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Key Points Apicomplexa are unicellular eukaryotic parasites that exhibit two types of secretory organelle at their apical pole and a membranous system that underlies their plasma membrane. Apicomplexa are obligate intracellular parasites that use a substrate-dependent gliding motility to move and to actively enter host cells, and to egress from the infected cells. Motility by Apicomplexa relies on the translocation of parasite surface adhesins from the apical pole, from where they are secreted to the posterior pole in a process powered by a machinery termed the glideosome. The rearward translocation of the adhesins bound to host cell receptors involves the actomyosin system, which propels the parasite forward. The invasion of host cells involves the formation of a moving junction at the point of apposition between the plasma membrane of the parasite and the host cell. Both ligands and receptors are secreted by the parasite, and they form a solid platform to support the force applied by the parasite during penetration. A tightly regulated signalling cascade coordinates the apical secretion of microneme proteins and the activation of the glideosome, which leads to gliding motility. Apicomplexa include important human pathogens and possess a unique cellular machinery that promotes gliding motility and is called the glideosome. In this Review, Soldati-Favre and colleagues discuss the principles that govern gliding motility, the characterization of the molecular machinery that comprises the glideosome, and its impact on parasite invasion and egress from infected cells. Protozoan parasites have developed elaborate motility systems that facilitate infection and dissemination. For example, amoebae use actin-rich membrane extensions called pseudopodia, whereas Kinetoplastida are propelled by microtubule-containing flagella. By contrast, the motile and invasive stages of the Apicomplexa — a phylum that contains the important human pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis) — have a unique machinery called the glideosome, which is composed of an actomyosin system that underlies the plasma membrane. The glideosome promotes substrate-dependent gliding motility, which powers migration across biological barriers, as well as active host cell entry and egress from infected cells. In this Review, we discuss the discovery of the principles that govern gliding motility, the characterization of the molecular machinery involved, and its impact on parasite invasion and egress from infected cells.

Apicomplexans are a major lineage of parasites, including causative agents of malaria and toxoplasmosis. How such highly adapted parasites evolved from free-living ancestors is poorly understood, particularly because they contain nonphotosynthetic plastids with which they have a complex metabolic dependency. Here, we examine the origin of apicomplexan parasitism by resolving the evolutionary distribution of several key characteristics in their closest free-living relatives, photosynthetic chromerids and predatory colpodellids. Using environmental sequence data, we describe the diversity of these apicomplexan-related lineages and select five species that represent this diversity for transcriptome sequencing. Phylogenomic analysis recovered a monophyletic lineage of chromerids and colpodellids as the sister group to apicomplexans, and a complex distribution of retention versus loss for photosynthesis, plastid genomes, and plastid organelles. Reconstructing the evolution of all plastid and cytosolic metabolic pathways related to apicomplexan plastid function revealed an ancient dependency on plastid isoprenoid biosynthesis, predating the divergence of apicomplexan and dinoflagellates. Similarly, plastid genome retention is strongly linked to the retention of two genes in the plastid genome,sufBandclpC, altogether suggesting a relatively simple model for plastid retention and loss. Lastly, we examine the broader distribution of a suite of molecular characteristics previously linked to the origins of apicomplexan parasitism and find that virtually all are present in their free-living relatives. The emergence of parasitism may not be driven by acquisition of novel components, but rather by loss and modification of the existing, conserved traits.

The dispersal of parasites is critical for epidemiology, and the interspecific vectoring of parasites when species share resources may play an underappreciated role in parasite dispersal. One of the best examples of such a situation is the shared use of flowers by pollinators, but the importance of flowers and interspecific vectoring in the dispersal of pollinator parasites is poorly understood and frequently overlooked. Here, we use an experimental approach to show that during even short foraging periods of 3 h, three bumblebee parasites and two honeybee parasites were dispersed effectively onto flowers by their hosts, and then vectored readily between flowers by non-host pollinator species. The results suggest that flowers are likely to be hotspots for the transmission of pollinator parasites and that considering potential vector, as well as host, species will be of general importance for understanding the distribution and transmission of parasites in the environment and between pollinators.

