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More than 60% of human infectious diseases are caused by pathogens shared with wild or domestic animals. Zoonotic disease organisms include those that are endemic in human populations or enzootic in animal populations with frequent cross-species transmission to people. Some of these diseases have only emerged recently. Together, these organisms are responsible for a substantial burden of disease, with endemic and enzootic zoonoses causing about a billion cases of illness in people and millions of deaths every year. Emerging zoonoses are a growing threat to global health and have caused hundreds of billions of US dollars of economic damage in the past 20 years. We aimed to review how zoonotic diseases result from natural pathogen ecology, and how other circumstances, such as animal production, extraction of natural resources, and antimicrobial application change the dynamics of disease exposure to human beings. In view of present anthropogenic trends, a more effective approach to zoonotic disease prevention and control will require a broad view of medicine that emphasises evidence-based decision making and integrates ecological and evolutionary principles of animal, human, and environmental factors. This broad view is essential for the successful development of policies and practices that reduce probability of future zoonotic emergence, targeted surveillance and strategic prevention, and engagement of partners outside the medical community to help improve health outcomes and reduce disease threats.

Plasmodium falciparum is the causative agent of malaria and remains a pathogen of global importance. Asexual blood stage replication, via a process called schizogony, is an important target for the development of new antimalarials. Here we use ultrastructure-expansion microscopy to probe the organisation of the chromosome-capturing kinetochores in relation to the mitotic spindle, the centriolar plaque, the centromeres and the apical organelles during schizont development. Conditional disruption of the kinetochore components, Pf NDC80 and Pf Nuf2, is associated with aberrant mitotic spindle organisation, disruption of the centromere marker, CENH3 and impaired karyokinesis. Surprisingly, kinetochore disruption also leads to disengagement of the centrosome equivalent from the nuclear envelope. Severing the connection between the nucleus and the apical complex leads to the formation of merozoites lacking nuclei. Here, we show that correct assembly of the kinetochore/spindle complex plays a previously unrecognised role in positioning the nascent apical complex in developing P. falciparum merozoites. Using Ultra-Expansion Microscopy of the malaria parasite, P. falciparum , Li et al. show that disruption of kinetochore components breaks a nexus between the mitotic spindle and the nascent apical organelles.

The sexual stage gametocytes of the malaria parasite, Plasmodium falciparum , adopt a falciform (crescent) shape driven by the assembly of a network of microtubules anchored to a cisternal inner membrane complex (IMC). Using 3D electron microscopy, we show that a non-mitotic microtubule organizing center (MTOC), embedded in the parasite’s nuclear membrane, orients the endoplasmic reticulum and the nascent IMC and seeds cytoplasmic microtubules. A bundle of microtubules extends into the nuclear lumen, elongating the nuclear envelope and capturing the chromatin. Classical mitotic machinery components, including centriolar plaque proteins, Pf centrin-1 and −4, microtubule-associated protein, End-binding protein-1, kinetochore protein, Pf NDC80 and centromere-associated protein, Pf CENH3, are involved in the nuclear microtubule assembly/disassembly process. Depolymerisation of the microtubules using trifluralin prevents elongation and disrupts the chromatin, centromere and kinetochore organisation. We show that the unusual non-mitotic hemispindle plays a central role in chromatin organisation, IMC positioning and subpellicular microtubule formation in gametocytes. The sexual blood stages of Plasmodium falciparum develop through five morphologically distinct stages culminating in mature crescent-shaped gametocytes that can be transmitted from the mammalian host to the mosquito vector. Here, Li et al. apply different microscopy and tomography approaches to characterize how the microtubule organizing center and cytoplasmic and nuclear microtubules are organized and oriented during these different stages in the absence of genome replication and mitosis.

