Abstract:Plasmodium sporozoites that are transmitted by blood-feeding female Anopheles mosquitoes invade hepatocytes for an initial round of intracellular replication, leading to the release of merozoites that invade and multiply within red blood cells. Sporozoites and merozoites share a number of proteins that are expressed by both stages, including the Apical Membrane Antigen 1 (AMA1) and the Rhoptry Neck Proteins (RONs). Although AMA1 and RONs are essential for merozoite invasion of erythrocytes during asexual blood… Show more
“…AMA1 is also required upstream of liver infection, during sporozoite invasion of the mosquito salivary glands. 46 This temporal functional difference between AMA1 and B9 is consistent with the observation that the two proteins are contained in distinct secretory compartments. Figure 7 Model for B9 interaction with P36 and P52 for sporozoite host cell invasion B9 may localize in distinct (1) or same (2) micronemes as P36 and P52.…”
“…AMA1 is also required upstream of liver infection, during sporozoite invasion of the mosquito salivary glands. 46 This temporal functional difference between AMA1 and B9 is consistent with the observation that the two proteins are contained in distinct secretory compartments. Figure 7 Model for B9 interaction with P36 and P52 for sporozoite host cell invasion B9 may localize in distinct (1) or same (2) micronemes as P36 and P52.…”
“…We collected and counted haemolymph sporozoites in rapamycin-exposed and untreated clamp cKO-infected mosquitoes and observed no significant difference ( Fig 2E ) . Mosquitoes infected with parasites expressing mCherry exhibit a red fluorescence of pericardial cells following uptake of sporozoites released in the haemolymph [ 4 ]. A large majority of infected mosquitoes presented such mCherry-labelled structures, with both rapamycin-exposed and untreated clamp cKO parasites ( S2C Fig ) , indicating efficient egress from oocysts in CLAMP-deficient parasites.…”
Section: Resultsmentioning
confidence: 99%
“…CLAMP-deficient sporozoites also have a distinct phenotype as compared to parasites lacking AMA1, a canonical component of the MJ. Although in both cases sporozoites show a defect in invasion of mosquito salivary glands and mammalian hepatocytes, AMA1 conditional mutant sporozoites have no defect in gliding motility and cell traversal [ 4 ]. Altogether, these observations strongly support a role of CLAMP upstream of host cell invasion and MJ formation in Plasmodium sporozoites, unlike previously observed in Toxoplasma tachyzoites [ 7 ].…”
Section: Discussionmentioning
confidence: 99%
“…In contrast, the nature of the junction during sporozoite entry into hepatocytes remains elusive [3]. Known components of the MJ, such as AMA1 and RONs, are also expressed in sporozoites, and are required during invasion not only of hepatocytes but also of the mosquito salivary glands [4][5][6]. A genome-wide CRISPR screen performed in T. gondii has identified a novel putative component of the MJ, the Claudin-Like Apicomplexan Microneme Protein (CLAMP) [7].…”
Invasion of host cells by apicomplexan parasites such as Toxoplasma and Plasmodium spp requires the sequential secretion of the parasite apical organelles, the micronemes and the rhoptries. The claudin-like apicomplexan microneme protein (CLAMP) is a conserved protein that plays an essential role during invasion by Toxoplasma gondii tachyzoites and in Plasmodium falciparum asexual blood stages. CLAMP is also expressed in Plasmodium sporozoites, the mosquito-transmitted forms of the malaria parasite, but its role in this stage is still unknown. CLAMP is essential for Plasmodium blood stage growth and is refractory to conventional gene deletion. To circumvent this obstacle and study the function of CLAMP in sporozoites, we used a conditional genome editing strategy based on the dimerisable Cre recombinase in the rodent malaria model parasite P. berghei. We successfully deleted clamp gene in P. berghei transmission stages and analyzed the functional consequences on sporozoite infectivity. In mosquitoes, sporozoite development and egress from oocysts was not affected in conditional mutants. However, invasion of the mosquito salivary glands was dramatically reduced upon deletion of clamp gene. In addition, CLAMP-deficient sporozoites were impaired in cell traversal and productive invasion of mammalian hepatocytes. This severe phenotype was associated with major defects in gliding motility and with reduced shedding of the sporozoite adhesin TRAP. Expansion microscopy revealed partial colocalization of CLAMP and TRAP in a subset of micronemes, and a distinct accumulation of CLAMP at the apical tip of sporozoites. Collectively, these results demonstrate that CLAMP is essential across invasive stages of the malaria parasite, and support a role of the protein upstream of host cell invasion, possibly by regulating the secretion or function of adhesins in Plasmodium sporozoites.
“…For instance, TRAP allows crossing the cell barriers in both hosts (Akhouri et al 2004), and AMA1 is important for the invasion of erythrocytes (Triglia et al 2000) and hepatocytes (Yang et al 2017). An adaptation of AMA1 to mosquitoes cannot be entirely ruled out because it was recently shown that this protein is involved in the invasion of the mosquito salivary glands (Fernandes et al 2022).…”
Section: Adaptation To New Hosts (Mosquitoes and Humans)mentioning
Plasmodium falciparum, the most virulent agent of human malaria, spread from Africa to all continents following the out-of-Africa human migrations. During the transatlantic slave trade between the 16th and 19th centuries, it was introduced twice independently to the Americas where it adapted to new environmental conditions (new human populations and mosquito species). Here, we analyzed the genome-wide polymorphisms of 2,635 isolates across the currentP. falciparumdistribution range in Africa, Asia, Oceania, and the Americas to investigate its genetic structure, invasion history, and selective pressures associated with its adaptation to the American environment. We confirmed that American populations originated from Africa with at least two independent introductions that led to two genetically distinct clusters, one in the North (Haiti and Columbia) and one in the South (French Guiana and Brazil), and the admixed Peruvian group. Genome scans revealed recent and more ancient signals of positive selection in the American populations. Particularly, we detected positive selection signals in genes involved in interactions with host (human and mosquito) cells and in genes involved in resistance to malaria drugs in both clusters. We found that some genes were under selection in both clusters. Analyses suggested that for five genes, adaptive introgression between clusters or selection on standing variation was at the origin of this repeated evolution. This study provides new genetic evidence onP. falciparumcolonization history and on its local adaptation in the Americas.
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