Actin subversion for productive Plasmodium hepatocyte invasion.

Productive invasion of hepatocytes by Plasmodium sporozoites is a key step of infection. The parasites traverse hepatocytes before targeting one of them to form a parasitophorous vacuole for parasite expansion. Schepis et al. show the induction of membrane ruffling via host Rho GTPases by Plasmodium sporozoites facilitating productive invasion.

Pathways of host cell exit by intracellular pathogens.

Host cell exit is a critical step in the life-cycle of intracellular pathogens, intimately linked to barrier penetration, tissue dissemination, inflammation, and pathogen transmission. Like cell invasion and intracellular survival, host cell exit represents a well-regulated program that has evolved during host-pathogen co-evolution and that relies on the dynamic and intricate interplay between multiple host and microbial factors. Three distinct pathways of host cell exit have been identified that are employed by three different taxa of intracellular pathogens, bacteria, fungi and protozoa, namely (i) the initiation of programmed cell death, (ii) the active breaching of host cellderived membranes, and (iii) the induced membrane-dependent exit without host cell lysis. Strikingly, an increasing number of studies show that the majority of intracellular pathogens utilize more than one of these strategies, dependent on life-cycle stage, environmental factors and/or host cell type. This review summarizes the diverse exit strategies of intracellular-living bacterial, fungal and protozoan pathogens and discusses the convergently evolved commonalities as well as system-specific variations thereof. Key microbial molecules involved in host cell exit are highlighted and discussed as potential targets for future interventional approaches.

Progress in imaging methods: insights gained into Plasmodium biology.

Over the past decade, major advances in imaging techniques have enhanced our understanding of Plasmodium spp. parasites and their interplay with mammalian hosts and mosquito vectors. Cryoelectron tomography, cryo-X-ray tomography and super-resolution microscopy have shifted paradigms of sporozoite and gametocyte structure, the process of erythrocyte invasion by merozoites, and the architecture of Maurer's clefts. Intravital time-lapse imaging has been revolutionary for our understanding of pre-erythrocytic stages of rodent Plasmodium parasites. Furthermore, high-speed imaging has revealed the link between sporozoite structure and motility, and improvements in time-lapse microscopy have enabled imaging of the entire Plasmodium falciparum erythrocytic cycle and the complete Plasmodium berghei pre-erythrocytic stages for the first time. In this Review, we discuss the contribution of key imaging tools to these and other discoveries in the malaria field over the past 10 years.

Active migration and passive transport of malaria parasites.

Malaria parasites undergo a complex life cycle between their hosts and vectors. During this cycle the parasites invade different types of cells, migrate across barriers, and transfer from one host to another. Recent literature hints at a misunderstanding of the difference between active, parasite-driven migration and passive, circulation-driven movement of the parasite or parasite-infected cells in the various bodily fluids of mosquito and mammalian hosts. Because both active migration and passive transport could be targeted in different ways to interfere with the parasite, a distinction between the two ways the parasite uses to get from one location to another is essential. We discuss the two types of motion needed for parasite dissemination and elaborate on how they could be targeted by future vaccines or drugs.

Invasion factors of apicomplexan parasites: essential or redundant?

Apicomplexa are obligate intracellular parasites that cause several human and veterinary diseases worldwide. In contrast to most intracellular pathogens these protozoans are believed to invade a rather passive host cell in a process, that is, tightly linked to the ability of the parasites to move by gliding motility. Indeed specific inhibitors against components of the gliding machinery and the analysis of knockdown mutants demonstrate a linkage of gliding motility and invasion. Intriguingly, new data show that it is possible to block gliding motility, while host cell invasion still occurs. This suggests that either the current models established for host cell invasion need to be critically revised or that alternative, motor independent mechanisms are in place including a more active role of the host cell that can complement a missing actin-myosin-system. Here we discuss some of the discrepancies that need to be addressed for a better understanding of invasion.

Understanding parasite transmission through imaging approaches.

Unicellular parasites are of high medical relevance as they cause such devastating diseases as malaria or sleeping sickness. Besides the search for improved treatments, research on these parasites is valuable as they constitute interesting model cells to study basic processes of life. They can also serve as valuable reality checks for our presumed understanding of biological processes that emerge from the study of human or yeast cells, as our common ancestor with many parasites is much older than the one with yeast. But working with parasites can be tricky and time-consuming, if not outright impossible. Here, we focus on examples from imaging studies investigating the transmission of the malaria parasite. Achieving an understanding of the processes important for malaria transmission necessitates different imaging approaches and new molecular and material technologies. The discussed techniques will include in vivo imaging of pathogens in living animals, screening methodologies, and new materials as surrogate 3D environments.

Are neutrophils important host cells for Leishmania parasites?

Neutrophils are the most crucial cells for early defence against infections. When appropriately activated, they can kill obligate intracellular pathogens such as Leishmania. However, once the phagocytotic killing has been evaded, neutrophils can serve as host cells for Leishmania. Parasitized neutrophils were suggested to function as a 'Trojan horse', to transfer Leishmania silently to macrophages. In vivo imaging has contributed a second evasion mechanism. We termed it the 'Trojan rabbit' strategy, whereby parasites escape dying neutrophils to infect macrophages. Here, we discuss the different experimental models used to study neutrophil function in leishmaniasis. We suggest that the capacity of neutrophils to function as an immune evasion target depends on the genetic background of the host and the parasite strain used for the experiments.

Host-cell invasion by malaria parasites: insights from Plasmodium and Toxoplasma.

Recent years have seen tremendous progress in our understanding of malaria parasite molecular biology. To a large extent, this progress follows significant developments in genetic, molecular and chemical tools available to study the malaria parasites and related Apicomplexa, in particular Toxoplasma gondii. One area of major advancement has been in understanding parasite host-cell invasion, a process that utilizes several essential molecular mechanisms that are conserved across the different lifecycle stages. Here, we summarize some of the most recent experimental data that shed light on the events underlying preparation and execution of malaria parasite invasion and how these insights might relate to the development of new antimalarial drugs.

The skin as interface in the transmission of arthropod-borne pathogens.

Animal skin separates the inner world of the body from the largely hostile outside world and is actively involved in the defence against microbes. However, the skin is no perfect defence barrier and many microorganisms have managed to live on or within the skin as harmless passengers or as disease-causing pathogens. Microbes have evolved numerous strategies that allow them to gain access to the layers underneath the epidermis where they either multiply within the dermis or move to distant destinations within the body for replication. A number of viruses, bacteria and parasites use arthropod vectors, like ticks or mosquitoes, to deliver them into the dermis while taking their blood meal. Within the dermis, successful pathogens subvert the function of a variety of skin resident cells or cells of the innate immune system that rush to the site of infection. In this review several interactions with cells of the skin by medically relevant vector-borne pathogens are discussed to highlight the different ways in which these pathogens have come to survive within the skin and to usurp the defence mechanisms of the host for their own ends.