Transmission of malaria parasites relies on the formation of a specialized blood form called the gametocyte. Gametocytes of the human pathogen, Plasmodium falciparum, adopt a crescent shape. Their dramatic morphogenesis is driven by the assembly of a network of microtubules and an underpinning inner membrane complex (IMC). Using super-resolution optical and electron microscopies we define the ultrastructure of the IMC at different stages of gametocyte development. We characterize two new proteins of the gametocyte IMC, called PhIL1 and PIP1. Genetic disruption of PhIL1 or PIP1 ablates elongation and prevents formation of transmission-ready mature gametocytes. The maturation defect is accompanied by failure to form an enveloping IMC and a marked swelling of the digestive vacuole, suggesting PhIL1 and PIP1 are required for correct membrane trafficking. Using immunoprecipitation and mass spectrometry we reveal that PhIL1 interacts with known and new components of the gametocyte IMC.

Retrospective cohort studies in Cameroon found an association between Onchocerca volvulus microfilarial load in childhood (measured in 1991–1993) and risk of developing epilepsy later in life (measured in 2017). We parameterised and integrated this relationship (across children aged 3–15 years) into the previously published, stochastic transmission model, EPIONCHO-IBM, for Simulium damnosum sensu lato-transmitted onchocerciasis. We simulated 19 years (1998–2017) of annual ivermectin mass drug administration (MDA) reflecting coverage in the study area, and modelled epilepsy prevalence and incidence. Scenario-based simulations of 25 years of (annual and biannual) MDA in hyper- and holoendemic settings, with 65% and 80% therapeutic coverage, were also conducted. EPIONCHO-IBM predicted 7.6% epilepsy prevalence (compared to 8.2% in the Cameroon study) and incidence of 317 cases/100,000 person-years (compared to 350). In hyperendemic areas, 25 years of biannual MDA (80% coverage) eliminated onchocerciasis-associated epilepsy (OAE) and protected untreated under-fives from its development. Strengthening onchocerciasis programmes, implementing alternative strategies, and evaluating treatment for under-fives and school-age children are crucial to prevent OAE in highly-endemic settings. Onchocerciasis is a vector-borne disease endemic to parts of sub-Saharan Africa and associated with substantial morbidity including reports of onchocerciasis-associated epilepsy. Here, the authors use mathematical modelling to assess the impact of community-directed treatment with ivermectin on onchocerciasis-associated epilepsy.

The disease-causing blood-stage of the Plasmodium falciparum lifecycle begins with invasion of human erythrocytes by merozoites. Many vaccine candidates with key roles in binding to the erythrocyte surface and entry are secreted from the large bulb-like rhoptry organelles at the apical tip of the merozoite. Here we identify an essential role for the conserved protein P. falciparum Cytosolically Exposed Rhoptry Leaflet Interacting protein 1 (PfCERLI1) in rhoptry function. We show that PfCERLI1 localises to the cytosolic face of the rhoptry bulb membrane and knockdown of PfCERLI1 inhibits merozoite invasion. While schizogony and merozoite organelle biogenesis appear normal, biochemical techniques and semi-quantitative super-resolution microscopy show that PfCERLI1 knockdown prevents secretion of key rhoptry antigens that coordinate merozoite invasion. PfCERLI1 is a rhoptry associated protein identified to have a direct role in function of this essential merozoite invasion organelle, which has broader implications for understanding apicomplexan invasion biology. Rhoptries are essential organelles for invasion of erythrocytes by Plasmodium . Here, the authors characterize the rhoptry-associated protein CERLI1 using quantitative super-resolution microscopy, showing that it is important for parasite invasion and secretion of rhoptry proteins including vaccine antigens.

