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The Cryptosporidium signaling kinase CDPK5 plays an important role in male gametogenesis and parasite virulence.

ABSTRACT: The protozoan parasite Cryptosporidium is a leading cause of diarrhea in young children. The parasite's life cycle involves a coordinated and timely progression from asexual to sexual stages, leading to the formation of the transmissible oocyst. Underlying molecular signaling mechanisms orchestrating sexual development are not known. Here, we describe the function of a signaling kinase in Cryptosporidium male gametogenesis. We reveal the expression of Cryptosporidium parvum calcium-dependent protein kinase 5 (CDPK5) during male gamete development and its important role in the egress of mature gametes. Genetic ablation of this kinase results in viable parasites, indicating that this gene is dispensable for parasite survival. Interestingly, cdpk5 deletion decreases parasite virulence and impacts oocyst shedding in immunocompromised mice. Using phosphoproteomics, we identify possible CDPK5 substrates and biological processes regulated by this kinase. Collectively, these findings illuminate parasite cell biology by revealing a mechanism controlling male gamete production and a potential target to block disease transmission.

SUBMITTER: Nava MG

PROVIDER: S-EPMC11312397 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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The Cryptosporidium signaling kinase CDPK5 plays an important role in male gametogenesis and parasite virulence.

Nava Maria G MG Szewczyk Joanna J Arrington Justine V JV Alam Tauqeer T Vinayak Sumiti S

Cell reports 20240529 6

The protozoan parasite Cryptosporidium is a leading cause of diarrhea in young children. The parasite's life cycle involves a coordinated and timely progression from asexual to sexual stages, leading to the formation of the transmissible oocyst. Underlying molecular signaling mechanisms orchestrating sexual development are not known. Here, we describe the function of a signaling kinase in Cryptosporidium male gametogenesis. We reveal the expression of Cryptosporidium parvum calcium-dependent pro ...[more]

PMID: 38814783

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Project description:Gametogenesis, the formation of gametes from gametocytes, an essential step for malaria parasite transmission, is targeted by transmission-blocking drugs and vaccines. We identified a conserved protein (PBANKA_0305900) in Plasmodium berghei, which encodes a protein of 22 kDa (thus named Pb22) and is expressed in both asexual stages and gametocytes. Its homologues are present in all Plasmodium species and its closely related, Hepatocystis, but not in other apicomplexans. Pb22 protein was localised in the cytosols of schizonts, as well as male and female gametocytes. During gamete-to-ookinete development, Pb22 became localised on the plasma membranes of gametes and ookinetes. Compared to the wild-type (WT) parasites, P. berghei with pb22 knockout (KO) showed a significant reduction in exflagellation (~89%) of male gametocytes and ookinete number (~97%) during in vitro ookinete culture. Mosquito feeding assays showed that ookinete and oocyst formation of the pb22-KO line in mosquito midguts was almost completely abolished. These defects were rescued in parasites where pb22 was restored. Cross-fertilisation experiments with parasite lines defective in either male or female gametes confirmed that the defects in the pb22-KO line were restricted to the male gametes, whereas female gametes in the pb22-KO line were fertile at the WT level. Detailed analysis of male gametogenesis showed that 30% of the male gametocytes in the pb22-KO line failed to assemble the axonemes, whereas ~48.9% of the male gametocytes formed flagella but failed to egress from the host erythrocyte. To explore its transmission-blocking potential, recombinant Pb22 (rPb22) was expressed and used to immunise mice. in vitro assays showed that the rPb22-antisera significantly inhibited exflagellation by ~64.8% and ookinete formation by ~93.4%. Mosquitoes after feeding on rPb22-immunised mice also showed significant decreases in infection prevalence (83.3-93.3%) and oocyst density (93.5-99.6%). Further studies of the Pb22 orthologues in human malaria parasites are warranted.

Project description:BackgroundThe production of bioethanol from lignocellulosic feedstocks is dependent on lignocellulosic biomass degradation by hydrolytic enzymes. The main component of lignocellulose is cellulose and different types of organisms are able to secrete cellulases. The filamentous fungus Aspergillus nidulans serves as a model organism to study cellulase production and the available tools allow exploring more in depth the mechanisms governing cellulase production and carbon catabolite repression.ResultsIn A. nidulans, microarray data identified the cAMP-dependent protein kinase A (PkaA) as being involved in the transcriptional modulation and the production of lignocellulolytic enzymes in the presence of cellulose. Deletion of pkaA resulted in increased hydrolytic enzyme secretion, but reduced growth in the presence of lignocellulosic components and various other carbon sources. Furthermore, genes involved in fungal development were increased in the ΔpkaA strain, probably leading to the increased hyphal branching as was observed in this strain. This would allow the secretion of higher amounts of proteins. In addition, the expression of SynA, encoding a V-SNARE synaptobrevin protein involved in secretion, was increased in the ΔpkaA mutant. Deletion of pkaA also resulted in the reduced nuclear localization of the carbon catabolite repressor CreA in the presence of glucose and in partial de-repression when grown on cellulose. PkaA is involved in the glucose signaling pathway as the absence of this protein resulted in reduced glucose uptake and lower hexokinase/glucokinase activity, directing the cell to starvation conditions. Genome-wide transcriptomics showed that the expression of genes encoding proteins involved in fatty acid metabolism, mitochondrial function and in the use of cell storages was increased.ConclusionsThis study shows that PkaA is involved in hydrolytic enzyme production in A. nidulans. It appears that this protein kinase blocks the glucose pathway, hence forcing the cell to change to starvation conditions, increasing hydrolytic enzyme secretion and inducing the usage of cellular storages. This work uncovered new regulatory avenues governing the tight interplay between the metabolic states of the cell, which are important for the production of hydrolytic enzymes targeting lignocellulosic biomass. Deletion of pkaA resulted in a strain with increased hydrolytic enzyme secretion and reduced biomass formation.

Dataset Information

The Cryptosporidium signaling kinase CDPK5 plays an important role in male gametogenesis and parasite virulence.

Publications

The Cryptosporidium signaling kinase CDPK5 plays an important role in male gametogenesis and parasite virulence.

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