Associations between an IgG3 polymorphism in the binding domain to FcRn transplacental transfer of malaria-specific IgG3 and protection against Plasmodium falciparum malaria during infancy

A mutation of IgG3-R435H that enhances binding to FcRn results in increased transplacental transfer of maternal malaria-specific IgG3, extended IgG3 half-life in the neonate and reduced risk of Plasmodium falciparum infection and disease in infancy

An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum

Apicomplexa phylum includes numerous obligate intracellular protozoan parasites that are life threatening for humans and animals. In this context, Plasmodium falciparum and Toxoplasma gondii are of particular interest, as they are responsible for malaria and toxoplasmosis, respectively, for which efficient vaccines are presently lacking and therapies need to be improved. Apicomplexan parasites have a highly polarized morphology, with their apical end containing specific secretory organelles named rhoptries and micronemes, which depend on the unique receptor and transporter sortilin TgSORT for their biogenesis. In the present study, we took advantage of the subcellular polarity of the parasite to engineer a clonal transgenic Toxoplasma line that expresses simultaneously the green fluorescent protein TgSORT-GFP in the post-Golgi-endosome-like compartment and the red fluorescent protein rhoptry ROP1-mCherry near the apical end. We utilized this fluorescent transgenic T. gondii to develop a miniaturized image-based phenotype assay coupled to an automated image analysis. By applying this methodology to 1,120 compounds, we identified 12 that are capable of disrupting the T. gondii morphology and inhibiting intracellular replication. Analysis of the selected compounds confirmed that all 12 are kinase inhibitors and intramembrane pumps, with some exhibiting potent activity against Plasmodium falciparum. Our findings highlight the advantage of comparative and targeted phenotypic analysis involving two related parasite species as a means of identifying molecules with a conserved mode of action

Cord-to-mother IgG transfer according to placental malaria.

<p>CIRC: maternal peripheral blood at delivery; CORD: cord blood, ln(CORD/CIRC): ratio representing the transfer of maternal IgG to the neonate at birth; * <0.05; ** ≤0.01; *** ≤0.001.</p

Susceptibility to Plasmodium falciparum malaria : influence of combined polymorphisms of IgG3 Gm allotypes and Fc gamma receptors IIA, IIIA, and IIIb

The binding of immunoglobulin (Ig) to Fc gamma receptors (FcgR) at the immune cell surface is an important step to initiate immunological defense against malaria. However, polymorphisms in receptors and/or constant regions of the IgG heavy chains may modulate this binding. Here, we investigated whether polymorphisms located in FcgR and constant regions of the heavy chain of IgG are associated with susceptibility to P. falciparum malaria. For this purpose, a clinical and parasitological follow-up on malaria was conducted among 656 infants in southern Benin. G3m allotypes (from total IgG3) were determined by a serological method of hemagglutination inhibition. FcgRIIA 131R/H and FcgRIIIA 176F/V genotypes were determined using the TaqMan method and FcgRIIIB NA1/NA2 genotypes were assessed by polymerase chain reaction using allele-specific primers. Association analyses between the number of malaria infections during the follow-up and polymorphisms in IgG G3m allotypes and FcgR were studied independently by zero inflated binomial negative regression. The influence of combinations of G3m allotypes and FcgRIIA/FcgRIIIA/FcgRIIIB polymorphisms on the number of P. falciparum infections, and their potential interaction with environmental exposure to malaria was assessed by using the generalized multifactor dimensionality reduction (GMDR) method. Results showed that individual carriage of G3m24 single allotype and of G3m5,6,10,11,13,14,24 phenotype was independently associated with a high risk of malaria infection. A risk effect for G3m6 was observed only under high environmental exposure. FcgRIIIA 176VV single genotype and combined carriage of FcgRIIA 131RH/FcgRIIIA 176VV/FcgRIIIB NA1NA2, FcgRIIA 131HH/FcgRIIIA 176FF/FcgRIIIB NA1NA1, FcgRIIA 131HH/FcgRIIIA 176VV/FcgRIIIB NA2NA2 and FcgRIIA 131HH/FcgRIIIA 176VV/FcgRIIIB NA1NA2 genotypes were related to a high number of malaria infections. The risk was accentuated for FcgRIIIA 176VV when considering the influence of environmental exposure to malaria. Finally, the GMDR analysis including environmental exposure showed strengthened associations with a malaria risk when FcgRIIA/FcgRIIIA/FcgRIIIB genotypes were combined to G3m5,6,11,24 and G3m5,6,10,11,13,15,24 phenotypes or G3m10 and G3m13 single allotypes. Our results highlight the relevance of studying IgG heavy chain and FcgR polymorphisms, independently as well as in combination, in relation to the individual susceptibility to P. falciparum infection. The intensity of individual exposure to mosquito bites was demonstrated to impact the relationships found

