Biology subjects

Lehmann, F.

Publications and source records attributed to Lehmann, F..

6 recordsLinked to original sources

bioRxiv2026

Infection of neotropical non-human primates with bat deltaviruses

Background & Aims: The origin of hepatitis D virus (HDV) and related deltaviruses remains elusive. Contrarily, hepatitis B virus, HDV's helper virus, and related hepadnaviruses display long-term association with primates. Current data suggest cross-order host shifts as a common mechanism in deltavirus ecology, but corroborative evidence is lacking. Here, we aimed to elucidate the genealogy of primate deltaviruses. Methods: We screened 961 non-human primate (NHP) liver specimens obtained in Brazil between 2017-2023 for deltaviruses and hepadnaviruses. Complete deltaviral genomes were obtained via overlapping nested RT-PCR, cloned, expressed in vitro and analyzed via immunoblot and immunofluorescence analysis. Anti-deltaviral antibodies in NHP and vampire bats were detected via immunofluorescence analysis. Results: We detected deltaviruses in two NHP. Complete deltaviral genomes exhibited common features including high self-complementarity, genomic and antigenomic ribozymes, and a delta antigen open reading frame. NHP deltaviruses were phylogenetically related to viruses found in common vampire bats. The NHP deltaviruses replicated in vitro without the expression of a large delta antigen. We did not detect anti-deltaviral antibodies in NHP sera (0/249), in contrast to sera from common vampire bats (7/112; 6.2%, 95% CI: 1.8-10.7), indicating viral circulation in bats. Ancestral state reconstruction suggested a bat origin of NHP deltaviruses. Targeted screening excluded a coinfecting hepadnavirus in the deltavirus-positive animals but led to the discovery of a hepadnavirus, corroborating a non-recent introduction of hepadnaviruses into the primate stem-lineage. Conclusions: Our data are consistent with deltaviral cross-order host shifts and suggestive of the susceptibility of primates to reservoir-bound deltaviruses, lending credibility to a zoonotic origin of HDV.

microbiology↗

bioRxiv2026

CD117 epitope-shielded hematopoietic stem cell transplantation with toxin-free conditioning and in vivo selection ameliorates β-thalassemia model

Clinical evidence demonstrates that ex vivo gene therapy and genome engineering of hematopoietic stem and progenitor cells (HSPCs) could represent one-time cures. However, while genome editing itself has become increasingly efficient and precise, the toxic conditioning required for hematopoietic stem cell transplantation remains a major barrier to broad clinical implementation of these otherwise curative therapies. In particular, the use of busulfan for myeloablative conditioning constitutes a major safety concern. While preclinical studies established CD117 as a promising target for antigen-specific therapy, clinical translation faced setbacks balancing efficacy and safety. To overcome current limitations, we generated a new CD117-blocking monoclonal antibody (CIM058) and demonstrate its potency to block wild-type HSPCs. To enable long-term blockade of host HSPCs even after transplantation, we used prime editing to engineer CIM058-resistant human CD34+ HSPCs. When combined, CIM058 and the epitope engineered CD34+ HSPCs ameliorated disease phenotype in a {beta}-thalassemia model. Our results suggest that this approach may overcome the reliance on busulfan or other myeloablative conditioning regimens with their associated morbidities, and by enabling toxin-free conditioning and in vivo selection of edited cells, may facilitate clinical implementation of these highly valuable genetic therapies.

bioengineering↗

bioRxiv2025

Muscle power output reflects elevated viscosity in the propulsion system of flying miniature wasps