Plasmodium falciparum mediates adhesion of infected red blood cells (RBCs) to blood vessel walls by assembling a multi-protein complex at the RBC surface. This virulence-mediating structure, called the knob, acts as a scaffold for the presentation of the major virulence antigen, P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1). In this work we developed correlative STochastic Optical Reconstruction Microscopy-Scanning Electron Microscopy (STORM-SEM) to spatially and temporally map the delivery of the knob-associated histidine-rich protein (KAHRP) and PfEMP1 to the RBC membrane skeleton. We show that KAHRP is delivered as individual modules that assemble in situ, giving a ring-shaped fluorescence profile around a dimpled disk that can be visualized by SEM. Electron tomography of negatively-stained membranes reveals a previously observed spiral scaffold underpinning the assembled knobs. Truncation of the C-terminal region of KAHRP leads to loss of the ring structures, disruption of the raised disks and aberrant formation of the spiral scaffold, pointing to a critical role for KAHRP in assembling the physical knob structure. We show that host cell actin remodeling plays an important role in assembly of the virulence complex, with cytochalasin D blocking knob assembly. Additionally, PfEMP1 appears to be delivered to the RBC membrane, then inserted laterally into knob structures.

Presentation of the variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (EMP1), at knob-like protrusions on the surface of infected red blood cells, underpins the parasite’s pathogenicity. Here we describe a protein PF3D7_0301700 (PTP7), that functions at the nexus between the intermediate trafficking organelle, the Maurer’s cleft, and the infected red blood cell surface. Genetic disruption of PTP7 leads to accumulation of vesicles at the Maurer’s clefts, grossly aberrant knob morphology, and failure to deliver EMP1 to the red blood cell surface. We show that an expanded low complexity sequence in the C-terminal region of PTP7, identified only in the Laverania clade of Plasmodium , is critical for efficient virulence protein trafficking.

Transmission of the malaria parasite Plasmodium falciparum requires the formation of specialised sexual cells called gametocytes. A hallmark of P. falciparum gametocyte development is its long duration, during which the parasite undergoes dramatic cellular remodelling including morphological, physiological and metabolic changes which result in the formation of a transmission ready, stage V gametocyte. Here we show that the PfGID E3 ubiquitin ligase complex regulates critical gametocyte cell fate programmes through the targeted ubiquitination of key proteins. Deletion of PfGID complex components leads to an arrest in gametocyte development and a loss of transmission to mosquitoes. PfGID governs gametocyte development by fine-tuning the protein levels of two substrates: the ZFP36 family RNAbinding protein GD1, and PfDPL, a cryptochrome-like protein. Our findings reveal that PfDPL regulates the expression of male-specific proteins early in gametocyte development that are essential for gametogenesis. In parallel to the PfDPL controlled cell fate program the RNA binding protein GD1 regulates transcripts crucial for gametocyte development by holding them in a state of translational repression. These findings illuminate the intricate molecular choreography underlying Plasmodium sexual development and provide insights into how single-celled eukaryotes execute cell-fate programmes to navigate complex life cycles and adapt to diverse host environments. Transmission of Plasmodium falciparum relies on the development of gametocytes, which undergo extensive cellular remodelling. Here, the authors demonstrate that the PfGID E3 ubiquitin ligase complex affects gametocyte development by regulating key proteins, producing defective cells that cannot infect mosquitoes.

The sexual blood stage of the human malaria parasite Plasmodium falciparum undergoes remarkable biophysical changes as it prepares for transmission to mosquitoes. During maturation, midstage gametocytes show low deformability and sequester in the bone marrow and spleen cords, thus avoiding clearance during passage through splenic sinuses. Mature gametocytes exhibit increased deformability and reappear in the peripheral circulation, allowing uptake by mosquitoes. Here we define the reversible changes in erythrocyte membrane organization that underpin this biomechanical transformation. Atomic force microscopy reveals that the length of the spectrin cross-members and the size of the skeletal meshwork increase in developing gametocytes, then decrease in mature-stage gametocytes. These changes are accompanied by relocation of actin from the erythrocyte membrane to the Maurer’s clefts. Fluorescence recovery after photobleaching reveals reversible changes in the level of coupling between the membrane skeleton and the plasma membrane. Treatment of midstage gametocytes with cytochalasin D decreases the vertical coupling and increases their filterability. A computationally efficient coarse-grained model of the erythrocyte membrane reveals that restructuring and constraining the spectrin meshwork can fully account for the observed changes in deformability.