Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity
Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. 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. 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. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes.
Gamete surface immuno-fluorescence assay (SIFA) using wild-type and Pfs48/45 knockout (KO) NF54 gametes, with Pfs48/45 mAb, Pfs230 mAb, and IgG from a malaria-exposed serum donor. Donor IgG is from donor A in Table 2, and was performed using total IgG, and total IgG depleted of α-Pfs48/45-10c and α-Pfs230 (230CMB) IgG. Δ Pfs48/45 = Pfs48/45 KO3. BF Bright-field, FITC fluorescein isothiocyanate. Anti-Pfs48/45 is mAb 45.1, and anti-Pfs230 is mAb 2A2, as described in the methods. Scale bar is 20 µm
Antibody responses to gametocyte antigensPlasma was collected in epidemiological studies in Burkina, Faso37, Cameroon and the Gambia, as well as from Dutch migrants who had lived for several years in malaria-endemic areas and reported repeated malaria episodes. Individuals from malaria-endemic areas were all asymptomatic when sampled, and were either recruited randomly from the community, or based on the observation of malaria parasites or specifically gametocytes (n = 276) in blood smears.