Air viscosity compromises aerodynamic lift production in the smallest flying insects, leading to increased flight costs. Miniature insects thus utilize both lift and drag for weight support but the exact energetic costs of wing flapping at low Reynolds number are widely unexplored. We estimated flight power in the miniature wasp Eretmocerus mundus. Wing kinematics was three-dimensionally reconstructed using high-speed video and computational fluid dynamics simulated air flows, aerodynamic forces and moments. We found an asymmetrical crescent-shaped wingtip trajectory with the upstroke posterior to the downstroke path. This fore-aft distance increases with increasing horizontal flight velocity, maintaining the wings backwards rowing motion needed for drag-based propulsion. Although the wings lift-to-drag ratio is below unity, lift is the predominant force responsible for weight support and forward thrust. Elevated drag leads to mass-specific mechanical power output of 118{+/-}9.0 Wkg-1 flight muscle, which exceeds most power estimates reported for other insects, birds and bats. The elevated energetic costs for flight may have fostered the development of bristled wings in miniature insects. Altogether, our study of wingbeat control and flight costs in a miniature insect extends the scope of flight mechanisms to the smallest flying animals revealing limits of miniaturization during the evolution of flight.

biophysics↗

bioRxiv2024

Borg3 / Cdc42EP5 regulates septin recruitment to primary cilia

Septin GTPases form linear hexa- or octameric rods that polymerize into higher order structures. They are incorporated into the cytoskeleton and involved in vital cellular functions. Among these, they play a role in the formation of primary cilia. Primary cilia are evolutionary conserved cellular signaling hubs. While it is accepted that septins localize to primary cilia and are involved in their formation and function, the regulation of septin assembly in the confined ciliary compartment remains elusive. Here we show, that Borg3, also known as Cdc42 effector protein 5 (Cdc42EP5), is an essential component of primary cilia. Specific Borg3 localization is facilitated by switching the Rho-GTPase Cdc42 between an inactive- and active state at the base of the primary cilium. The active form of Cdc42 has a defined localization restricted to the base of the primary cilium. Knockout of Borg3 as well as dysregulation of Cdc42 reduces septin dynamics at cilia and consequently, the formation of cilia. The study demonstrates that Borg3 is a novel and essential regulator of ciliogenesis through the spatiotemporal control of septin dynamics downstream of Cdc42.

cell biology↗

bioRxiv2023

Structure-function analysis of the cyclic beta-1,2-glucan synthase

The synthesis of complex sugars is a key aspect of microbial biology. Cyclic {beta}-1,2-glucan (C{beta}G) is a circular polysaccharide critical for host interactions of many bacteria, including major pathogens of humans (Brucella) and plants (Agrobacterium). C{beta}G is produced by the cyclic glucan synthase (Cgs), a massive multi-domain membrane protein. So far, its structure as well as the mechanisms underlining the synthesis have not been clarified. Here we use cryo-electron microscopy (cryo-EM) and functional approaches to study Cgs from A. tumefaciens. We were able to determine the structure of this complex protein machinery and clarify key aspects of C{beta}G synthesis. Our research opens new possibilities for combating pathogens that rely on polysaccharide virulence factors and can lead to new synthetic biology approaches for producing complex cyclic sugars.

molecular biology↗

bioRxiv2020

Structural investigation of ACE2 dependent disassembly of the trimeric SARS-CoV-2 Spike glycoprotein

The human membrane protein Angiotensin-converting enzyme 2 (hACE2) acts as the main receptor for host cells invasion of the new coronavirus SARS-CoV-2. The viral surface glycoprotein Spike binds to hACE2, which triggers virus entry into cells. As of today, the role of hACE2 for virus fusion is not well understood. Blocking the transition of Spike from its prefusion to post-fusion state might be a strategy to prevent or treat COVID-19. Here we report a single particle cryo-electron microscopy analysis of SARS-CoV-2 trimeric Spike in presence of the human ACE2 ectodomain. The binding of purified hACE2 ectodomain to Spike induces the disassembly of the trimeric form of Spike and a structural rearrangement of its S1 domain to form a stable, monomeric complex with hACE2. This observed hACE2 dependent dissociation of the Spike trimer suggests a mechanism for the therapeutic role of recombinant soluble hACE2 for treatment of COVID-19.

biophysics↗