Abstract
After being ingested by a female Anopheles mosquito during a bloodmeal on an infected host, and before they can reach the mosquito salivary glands to be transmitted to a new host, Plasmodium parasites must establish an infection of the mosquito midgut in the form of oocysts. To achieve this, they must first survive a series of robust innate immune responses that take place prior to, during, and immediately after ookinete traversal of the midgut epithelium. Understanding how parasites may evade these responses could highlight new ways to block malaria transmission. We show that an ookinete and sporozoite surface protein designated as PIMMS43 (Plasmodium Infection of the Mosquito Midgut Screen 43) is required for parasite evasion of the Anopheles coluzzii complement-like response. Disruption of PIMMS43 in the rodent malaria parasite Plasmodium berghei triggers robust complement activation and ookinete elimination upon mosquito midgut traversal. Silencing components of the complement-like system through RNAi largely restores ookinete-to-oocyst transition but oocysts remain small in size and produce a very small number of sporozoites that additionally are not infectious, indicating that PIMMS43 is also essential for sporogonic development in the oocyst. Antibodies that bind PIMMS43 interfere with parasite immune evasion when ingested with the infectious blood meal and significantly reduce the prevalence and intensity of infection. PIMMS43 genetic structure across African Plasmodium falciparum populations indicates allelic adaptation to sympatric vector populations. These data add to our understanding of mosquito-parasite interactions and identify PIMMS43 as a target of malaria transmission blocking.
Highlights
| | malaria transmission mosquito innate immunity complement-like | | response transmission blocking vaccines mosquito population replacement
We further demonstrate that A. coluzzii ingestion of antibodies against P. falciparum PIMMS43 leads to strong inhibition of oocyst development
The results revealed low levels of PbPIMMS43 transcripts in mixed blood stages (MBS) and purified c507 gametocytes, which together with absence of transcripts from nongametocyte producing ANKA 2.33 (NGP) MBS indicated that PbPIMMS43 transcription begins in gametocytes, similar to PfPIMMS43
Summary
| | malaria transmission mosquito innate immunity complement-like | | response transmission blocking vaccines mosquito population replacement. Ookinete traversal of the mosquito midgut leads to activation of JNK (c-Jun N-terminal kinase) signaling, inducing apoptosis of the invaded cells. This response involves various effectors, including heme peroxidase 2 and NADPH oxidase 5 that potentiate nitration of ookinetes that are marked for elimination by reactions of the mosquito complement-like system [5, 6]. These reactions are triggered upon ookinete exit at the Significance. We conclude that targeting PIMMS43 can block malaria parasites inside mosquitoes before they can infect humans
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