Key Points Apicomplexa are eukaryotic parasites that cause important human and veterinary diseases, such as malaria, toxoplasmosis and cryptosporidiosis. Apicomplexa replicate within the cells of their hosts by highly flexible and adaptable mechanisms, which can generate thousands of progeny to spread the infection. The cell division of Apicomplexa occurs by closed mitosis of the nucleus and budding of daughter cells. The regulation of apicomplexan cell cycle progression occurs at a global level throughout the cytoplasm and at a local level for each individual nucleus. Control is exerted by the activity of regulatory kinases, by modulating transcription, translation and protein stability and by the presence of physical tethers. The apicomplexan nucleus is highly structured into defined nuclear territories. Centromeres and telomeres occupy defined positions, which are closely connected to the position of the centrosome to ensure genome and epigenome integrity during division. Daughter cells are assembled in a stepwise and highly ordered process that is temporally and spatially guided by cytoskeletal self-organization and that is physically linked to the centrosome. The centrosome emerges as a central regulatory location for the progression and completion of cell division in Apicomplexa. Apicomplexan parasites have a complex life cycle that relies on highly regulated development inside host cells. Here, Francia and Striepen give an overview of apicomplexan cell cycle progression and cell division and the ways in which these processes are spatially and temporally guided by the centrosome in these pathogenic parasites. Toxoplasma gondii and Plasmodium falciparum are important human pathogens. These parasites and many of their apicomplexan relatives undergo a complex developmental process in the cells of their hosts, which includes genome replication, cell division and the assembly of new invasive stages. Apicomplexan cell cycle progression is both globally and locally regulated. Global regulation is carried out throughout the cytoplasm by diffusible factors that include cell cycle-specific kinases, cyclins and transcription factors. Local regulation acts on individual nuclei and daughter cells that are developing inside the mother cell. We propose that the centrosome is a master regulator that physically tethers cellular components and that provides spatial and temporal control of apicomplexan cell division.

Obligate intracellular Apicomplexa parasites share a unique invasion mechanism involving a tight interaction between the host cell and the parasite surfaces called the moving junction (MJ). The MJ, which is the anchoring structure for the invasion process, is formed by secretion of a macromolecular complex (RON2/4/5/8), derived from secretory organelles called rhoptries, into the host cell membrane. AMA1, a protein secreted from micronemes and associated with the parasite surface during invasion, has been shown in vitro to bind the MJ complex through a direct association with RON2. Here we show that RON2 is inserted as an integral membrane protein in the host cell and, using several interaction assays with native or recombinant proteins, we define the region that binds AMA1. Our studies were performed both in Toxoplasma gondii and Plasmodium falciparum and although AMA1 and RON2 proteins have diverged between Apicomplexa species, we show an intra-species conservation of their interaction. More importantly, invasion inhibition assays using recombinant proteins demonstrate that the RON2-AMA1 interaction is crucial for both T. gondii and P. falciparum entry into their host cells. This work provides the first evidence that AMA1 uses the rhoptry neck protein RON2 as a receptor to promote invasion by Apicomplexa parasites.

Long-distance animal migrations have important consequences for infectious disease dynamics. In some cases, migration lowers pathogen transmission by removing infected individuals during strenuous journeys and allowing animals to periodically escape contaminated habitats. Human activities are now causing some migratory animals to travel shorter distances or form sedentary (non-migratory) populations. We focused on North American monarch butterflies and a specialist protozoan parasite to investigate how the loss of migratory behaviours affects pathogen spread and evolution. Each autumn, monarchs migrate from breeding grounds in the eastern US and Canada to wintering sites in central Mexico. However, some monarchs have become non-migratory and breed year-round on exotic milkweed in the southern US. We used field sampling, citizen science data and experimental inoculations to quantify infection prevalence and parasite virulence among migratory and sedentary populations. Infection prevalence was markedly higher among sedentary monarchs compared with migratory monarchs, indicating that diminished migration increases infection risk. Virulence differed among parasite strains but was similar between migratory and sedentary populations, potentially owing to high gene flow or insufficient time for evolutionary divergence. More broadly, our findings suggest that human activities that alter animal migrations can influence pathogen dynamics, with implications for wildlife conservation and future disease risks.

