Sugar epitopes as potential universal disease transmission blocking targets

Dinglasan, Rhoel R.; Valenzuela, Jesús G.; Azad, Abdu F.

doi:10.1016/j.ibmb.2004.09.005

Cited by 50 publications

(36 citation statements)

References 39 publications

(40 reference statements)

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“…7). Furthermore, a similar level of inhibition was observed when P. falciparum gametocytes, along with MAb CS-56, were fed to mosquitoes (SI Table 1), suggesting the utility of CS proteoglycans as transmission-blocking vaccine targets (20).…”

Section: Rnai-mediated Depletion Of Midgut Cs Blocks Parasite Invasionmentioning

confidence: 61%

Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion

Dinglasan

Alaganan

Ghosh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Malaria transmission entails development of the Plasmodium parasite in its insect vector, the Anopheles mosquito. Parasite invasion of the mosquito midgut is the critical first step and involves adhesion to host epithelial cell ligands. Partial evidence suggests that midgut oligosaccharides are important ligands for parasite adhesion; however, the identity of these glycans remains unknown. We have identified a population of chondroitin glycosaminoglycans along the apical midgut microvilli of Anopheles gambiae and further demonstrated ookinete recognition of these glycans in vitro. By repressing the expression of the peptide-Oxylosyltransferase homolog of An. gambiae by means of RNA interference, we blocked glycosaminoglycan chain biosynthesis, diminished chondroitin sulfate levels in the adult midgut, and substantially inhibited parasite development. We provide evidence for the in vivo role of chondroitin sulfate proteoglycans in Plasmodium falciparum invasion of the midgut and insight into the molecular mechanisms mediating parasite-mosquito interactions.Anopheles ͉ glycosaminoglycans ͉ glycosytransferase ͉ malaria ͉ RNAi M alaria is caused by Plasmodium parasites, among which, Plasmodium falciparum inflicts the severest infection on human populations. The complex parasite life cycle includes developmental stages within both mammals and its obligatory insect vector, the Anopheles mosquito (1). Plasmodium gametocytes that are taken up in an infected blood meal transform into ookinetes in the mosquito midgut lumen. Ookinetes then migrate to the gut periphery where they are thought to recognize and adhere to midgut ligands. These steps directly precede cell invasion, traversal, and the differentiation of ookinetes into oocysts beneath the basal lamina. Each oocyst produces thousands of sporozoites that subsequently invade the mosquito salivary glands and are delivered to a vertebrate host during a succeeding blood meal. Clearly, ookinete invasion of midgut epithelia is the critical step for parasite establishment in the mosquito and, therefore, represents the best paradigm to develop novel transmission-blocking strategies (i.e., approaches that prevent parasite passage through the mosquito and therefore impede the subsequent cascade of secondary infections in humans).Plasmodium ookinete molecules belonging to the Thrombospondin-related adhesive protein (TRAP) family, which includes the sporozoite surface protein, TRAP, and two ookinete proteins, the circumsporozoite and TRAP-related protein (CTRP) and the von Willebrand Factor A domain protein (WARP), have been demonstrated to bind to the glycosaminoglycan (GAG), heparin, in vitro (2). The major circumsporozoite protein (CSP) and TRAP both recognize heparan sulfate (HS) proteoglycans on the liver sinusoid, a critical step toward the establishment of parasite infection in humans (3, 4). Similarly, ookinete CTRP and WARP gene knockouts were shown to be incapable of invading the mosquito midgut, strongly implying their essential role in mosquito midgut cell invasion ...

