Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission

Niu, Guodong; Wang, Bin; Zhang, Genwei; King, Jarrod B.; Cichewicz, Robert H.; Li, Jun

doi:10.1038/srep14694

Cited by 34 publications

(53 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fortunately, we successfully cultured two wild malaria isolates under laboratory conditions. Using the IFA method as we described previously 16 , 17 , results clearly showed that FBN30 co-localized with wild type P. falciparum ookinetes (Fig. 3c ).…”

Section: Resultssupporting

confidence: 60%

“…gambiae to clinically circulating P. falciparum . Variations in length and composition of signal peptide sequences that change secretory efficiency of a mature protein have been reported in other organisms including humans 17 , 26 , 27 . For example, the insertion/deletion polymorphisms of apolipoprotein B within its signal peptide are associated with plasma glucose levels in Europeans and Mexican Americans 28 .…”

Section: Discussionmentioning

confidence: 85%

See 1 more Smart Citation

FBN30 in wild Anopheles gambiae functions as a pathogen recognition molecule against clinically circulating Plasmodium falciparum in malaria endemic areas in Kenya

Niu

Zhang

Franca

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Malaria is a worldwide health problem that affects two-thirds of the world population. Plasmodium invasion of anopheline mosquitoes is an obligatory step for malaria transmission. However, mosquito-malaria molecular interactions in nature are not clear. A genetic variation within mosquito fibrinogen related-protein 30 (FBN30) was previously identified to be associated with Plasmodium falciparum infection in natural Anopheles gambiae populations at malaria endemic areas in Kenya, and reducing FBN30 expression by RNAi makes mosquitoes more susceptible to P. berghei. New results show that FBN30 is a secreted octamer that binds to both P. berghei and clinically circulating P. falciparum from malaria endemic areas in Kenya, but not laboratory P. falciparum strain NF54. Moreover, the natural genetic mutation (T to C) within FBN30 signal peptide, which changes the position 10 amino acid from phenylalanine to leucine, reduces protein expression by approximately half. This change is consistent to more susceptible An. gambiae to P. falciparum infection in the field. FBN30 in natural An. gambiae is proposed to work as a pathogen recognition molecule in inhibiting P. falciparum transmission in malaria endemic areas.

show abstract

Section: Resultssupporting

confidence: 60%

Section: Discussionmentioning

confidence: 85%

FBN30 in wild Anopheles gambiae functions as a pathogen recognition molecule against clinically circulating Plasmodium falciparum in malaria endemic areas in Kenya

Niu

Zhang

Franca

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Standard membrane feeding assays (SMFA) were performed as the previous reports [12, 24]. About 30 μL anti-sera were mixed with 330 μL cultured P. falciparum and fed 3-5-day-old female An.…”

Section: Methodsmentioning

confidence: 99%

Malaria transmission assisted by interaction betweenPlasmodium α-tubulin-1 andAnophelesFREP1 protein