Hepatocystis is a genus of single-celled parasites infecting, amongst other hosts, monkeys, bats and squirrels. Although thought to have descended from malaria parasites (Plasmodium spp.), Hepatocystis spp. are thought not to undergo replication in the blood-the part of the Plasmodium life cycle which causes the symptoms of malaria. Furthermore, Hepatocystis is transmitted by biting midges, not mosquitoes. Comparative genomics of Hepatocystis and Plasmodium species therefore presents an opportunity to better understand some of the most important aspects of malaria parasite biology. We were able to generate a draft genome for Hepatocystis sp. using DNA sequencing reads from the blood of a naturally infected red colobus monkey. We provide robust phylogenetic support for Hepatocystis sp. as a sister group to Plasmodium parasites infecting rodents. We show transcriptomic support for a lack of replication in the blood and genomic support for a complete loss of a family of genes involved in red blood cell invasion. Our analyses highlight the rapid evolution of genes involved in parasite vector stages, revealing genes that may be critical for interactions between malaria parasites and mosquitoes.

Why do parasites harm their hosts? Conventional wisdom holds that because parasites depend on their hosts for survival and transmission, they should evolve to become benign, yet many parasites cause harm. Theory predicts that parasites could evolve virulence (i.e., parasite-induced reductions in host fitness) by balancing the transmission benefits of parasite replication with the costs of host death. This idea has led researchers to predict how human interventions--such as vaccines--may alter virulence evolution, yet empirical support is critically lacking. We studied a protozoan parasite of monarch butterflies and found that higher levels of within-host replication resulted in both higher virulence and greater transmission, thus lending support to the idea that selection for parasite transmission can favor parasite genotypes that cause substantial harm. Parasite fitness was maximized at an intermediate level of parasite replication, beyond which the cost of increased host mortality outweighed the benefit of increased transmission. A separate experiment confirmed genetic relationships between parasite replication and virulence, and showed that parasite genotypes from two monarch populations caused different virulence. These results show that selection on parasite transmission can explain why parasites harm their hosts, and suggest that constraints imposed by host ecology can lead to population divergence in parasite virulence.

Inbreeding and a consequent loss of genetic diversity threaten small, isolated populations. One mechanism by which genetically impoverished populations may become extinct is through decreased immunocompetence and higher susceptibility to parasites. Here, we investigate the relationship between immunity and inbreeding in bumblebees, using Hebridean island populations of Bombus muscorum. We sampled nine populations and recorded parasite prevalence and measured two aspects of immunity: the encapsulation response and levels of phenoloxidase (PO). We found that prevalence of the gut parasite Crithidia bombi was higher in populations with lower genetic diversity. Neither measure of immune activity was correlated with genetic diversity. However, levels of PO declined with age and were also negatively correlated with parasite abundance. Our results suggest that as insect populations lose heterozygosity, the impact of parasitism will increase, pushing threatened populations closer to extinction.

Intracellular parasites use various strategies to invade cells and to subvert cellular signaling pathways and, thus, to gain a foothold against host defenses. Efficient cell entry, ability to exploit intracellular niches, and persistence make these parasites treacherous pathogens. Most intracellular parasites gain entry via host-mediated processes, but apicomplexans use a system of adhesion-based motility called \"gliding\" to actively penetrate host cells. Actin polymerization-dependent motility facilitates parasite migration across cellular barriers, enables dissemination within tissues, and powers invasion of host cells. Efficient invasion has brought widespread success to this group, which includes Toxoplasma, Plasmodium, and Cryptosporidium.