Plasmodium chitinases: revisiting a target of transmission‐blockade against malaria

Abstract

Malaria is a life-threatening disease caused by one of the five species of Plasmodium, among which Plasmodium falciparum cause the deadliest form of the disease. Plasmodium species are dependent on a vertebrate host and a bloodsucking insect vector to complete their life cycle. Plasmodium chitinases belonging to the GH18 family are secreted inside the mosquito midgut, during the ookinete stage of the parasite. Chitinases mediate the penetration of parasite through the peritrophic membrane, facilitating access to the gut epithelial layer. In this review, we describe Plasmodium chitinases with special emphasis on chitinases from P. falciparum and P. vivax, the representative examples of the short and long forms of this protein. In addition to the chitinase domain, chitinases belonging to the long form contain a pro-domain and chitin-binding domain. Amino acid sequence alignment of long and short form chitinase domains reveals multiple positions containing variant residues. A subset of these positions was found to be conserved or invariant within long or short forms, indicating the role of these positions in attributing form-specific activity. The reported differences in affinities to allosamidin for P. vivax and P. falciparum were predicted to be due to different residues at two amino acid positions, resulting in altered interactions with the inhibitor. Understanding the role of these amino acids in Plasmodium chitinases will help us elucidate the mechanism of catalysis and the mode of inhibition, which will be the key for identification of potent inhibitors or antibodies demonstrating transmission-blocking activity.

Susceptibility of Field-Collected Nyssorhynchus darlingi to Plasmodium spp. in Western Amazonian Brazil

“…This pivotal degradation process is normally carried out by a chitinase secreted by the parasite. Interestingly, chitinase inhibitors and anti-chitinase antibodies are known to reduce parasite transmission from the vertebrate host to the mosquito, thus suggesting that the peritrophic matrix chitin is a critical feature related to Plasmodium penetration of the midgut [45][46][47]. Considering the major roles of chitinases in the crucial processes of the Plasmodium invasion, it is reasonable to presume that genetic variants of mosquito chitinases can be responsible for the integrity and variable thicknesses of the PM.…”

Plasmodium falciparum Development from Gametocyte to Oocyst: Insight from Functional Studies

“…The traversal of the midgut wall is mediated by an impressive set of microneme proteins discharged by the mature ookinete [ 183 ]. Proteomic [ 183 ] and genetics studies identified key proteins for midgut traversal, including the circumsporozoite-TRAP-related protein CTRP [ 184 ], the membrane-attack ookinete protein (MAOP) [ 185 ], the secreted ookinete adhesive protein SOAP [ 186 ], the von-Willebrand-Factor-A-domain-related protein WARP [ 187 ], the cell-traversal protein for ookinetes and sporozoites CelTOS [ 188 ], and the chitinase 1 (CHT1) [ 189 , 190 ]. A summary of the molecular and genetic mechanisms regulating zygote differentiation into ookinetes is provided in Table 4 .…”