cell division mode. The mechanisms regulating the number of daughter cells produced by a single progenitor are poorly understood. We investigated underlying regulatory principles by quantifying nuclear multiplication dynamics in Plasmodium falciparum and knowlesi using super-resolution time-lapse microscopy. This revealed that the number of daughter cells was statistically independent of the duration of the nuclear division phase, which confirms that a counter mechanism, rather than a timer, regulates multiplication. P. falciparum cell volume at the start of nuclear division correlated with the final number of daughter cells. As schizogony progressed, the nucleocytoplasmic volume ratio, which has been found to be constant in all eukaryotes characterized so far, increased significantly, possibly to accommodate the exponentially multiplying nuclei. Depleting nutrients by dilution of culture medium caused parasites to produce less merozoites and reduced proliferation but did not affect cell volume or total nuclear volume at the end of schizogony. Our findings suggest that the counter mechanism implicated in malaria parasite proliferation integrates extracellular resource status to modify progeny number during blood stage infection.

cell biology↗

bioRxiv2021

Asynchronous nuclear cycles in multinucleated Plasmodium falciparum enable rapid proliferation

Malaria-causing parasites proliferate within erythrocytes through schizogony, forming multinucleated stages before cellularization. Nuclear multiplication does not follow a strict geometric 2n progression and each proliferative cycle produces a heterogeneous number of progeny. Here, by tracking nuclei and DNA replication, we show that individual nuclei replicate their DNA at different times, despite residing in a shared cytoplasm. Extrapolating from experimental data using mathematical modeling, we demonstrate that a limiting factor must exist that slows down the nuclear multiplication rate. Indeed, our data show that temporally overlapping DNA replication events were significantly slower than partially or non-overlapping events. Our findings suggest an evolutionary pressure that selects for asynchronous DNA replication, balancing available resources with rapid pathogen proliferation.

microbiology↗