Biology subjects

Hentzschel, F.

Publications and source records attributed to Hentzschel, F..

5 recordsLinked to original sources

bioRxiv2023

A non-canonical Arp2/3 complex is essential for Plasmodium DNA segregation and transmission of malaria.

The malaria-causing parasite Plasmodium has a complex life cycle involving both vertebrate and mosquito hosts. Sexual stages or gametocytes are the only stage competent for transmission to mosquitoes. Formation of flagellated male gametes from gametocytes requires rapid rounds of genome replication. Here we discovered a non-canonical Plasmodium actin-related protein 2/3 (Arp2/3) complex essential for DNA segregation during male gametogenesis. Plasmodium Arp2/3 dynamically localizes within the nucleus to the endomitotic spindles and interacts with a kinetochore protein. Deletion of key Arp2/3 subunits or interfering with actin polymerisation leads to the formation of sub-haploid male gametes and a complete block in transmission through delayed developmental arrest at the oocyst stage. Our work identified an evolutionary divergent protein complex in malaria parasites that offers potential targets for transmission-blocking interventions.

microbiology↗

bioRxiv2023

Vaccination by single dose sporozoite injection of blood stage attenuated malaria parasites

An efficient malaria vaccine remains elusive. As an alternative to malaria subunit vaccines, vaccination approaches are currently explored using live Plasmodium parasites, either attenuated mosquito-derived sporozoites or attenuated blood stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood stage multiplication rate. Ideally, such slow growing parasites would proceed normally through the mosquito but cause a self-limiting infection upon transmission. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. In addition, we tested the P. berghei mutants for avirulence in mice and self-resolving blood stage infections, while preserving sporozoite formation and liver infection. Targeting fifty genes yielded seventeen P. berghei gene-deletion mutants with two mutants causing self-clearing infections in mice while retaining full transmissibility through mosquitoes. For those, infection of mice by a low number of blood stages, infected-mosquito bites or by single injection of sporozoites led to protection from disease after challenge with wild type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and aid in developing new as well as safeguarding existing attenuated parasite vaccines.

cell biology↗

bioRxiv2023

Microtubule inner proteins of Plasmodium are essential for transmission of malaria parasites

Microtubule inner proteins, MIPs, are microtubule associated proteins that bind to tubulin from the luminal side. MIPs can be found in axonemes to stabilize flagellar beat or within cytoplasmic microtubules. Plasmodium spp. are the causative agents of malaria that feature different forms across a complex life cycle with both unique and divergent microtubule-based arrays. Here we investigate the role of four MIPs in a rodent malaria parasite for their role in transmission to and from the mosquito. We show by single and double gene deletions that SPM1 and TrxL1, MIPs associated with the subpellicular microtubules are dispensable for transmission from the vertebrate host to the mosquito and back. In contrast, FAP20 and FAP52, MIPs associated with the axonemes of gametes, are essential for transmission to mosquitoes but only if both genes are deleted. In the absence of both, FAP20 and FAP52 the B-tubule of the axoneme partly detaches from the A-tubule resulting in the deficiency of axonemal beating and hence gamete formation and egress. Our data suggest that a high level of redundancy ensures microtubule stability in the transmissive stages of Plasmodium, which is important for parasite transmission.

microbiology↗

bioRxiv2022

Form follows function: Variable microtubule architecture in the malaria parasite

The malaria parasite undergoes a series of extensive morphological changes within its human host and mosquito vector. A scaffold of microtubules beneath a peripheral double membrane establishes and maintains the distinct shapes of all infectious forms, but the underlying structural basis remains unknown. Here we applied in situ electron cryo-tomography after focused ion beam milling to follow changes in the microtubule cytoskeleton throughout the Plasmodium life cycle. This revealed an unexpected level of structural and architectural diversity so far not observed in other organisms. Microtubules in migrating mosquito forms consist of 13 protofilaments reinforced by interrupted luminal helices. Conversely, gametocyte microtubules consist of 13 to 18 protofilaments with doublets, triplets and quadruplets of varying arrangements. We show the microtubule cytoskeleton within the native cellular context, highlighting structurally diverse apical rings which act as microtubule organising centres. This provides a unique view into a relevant human pathogen with an unusual microtubule cytoskeleton.

microbiology↗

bioRxiv2021

Host cell maturation modulates parasite invasion and sexual differentiation in Plasmodium.

Malaria remains a global health problem with over 400,000 deaths annually1. Plasmodium parasites, the causative agents of malaria, replicate asexually in red blood cells (RBCs) of their vertebrate host, while a subset differentiates into sexual stages (gametocytes) for mosquito transmission. Parasite replication and gametocyte maturation in the erythropoietic niches of the bone marrow and spleen contribute to pathogenesis and drive transmission2, but the mechanisms underlying this organ enrichment remain unknown. We performed a comprehensive single cell analysis of rodent P. berghei in spleen, bone marrow and blood to define parasite phenotypes specific to those niches. Single cell RNA-seq analysis of host and parasite cells reveals an interferon-driven host response to infection as well as transcriptional adaptations of Plasmodium to RBC maturation status. We show that P. berghei exhibits a bimodal invasion pattern into either normocytes or early reticulocytes and, using functional assays, identify CD71 as a host receptor for reticulocyte invasion. Importantly, we observe an increased rate of gametocyte formation in reticulocytes that is nutrient-dependent and triggered post invasion (i.e., same cycle sexual commitment). Our data provides a thorough characterisation of host-parasite interactions in erythropoietic niches and defines host cell maturation state as the key driver of parasite adaptation.

microbiology↗