Abstract
FREP1 in mosquito midguts facilitates Plasmodium falciparum parasite transmission. The fibrinogen-like (FBG) domain of FREP1 is highly conserved (>90% identical) among Anopheles species from different continents, suggesting that anti-FBG antibodies may block malaria transmission to all anopheline mosquitoes. Using standard membrane-feeding assays, anti-FREP1 polyclonal antibodies significantly blocked transmission of Plasmodium berghei and Plasmodium vivax to Anopheles gambiae and Anopheles dirus, respectively. Furthermore, in vivo studies of mice immunized with FBG achieved >75% blocking efficacy of P. berghei to A. gambiae without triggering immunopathology. Anti-FBG serum also reduced >81% of P. falciparum infection to A. gambiae Finally, we showed that FBG interacts with Plasmodium gametocytes and ookinetes, revealing the molecular mechanism of its antibody transmission-blocking activity. Collectively, our data support that FREP1-mediated Plasmodium transmission to mosquitoes is a conserved pathway and that targeting the FBG domain of FREP1 will limit the transmission of multiple Plasmodium species to multiple Anopheles species.
Highlights
FREP1 in mosquito midguts facilitates Plasmodium falciparum parasite transmission
A. gambiae mosquitoes were fed with P. berghei–infected blood mixed with rabbit anti-FREP1 serum (1:1 dilution, final titer units, 5 ϫ 104), and we subsequently examined the number of developing oocysts in mosquito midg
Because FREP1 localizes in the mosquito midgut peritrophic matrix, it is readily accessible to antibodies in co-ingested blood
Summary
We examined the FREP1 orthologs among anopheline mosquitoes to find conserved regions. Because there is a highly conserved FBG domain among anopheline orthologs, we determined whether anti-FREP1 antibody would inhibit transmission of other Plasmodium species to additional Anopheles species To address this question, A. gambiae mosquitoes were fed with P. berghei–infected blood mixed with rabbit anti-FREP1 serum (1:1 dilution, final titer units, 5 ϫ 104), and we subsequently examined the number of developing oocysts in mosquito midg-. The results showed that the anti-FREP1 antibody significantly reduced the number of oocysts per midgut, more than 2-fold, compared with the control serum (Fig. 2b). The results were consistent in two biological replicates that were conducted with different P. vivax–infected human blood Together, these data support that anti-FREP1 antibodies can block the transmission of multiple species of malaria parasites to multiple mosquito species. Sexual-stage parasites and gametocytes are within red blood cells; the DAPI
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