Zhang

Niu

Perez

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Passage of Plasmodium through a mosquito midgut is essential for malaria transmission. FREP1, a peritrophic matrix protein in a mosquito midgut, binds to the parasite and mediates Plasmodium infection in Anopheles. The FREP1-mediated Plasmodium invasion pathway is highly conserved across multiple species of Plasmodium and Anopheles. Through pulldown, nine P. berghei proteins were co-precipitated with FREP1-conjugated beads. After cloning these nine genes from P. berghei and expressing them in insect cells, six of them were confirmed to interact with recombinant FREP1 protein. Among them, α-tubulin-1 and heat shock protein 70 (Hsp70) were highly conserved in Plasmodium species with >95% identity. Thus, P. falciparum α-tubulin-1 and Hsp70 were cloned and expressed in E. coli to stimulate antibody (Ab) in mice. Our results showed that anti-serum against P. falciparum α-tubulin-1 significantly inhibited P. falciparum transmission to An. gambiae, while Ab against P. falciparum Hsp70 serum did not. The polyclonal Ab against human α-tubulin did not interfere formation of ookinetes, however, significantly reduced the number of P. falciparum oocysts in An. gambiae midguts. Moreover, fluorescence microscope assays showed that anti-α-tubulin Ab bound to impermeable Plasmodium ookinete apical invasive apparatus. Therefore, we propose that the interaction between Anopheles FREP1 protein and Plasmodium α-tubulin-1 directs the ookinete invasive apparatus towards midgut peritrophic matrix for the efficient passage of the parasite. Anopheles FREP1 and Plasmodium α-tubulin-1 are potential targets for blocking malaria transmission to the mosquito host.AUTHOR SUMMARYThe molecular mechanisms of malaria transmission to mosquito are not well-understood. FREP1 proteins in mosquito midget PM has been proved to mediate malaria transmission by binding to parasite ookinetes. Here we reported that Plasmodium parasite α-tubulin-1 is an FREP1 binding partner. We initially identified the α-tubulin-1 through the FREP1-pulldown assay; Then we cloned P. falciparum α-tubulin-1, and demonstrated that the insect cell expressed recombinant Plasmodium α-tubulin-1 bound to FREP1 in vitro; Next, mouse anti-serum against P. falciparum α-tubulin-1 was found to inhibit P. falciparum transmission to An. gambiae. P. falciparum α-tubulin-1 shares >84% identical amino acid sequence with human α-tubulin, purified Ab against human α-tubulin significantly inhibited malaria transmission. Anti-human α-tubulin Ab did not interfere the gametocyte-to-ookinetes conversion. Final, we found that anti-α-tubulin Ab bound to the apical end of impermeable ookinetes. Structurally, ookinete invasive apparatus locates at the apical opening. Therefore, we propose that the interaction between Anopheles midgut FREP1 protein and Plasmodium apical α-tubulin-1 directs the ookinete invasive apparatus towards midgut PM for the efficient parasite invasion.

show abstract

“…The efficacy of these interventions is however continually challenged and threatened by the evolution of insecticide (3, 4) and drug resistances (5, 6). To overcome resistance issues, the re-emergence of the concept of malaria transmission-blocking strategies (7–10) has boosted the research efforts to find molecules (11, 12) or microorganisms (13–16) able to inhibit the transmission of parasites or to disturb the life cycle of Plasmodium in the mosquito vector. Understanding the fundamental processes of parasite transmission from human to mosquito vector is therefore essential to this aim.…”

Section: Introductionmentioning

confidence: 99%

Opening Pandora’s Box: Distribution of Plasmodium gametocytes in bloodstream

Pigeault¹,

Isaïa²,

Yerbanga

et al. 2019

Preprint

View full text Add to dashboard Cite

10Malaria, a vector borne disease caused by Plasmodium spp., remains a major global cause of 11 morbidity and mortality. Optimization of the disease control strategies requires a thorough 12 understanding of the fundamental processes underlying parasite transmission. Although the 13 number of transmissible stages of Plasmodium (gametocyte) in human blood is frequently 14 used as an indicator of human-to-mosquito transmission potential, this relationship is not 15 always clear. Important efforts have been made to develop molecular tools to fine-tune 16 gametocyte densities estimation and therefore improve the prediction of mosquito infection 17 rates, but a significant level of uncertainty around this estimate remains. Here we show with 18 both human and avian malaria system that the within-vertebrate host distribution of 19 gametocytes could explain much of this uncertainty. By comparing gametocyte densities in 20 bloodstream between different body parts, we found a difference by nearly 50% in humans 21 and by more than 15% in birds. An estimation of gametocyte density from only one blood 22 sample, as is usually the case, could therefore drastically over-or underestimated the 23 infectivity of gametocyte carriers. This might have important consequences on the 24 epidemiology of the disease since we show, using the avian malaria system, that this variation 25 influences the transmission of the parasite to the mosquito vector. In the light of our results, 26 we argue that it is essential to consider the heterogeneous distribution of gametocyte to 27 improve human diagnosis, identify infectious reservoirs and to test new malaria control 28 strategies. 29 30

show abstract

Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission

Cited by 34 publications

References 50 publications

FBN30 in wild Anopheles gambiae functions as a pathogen recognition molecule against clinically circulating Plasmodium falciparum in malaria endemic areas in Kenya

FBN30 in wild Anopheles gambiae functions as a pathogen recognition molecule against clinically circulating Plasmodium falciparum in malaria endemic areas in Kenya

Malaria transmission assisted by interaction betweenPlasmodium α-tubulin-1 andAnophelesFREP1 protein

Opening Pandora’s Box: Distribution of Plasmodium gametocytes in bloodstream

Contact Info

Product

Resources

About