TRA can be experimentally induced after immunisation of animals with inactivated Plasmodium gametocytes or gametes 8, 11. Evidence for naturally acquired transmission-reducing activity (TRA) is provided if test antibodies in endemic serum cause a reduction in the number of developing Plasmodium oocysts relative to mosquitoes fed the same infectious blood meal without test antibodies. The role of antibodies in determining transmission efficiency can be tested in mosquito-feeding assays, in which purified antibodies are added to a mosquito blood meal that contains gametocytes 9, 10. This may be associated with naturally acquired antibodies that interfere with parasite development within mosquitoes to reduce or prevent mosquito infection 7, 8. In surveys where mosquitoes were fed directly on the skin or on a blood sample, it was noted that some gametocytaemic individuals including those with high gametocyte densities were not infectious 5, 6. Some of these have essential roles in mosquito-stage development 3, 4, which culminates in the insect becoming infectious to humans. In preparation for their development in the mosquito, gametocytes cease to express many proteins involved in the parasites cycle of asexual replication, and upregulate others that are involved in sexual development 1, 2. Plasmodium gametocytes develop from their asexual progenitors and are the only malaria parasite life-stage infective to mosquitoes. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes. We also show that naturally acquired purified antibodies against key transmission-blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement-independent TRA. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Nature Communications volume 9, Article number: 558 ( 2018) Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity
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