Where is the EXIT? Phenotypic screens for new egress factors in apicomplexan parasites

Abstract

Apicomplexans, such as Plasmodium and Toxoplasma are obligate intracellular parasites that invade, replicate and finally EXIT their host cell. During replication within a parasitophorous vacuole (PV), the parasites establish an extensive F‐actin‐containing network that connects individual parasites and is required for material exchange, recycling and the final steps of daughter cell assembly. After multiple rounds of replication, the parasites exit the host cell involving multiple signalling cascades, disassembly of the network, secretion of microneme proteins and activation of the acto‐myosin motor. Blocking the host cell EXIT process leads to the formation of large PVs, making the screening for genes involved in exiting the cell relatively straightforward. Given that apicomplexans are highly diverse from other eukaryotes, approximately 30% of all genes are annotated as hypothetical, some apicomplexan‐specific factors are likely to be critical during EXIT. This motivated several labs to design and perform forward genetic and phenotypic screens using various approaches, such as random insertion mutagenesis, temperature‐sensitive mutants and, more recently, CRISPR/Cas9‐mediated targeted editing and conditional mutagenesis. Here we will provide an overview of the technological developments over recent years and the most successful stories that led to the identification of new critical factors in Toxoplasma gondii.

Mechanisms of host cell exit by intracellular pathogens

“…In this issue, various articles provide novel insight into molecules involved during host cell exit by Plasmodium and Toxoplasma, like phospholipases (Pietsch et al, 2023), zinc-finger proteins (Farrukh et al, 2023), cytoskeletal elements (Beyeler et al, 2023) or vesicle-resident factors (Sassmannshausen et al, 2023) and plasma membrane-bound proteins (Jennison et al, 2023;Thieleke-Matos et al, 2024). In addition, two reviews summarize apicomplexan exit strategies (Jimenéz-Ruiz et al, 2023;Scheiner et al, 2023). Three more research articles and a review deal with the lytic vacuolar exit by the bacterial pathogens Legionella (Hiller et al, 2023;Neuber et al, 2023), Rhodococcus (Nehls et al, 2024), Salmonella (Scharte et al, 2023), and Staphylococcus (Bayer et al, 2023).…”