Motility precedes egress of malaria parasites from oocysts

Klug, Dennis; Frischknecht, Friedrich

doi:10.7554/elife.19157

Cited by 63 publications

(100 citation statements)

References 76 publications

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“…The linearized α1‐tubulin (‐) vector was transfected into an unmodified P. berghei strain ANKA or P. berghei strain ANKA expressing mCherry under the CSP and eGFP under the ef1α promoter (Klug & Frischknecht, ) using standard protocols (Janse et al , ,b). Parasites that integrated the desired DNA construct were selected by administration of pyrimethamine (0.07 mg/ml) via the mouse drinking water.…”

Section: Methodsmentioning

confidence: 99%

Microtubule number and length determine cellular shape and function in Plasmodium

et al. 2019

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Microtubules are cytoskeletal filaments essential for many cellular processes, including establishment and maintenance of polarity, intracellular transport, division and migration. In most metazoan cells, the number and length of microtubules are highly variable, while they can be precisely defined in some protozoan organisms. However, in either case the significance of these two key parameters for cells is not known. Here, we quantitatively studied the impact of modulating microtubule number and length in Plasmodium , the protozoan parasite causing malaria. Using a gene deletion and replacement strategy targeting one out of two α‐tubulin genes, we show that chromosome segregation proceeds in the oocysts even in the absence of microtubules. However, fewer and shorter microtubules severely impaired the formation, motility and infectivity of Plasmodium sporozoites, the forms transmitted by the mosquito, which usually contain 16 microtubules. We found that α‐tubulin expression levels directly determined the number of microtubules, suggesting a high nucleation barrier as supported by a mathematical model. Infectious sporozoites were only formed in parasite lines featuring at least 10 microtubules, while parasites with 9 or fewer microtubules failed to transmit.

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Section: Methodsmentioning

confidence: 99%

Microtubule number and length determine cellular shape and function in Plasmodium

et al. 2019

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“…Lastly, belonging to the thrombospondin-related anonymous protein family, TRP1 has an important role in the egress of sporozoites from the oocyst. Trp1(-) parasites produce oocysts in numbers similar to the WT and show no defect in gliding motility in vitro, however no sporozoites could be detected in the hemolymph, demonstrating that they could not egress from oocysts (Klug and Frischknecht, 2017). In the same work, in vivo imaging of the WT sporozoites egressing from oocysts was performed for the first time.…”

Section: Oocyst Egressmentioning

confidence: 97%

“…While all of the proteins described above have a substantial impact on sporozoite egress, information on their specific function in the egress process is still missing, as is how they cooperate. Klug and Frischknecht (2017) propose two models for this event, the intracellular pathway and the extracellular pathway. In the former, sporozoites express proteins due to quorum sensing that trigger gliding motility and degradation of the oocyst wall for parasite release.…”

Section: Oocyst Egressmentioning

confidence: 99%

The Sporozoite's Journey Through the Mosquito: A Critical Examination of Host and Parasite Factors Required for Salivary Gland Invasion

Kojin

Adelman

2019

Front. Ecol. Evol.

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Although much progress has been made in the fight against malaria, the number of people that contract this disease due to the bite of an Anopheline mosquito remains unacceptably high. A better understanding of the relationship between the Plasmodium parasite and its vector is of extreme importance and may allow for the development of new tools to fight the disease. In particular, new genome editing techniques may allow the modification or removal of factors critical for parasite traversal of the vector mosquito. In this review, we aim to highlight what is known about important molecules encoded by the mosquito or parasite involved in this close interaction, focused on a specific window of the parasite life cycle inside the mosquito: from egress and release of the sporozoites from the oocyst into the hemolymph, until salivary gland penetration. While sophisticated molecular tools have already helped to understand aspects of parasite-mosquito interactions, our understanding of this brief period is still limited. Here, we discuss the evidence surrounding essential parasite and mosquito factors relating to sporozoite invasion of the salivary glands, and emphasize the areas where the lack of information is limiting the advance of strategies to manipulate the mosquito in order to block the transmission of malaria parasites.

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“…For the generation of trapΔI parasites we made use of the Pb238 vector (Deligianni et al 2011;Klug & Frischknecht 2017). In a first step the trap 3'UTR (970 bp) was amplified with the primers P165/P166 and cloned (BamHI and EcoRV) downstream of the resistance cassette in the Pb238 vector.…”

Section: Generation Of Trap(-)rec and Trapδi Parasitesmentioning

confidence: 99%

“…Once the ookinete crosses the midgut epithelium it forms an oocyst wherein it differentiates into hundreds of sporozoites (Frischknecht & Matuschewski 2017). Sporozoites use active motility to egress from the oocyst into the hemolymph (Klug & Frischknecht 2017), and subsequently enter the salivary glands from where they can be transmitted back to a vertebrate host. Once deposited in the skin during a blood meal by an infected mosquito, sporozoites migrate rapidly to find and enter blood vessels (Amino et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Cationic charge and polyspecificity of an integrin domain regulates infectivity of malaria parasites

Klug

Goellner

Sattler

et al. 2018

Preprint

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Cell-cell and cell-substrate adhesion is critical for many functions in life. In eukaryotes, I-domains mediate functions as divergent as tissue traversal by malaria-causing Plasmodium parasites as well as cell adhesion and migration by human leucocytes. The Idomain containing protein TRAP is important for Plasmodium sporozoite motility and invasion. Here we show that the I-domain of TRAP is required to mediate adhesional properties which can be partially preserved when the native I-domain is replaced by Idomains from human integrins or from an apicomplexan parasite that does not infect insects.By putting in vivo data and structural features in perspective we conclude that polyspecificity and positive charge around the ligand binding site of the I-domain are important for TRAP function. Our data suggest a highly preserved functionality of I-domains across eukaryotic evolution that is used by apicomplexan parasites to invade a broad range of tissues in a variety of hosts. the domain (Figure 1A compared to 1B and Figure 1D compared to 1E). The distance pistoned is equivalent to two turns of an α-helix. Uniquely in the apicomplexan I-domains, a segment N-terminal to the I-domain is disulfide linked to the last helical turn of the α7-helix in its closed conformation (Figure 1A-C). As this segment pistons out of contact with the remainder of the I-domain in the open conformation, the last two turns of the α7-helix with its cysteine unwind, the N-terminal segment with its cysteine moves in a similar direction, and these segments reshape to form a β-ribbon (Figure 1A). Because of close structural homology between human integrin αI-and apicomplexan adhesin I-domains in the regions shown in green in Figure 1A-E, we were able to engineer exchanges between them in this study. P. berghei parasites expressing TRAP without an I-domain show the I-domain is essential for motility and invasion. Parasites expressing TRAP with I-domains from other organisms including humans can have nearly intact motility and invasion. However, a poly-specific, cationic integrin αI-domain functions much better than a more specific, anionic integrin αIdomain. Together with altering the charge of the native TRAP adhesin, our results suggest that cationic surface charge around the MIDAS motif can enable polyspecificity and permit TRAP to function as an adhesin with diverse ligands in both vertebrate and arthropod hosts.

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Motility precedes egress of malaria parasites from oocysts

Cited by 63 publications

References 76 publications

Microtubule number and length determine cellular shape and function in Plasmodium

Microtubule number and length determine cellular shape and function in Plasmodium

The Sporozoite's Journey Through the Mosquito: A Critical Examination of Host and Parasite Factors Required for Salivary Gland Invasion

Cationic charge and polyspecificity of an integrin domain regulates infectivity of malaria parasites

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