Platelet derived growth factor receptor β (PDGFRβ) is a host receptor for the human malaria parasite adhesin TRAP

Steel, Ryan; Вигдорович, В. И.; Dambrauskas, Nicholas; Wilder, Brandon K.; Arredondo, Silvia A.; Goswami, Debashree; Kumar, Sudhir; Carbonetti, Sara; Swearingen, Kristian E.; Nguyen, Trang; Betz, Will; Camargo, Nelly; Fisher, Bridget S.; Soden, Jo; Thomas, Helen E.; Freeth, Jim; Moritz, Robert L.; Sather, D. Noah; Kappe, Stefan H. I.

doi:10.1038/s41598-021-90722-5

Cited by 9 publications

(6 citation statements)

References 53 publications

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“…The salivary protein Saglin facilitates efficient midgut colonization by malaria parasites shown to bind ubiquitously to a wide range of different proteins such as fetuin-A on hepatocytes [44], alpha-v-containing integrins [45] and platelet derived growth factor receptor β [46]. Therefore, it is conceivable that a Saglin-TRAP interaction in the skin increases sporozoite transmissibility, independently from the Saglin effect on the gametocyte/ookinete stages.…”

Section: Plos Pathogensmentioning

confidence: 99%

The salivary protein Saglin facilitates efficient midgut colonization of Anopheles mosquitoes by malaria parasites

et al. 2023

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Malaria is caused by the unicellular parasite Plasmodium which is transmitted to humans through the bite of infected female Anopheles mosquitoes. To initiate sexual reproduction and to infect the midgut of the mosquito, Plasmodium gametocytes are able to recognize the intestinal environment after being ingested during blood feeding. A shift in temperature, pH change and the presence of the insect-specific compound xanthurenic acid have been shown to be important stimuli perceived by gametocytes to become activated and proceed to sexual reproduction. Here we report that the salivary protein Saglin, previously proposed to be a receptor for the recognition of salivary glands by sporozoites, facilitates Plasmodium colonization of the mosquito midgut, but does not contribute to salivary gland invasion. In mosquito mutants lacking Saglin, Plasmodium infection of Anopheles females is reduced, resulting in impaired transmission of sporozoites at low infection densities. Interestingly, Saglin can be detected in high amounts in the midgut of mosquitoes after blood ingestion, possibly indicating a previously unknown host-pathogen interaction between Saglin and midgut stages of Plasmodium. Furthermore, we were able to show that saglin deletion has no fitness cost in laboratory conditions, suggesting this gene would be an interesting target for gene drive approaches.

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Section: Plos Pathogensmentioning

confidence: 99%

The salivary protein Saglin facilitates efficient midgut colonization of Anopheles mosquitoes by malaria parasites

et al. 2023

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“…TRAP shedding after cleavage by rhomboid proteases in its transmembrane domain is also important for gliding (Ejigiri et al , 2012). Several proteins have been suggested to specifically bind to TRAP: fetuin‐A, a hepatocyte‐specific protein (Jethwaney et al , 2005), saglin, an Anopheles salivary gland protein (Ghosh et al , 2009), alpha‐v‐containing integrins (Dundas et al , 2018), and platelet‐derived growth factor beta (Steel et al , 2021). We have previously called into question the specificity of these interactions by reporting that an I domain from Toxoplasma gondii MIC2, and to a lesser extent from the human integrin αXβ2, can functionally replace the I domain of Plasmodium berghei TRAP (Klug et al , 2020).…”

Section: Resultsmentioning

confidence: 99%

Conformational change of PlasmodiumTRAP is essential for sporozoite migration and transmission

et al. 2023

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Eukaryotic cell adhesion and migration rely on surface adhesins connecting extracellular ligands to the intracellular actin cytoskeleton. Plasmodium sporozoites are transmitted by mosquitoes and rely on adhesion and gliding motility to colonize the salivary glands and to reach the liver after transmission. During gliding, the essential sporozoite adhesin TRAP engages actin filaments in the cytoplasm of the parasite, while binding ligands on the substrate through its inserted (I) domain. Crystal structures of TRAP from different Plasmodium species reveal the I domain in closed and open conformations. Here, we probe the importance of these two conformational states by generating parasites expressing versions of TRAP with the I domain stabilized in either the open or closed state with disulfide bonds. Strikingly, both mutations impact sporozoite gliding, mosquito salivary gland entry, and transmission. Absence of gliding in sporozoites expressing the open TRAP I domain can be partially rescued by adding a reducing agent. This suggests that dynamic conformational change is required for ligand binding, gliding motility, and organ invasion and hence sporozoite transmission from mosquito to mammal.

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“…There, TRAP may have a capacity to interact with Saglin. Indeed, TRAP has been shown to bind ubiquitously to a wide range of different proteins such as fetuin-A on hepatocytes (Jethwaney et al ., 2005), alpha-v-containing integrins (Dundas et al ., 2018) and platelet derived growth factor receptor β (Steel et al ., 2021).…”

Section: Discussionmentioning

confidence: 99%

The salivary protein Saglin facilitates efficient midgut colonization of Anopheles mosquitoes by malaria parasites

Klug

Gautier

Calvo

et al. 2022

Preprint

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Malaria is caused by the unicelullar parasite Plasmodium which is transmitted to humans through the bite of infected female Anopheles mosquitoes. To initiate sexual reproduction and to infect the midgut of the mosquito, Plasmodium gametocytes are able to recognize the intestinal environment after being ingested during blood feeding. A shift in temperature, pH change and the presence of the insect-specific compound xanthurenic acid have been shown to be important stimuli perceived by gametocytes to become activated and proceed to sexual reproduction. Here we report that the salivary protein Saglin, previously proposed to be a receptor for the recognition of salivary glands by sporozoites, facilitates Plasmodium colonization of the mosquito midgut, but does not contribute to salivary gland invasion. In mosquito mutants lacking Saglin, Plasmodium infection of Anopheles females is greatly reduced, resulting in impaired transmission of sporozoites at low infection densities. Interestingly, our results suggest that Saglin, present in mosquito saliva, must be ingested with the blood meal to affect Plasmodium development, indicating a previously unknown host-pathogen interaction. Furthermore, we were able to show that saglin deletion has no fitness cost in laboratory conditions, suggesting this gene would be an interesting target for gene drive approaches.

show abstract

Platelet derived growth factor receptor β (PDGFRβ) is a host receptor for the human malaria parasite adhesin TRAP

Cited by 9 publications

References 53 publications

The salivary protein Saglin facilitates efficient midgut colonization of Anopheles mosquitoes by malaria parasites

The salivary protein Saglin facilitates efficient midgut colonization of Anopheles mosquitoes by malaria parasites

Conformational change of PlasmodiumTRAP is essential for sporozoite migration and transmission

The salivary protein Saglin facilitates efficient midgut colonization of Anopheles mosquitoes by malaria parasites

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