Transmission-Blocking Strategies Against Malaria Parasites During Their Mosquito Stages

Abstract

Malaria is still the most widespread parasitic disease and causes the most infections globally. Owing to improvements in sanitary conditions and various intervention measures, including the use of antimalarial drugs, the malaria epidemic in many regions of the world has improved significantly in the past 10 years. However, people living in certain underdeveloped areas are still under threat. Even in some well-controlled areas, the decline in malaria infection rates has stagnated or the rates have rebounded because of the emergence and spread of drug-resistant malaria parasites. Thus, new malaria control methods must be developed. As the spread of the Plasmodium parasite is dependent on the part of its life cycle that occurs in mosquitoes, to eliminate the possibility of malaria infections, transmission-blocking strategies against the mosquito stage should be the first choice. In fact, after the gametocyte enters the mosquito body, it undergoes a series of transformation processes over a short period, thus providing numerous potential blocking targets. Many research groups have carried out studies based on targeting the blocking of transmission during the mosquito phase and have achieved excellent results. Meanwhile, the direct killing of mosquitoes could also significantly reduce the probability of malaria infections. Microorganisms that display complex interactions with Plasmodium, such as Wolbachia and gut flora, have shown observable transmission-blocking potential. These could be used as a biological control strategy and play an important part in blocking the transmission of malaria.

Keywords: Wolbachia; drug; malaria; mosquito intestinal flora; transmission-blocking; transmission-blocking vaccine.

Figure 1

The effect of transmission-blocking vaccines (TBVs) in the sexual reproductive stages of malaria. (1) TBV cannot act on gametocytes that have not escaped from red blood cells. The development of TBVs based on the (2) surface proteins of the gametocytes, (3) male gamete-related targets, and (4) fertilization process-related proteins can effectively block the development process of malaria in mosquito. (5) The lack of inherent antigenicity means that TBVs based on ookinete surface proteins need adjuvants in actual use. Blocking the ability of motility ookinetes to break through the (6) peritrophic matrix and the (7) physical and immune barriers of the midgut to prevent its colonization in the midgut is another development direction of TBVs. (8) TBVs targeting mosquito midgut proteins can also effectively block ookinete colonization. (9) Directly genetically modified mosquitoes to prevent the development of ookinetes. Candidate target proteins for transmission blocking antibodies in different stages of malaria life cycle were listed in green dotted boxes. Anti-malaria drugs that could influence the transmission were listed in yellow dotted box. ACT, artemisinin-based combination therapy; Pfs48/45, Plasmodium falciparum gametocyte surface protein; Pfs230, P. falciparum gametocyte surface antigen; Pb22, a conserved protein (PBANKA_0305900) in Plasmodium berghei; PbPH, P. berghei pleckstrin homology gene; PbGCS1, P. berghei Generative Cell Specific 1; FG1,female gamete peptide 1; Pfs25, P. falciparum sexual-stage surface protein; P25, the major surface proteins of Plasmodium ookinetes; P28, Ookinete surface antigen-like protein; PSOP25, putative secreted ookinete protein 25; PfCHT1, P. falciparum chitinase; PgCHT2, P. gallinaceum chitinase; PM4, plasmepsin 4; CPB, Carboxypeptidase B; FREP1, Fibrinogen-related protein 1.

Figure 2

Malaria transmission-blocking strategies based on Wolbachia. (1) Male mosquitoes infected with Wolbachia can only mate with female mosquitoes infected with the same Wolbachia to complete normal reproduction. (2) Numerous infected male mosquitoes can be released in the target area to kill the mosquitoes in the area and thus stop the spread of malaria. (3) Wolbachia can also prevent the normal sporozoites development of Plasmodium in mosquitoes. (4) Infected female mosquitoes accidentally released with the numerous infected male mosquitoes can still block the spread of malaria through the pathogen suppression ability of Wolbachia itself.