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Section: Rnai-mediated Depletion Of Midgut Cs Blocks Parasite Invasionmentioning

confidence: 61%

Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion

Dinglasan

Alaganan

Ghosh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…We had previously identified AnAPN1 by virtue of its C-terminal O-linked glycans (16), which are absent from near-full-length rAnAPN 60 -942 . Thus, we hypothesize that binding to AnAPN1 in vivo may require the initial interaction of an ookinete lectin-like molecule with preference for O-linked glycans (53)(54)(55)(56). Last, it has been shown that several ookinete-interacting proteins are present on the surface of the mosquito midgut epithelial microvilli 41,51) and that AnAPN1 interaction with the ookinete may require the coordination of several other mosquito midgut molecules.…”

Section: Discussionmentioning

confidence: 99%

Antibodies to a Single, Conserved Epitope in Anopheles APN1 Inhibit Universal Transmission of Plasmodium falciparum and Plasmodium vivax Malaria

et al. 2014

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h Malaria transmission-blocking vaccines (TBVs) represent a promising approach for the elimination and eradication of this disease. AnAPN1 is a lead TBV candidate that targets a surface antigen on the midgut of the obligate vector of the Plasmodium parasite, the Anopheles mosquito. In this study, we demonstrated that antibodies targeting AnAPN1 block transmission of Plasmodium falciparum and Plasmodium vivax across distantly related anopheline species in countries to which malaria is endemic. Using a biochemical and immunological approach, we determined that the mechanism of action for this phenomenon stems from antibody recognition of a single protective epitope on AnAPN1, which we found to be immunogenic in murine and nonhuman primate models and highly conserved among anophelines. These data indicate that AnAPN1 meets the established target product profile for TBVs and suggest a potential key role for an AnAPN1-based panmalaria TBV in the effort to eradicate malaria.

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“…More recently, an anticarbohydrate antibody against mosquito midgut microvillus epitopes was shown to completely inhibit Plasmodium development (27). Furthermore, the ability of this antibody to recognize its cognate mosquito carbohydrate receptor was significantly inhibited by jacalin (which is specific for Gal moieties on O glycans) and WGA by a competition enzyme-linked immunosorbent assay (28), suggesting that the antibody shares similar glycan specificities with these two lectins. To date, the identity of the midgut glycoprotein target(s) is unknown.…”

Section: Bacterial Pathogens the Tick-borne Rickettsial Pathogensmentioning

confidence: 99%

Insight into a Conserved Lifestyle: Protein-Carbohydrate Adhesion Strategies of Vector-Borne Pathogens

Dinglasan

Jacobs-Lorena

2005

Infect Immun

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The incidence of vector-borne diseases such as malaria, dengue, African sleeping sickness, and tick-borne fevers is increasing. Given that current global control efforts have met with limited success, the need to develop novel interventions has become all the more vital. Successful discovery of such interventions is contingent on improving our understanding of how the pathogen interacts with its vertebrate host and also with its invertebrate vector. In this review we examine a premise developed more than 20 years ago (94) that emphasized the role of protein-carbohydrate interactions in microbial pathogenesis, and we present it in the context of vector-pathogen dynamics.Glycans are "essential macromolecules for numerous cellular processes, such as signaling, structural-support, cell-cell interaction, cell-matrix adhesion, growth, protection and trafficking" (94). Their ubiquitous yet tissue-specific occurrence as cell surface glycoconjugates has, over evolutionary time, been exploited by several pathogenic microorganisms as receptors for attachment and invasion (95). While evidence for microbial adherence to mammalian glycolipids and glycoproteins continues to grow (for reviews see references 17, 18, 58, 95, and 115), only recently has evidence for a "protein-carbohydrate recognition strategy" for vector host-pathogen interactions emerged. This review focuses on the most recent advances that describe adherence mechanisms of three different classes of pathogens-bacteria, viruses, and protozoan parasites-to their obligate arthropod vectors. We also discuss how the proteincarbohydrate recognition strategies in both vector and mammalian life stages are apparently conserved and how this conservation could lead to the development of novel strategies for intervention.

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Sugar epitopes as potential universal disease transmission blocking targets

Cited by 50 publications

References 39 publications

Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion

Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion

Antibodies to a Single, Conserved Epitope in Anopheles APN1 Inhibit Universal Transmission of Plasmodium falciparum and Plasmodium vivax Malaria

Insight into a Conserved Lifestyle: Protein-Carbohydrate Adhesion Strategies of Vector-Borne Pathogens

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