Sickle cell trait modulates the proteome and phosphoproteome of Plasmodium falciparum-infected erythrocytes

The high prevalence of sickle cell disease in some human populations likely results from the protection afforded against severe Plasmodium falciparum malaria and death by heterozygous carriage of HbS. P. falciparum remodels the erythrocyte membrane and skeleton, displaying parasite proteins at the erythrocyte surface that interact with key human proteins in the Ankyrin R and 4.1R complexes. Oxidative stress generated by HbS, as well as by parasite invasion, disrupts the kinase/phosphatase balance, potentially interfering with the molecular interactions between human and parasite proteins. HbS is known to be associated with abnormal membrane display of parasite antigens. Studying the proteome and the phosphoproteome of red cell membrane extracts from P. falciparum infected and non-infected erythrocytes, we show here that HbS heterozygous carriage, combined with infection, modulates the phosphorylation of erythrocyte membrane transporters and skeletal proteins as well as of parasite proteins. Our results highlight modifications of Ser-/Thr- and/or Tyr- phosphorylation in key human proteins, such as ankyrin, beta-adducin, beta-spectrin and Band 3, and key parasite proteins, such as RESA or MESA. Altered phosphorylation patterns could disturb the interactions within membrane protein complexes, affect nutrient uptake and the infected erythrocyte cytoadherence phenomenon, thus lessening the severity of malaria symptoms

Association between cord-to-mother ratio (CMTR) and factors that could influence transplacental transfer: Placental malaria, maternal total IgG, and maternal malaria-specific IgG3.

<p>Association between cord-to-mother ratio (CMTR) and factors that could influence transplacental transfer: Placental malaria, maternal total IgG, and maternal malaria-specific IgG3.</p

Persistence of malaria-specific IgG3 at 6 months of age related to level of maternal anti-malaria IgG3.

<p>Persistence of malaria-specific IgG3 at 6 months of age related to level of maternal anti-malaria IgG3.</p

Increased persistence of maternally derived malaria-specific IgG3 among young infants born to women with the IgG3-H435 allele compared to those homozygous for IgG3-R435.

<p>The odds ratio (± 95% confidence interval) of maternal malaria-specific IgG3-H435 persistence at 6 months relative to homozygous IgG3-R435 based on dichotomized cord-to-mother transfer ratio (over or below the median) using multivariate regression analysis adjusted for the variables shown in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002403#pmed.1002403.t001" target="_blank">Table 1</a>. To reduce the possibility that IgG3 was produced by malaria-infected infants, samples from any infant showing an increase in malaria-specific IgG3 between 0 and 3 months or between 3 and 6 months of age (any antigen) were removed from the analysis (<i>N =</i> 195). The odds ratio was obtained after adjustment for malaria-specific IgG3 in maternal peripheral blood (see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002403#pmed.1002403.t003" target="_blank">Table 3</a>). Of 302 infants, between 3 and 11 had missing data (according to the tested antigen) and were not included in the analysis (see details in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002403#pmed.1002403.t003" target="_blank">Table 3</a>). There was no collinearity between all tested variables, and variance inflation factor (VIF) values were all ≤2.17.</p

Maternal IgG3-H435 polymorphism is associated with a decreased risk of symptomatic malaria in infants from birth to 12 months of age.

<p>The time to first symptomatic malaria episode during infancy is shown. The log-rank analysis yielded <i>p =</i> 0.102. The Cox proportional hazard analysis adjusted for malaria exposure and placental malaria gave a hazard ratio of 0.69 (95% CI 0.46, 1.05, <i>p =</i> 0.083).</p