Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity

Abstract

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.

Probabilistic data integration identifies reliable gametocyte-specific proteins and transcripts in malaria parasites

“…As an illustration of the utility of gametocyte-specific proteins as markers of gametocyte exposure, we utilized protein microarray data from a study that aimed to characterize the immune profile associated with transmission-reducing immunity in naturally infected gametocyte carriers (Stone, Campo et al 2017 accepted manuscript 36 ). For the current study, we compared responses to our gold standard gametocyte genes (n=40) and novel gametocyte genes from our 100 highest scoring proteins that were on the array (n=30).…”

“…As an alternative approach to the detection of gametocyte carriage in populations, we utilized a gametocyte-enriched protein microarray (Stone, Campo et al . 2017 accepted manuscript 36 ) to determine antibody responses to genes that we here describe as highly gametocyte-specific. The bacterial expression system used for the array has known limitations with the expression of conformational proteins 52 and should thus be considered a ‘rule in’ rather than ‘rule out’ approach to immune recognition.…”

Effect of irradiation on the survival and susceptibility of femaleAnopheles arabiensisto natural isolates ofPlasmodium falciparum

“…We first postulated that the natural blocking immunity of the human host could play a role. To test this possibility, the natural serum of isolates K to P was replaced by naive AB serum (Gouagna et al , 2004; Da et al , 2015; Stone et al , 2018) (Additional file 1). Similar to assays using unchanged natural serum (isolates A to J), assays with serum replacement showed either increased (L, N, O, and P) or decreased (K and M) infection in irradiated mosquitoes (Additional file 1: Figure S2).…”

“…Gametocyte carrier blood was collected by venipuncture into heparinized tubes. To test for a possible interaction between the natural blocking immunity of the human host (Gouagna et al ., 2004; Da et al ., 2015; Stone et al ., 2018) and the irradiation on mosquito infection, DMFA were performed using either whole donor blood or with replacement of the serum by a non-immune AB serum (see Additional file 1). Mosquitoes were starved of glucose solution for 12 h prior to the exposure.…”

Signatures of divergent antimalarial treatment responses in peripheral blood from infants and adults in Malawi

“…Total DNA and total RNA were isolated from subjects’ dried blood spots at V1 using nucleic acid purification kits (Norgen Biotek #35300, #36000), and cDNAs were used in qRT-PCR assays [20, 21]. These cDNAs were used to measure RNA expression levels of P. falciparum gametocyte-specific genes, including Pfs25 (mature gametocyte), Pfs16 (early gametocyte) [22], and Pfs230 , which encodes a gametocyte antigen important for eliciting host antibodies that inhibit parasite transmission to a mosquito host [23, 24].…”