Biology subjects

Massougbodji, A.

Publications and source records attributed to Massougbodji, A..

4 recordsLinked to original sources

bioRxiv2022

Revealing invisible cell phenotypes with conditional generative modeling

Biological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and observation. Aside from dramatic events such as cell division or cell death, most cell phenotypic changes that keep cells alive are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. While we show that deep learning models can leverage invisible features from microscopy images, to discriminate between close conditions, these features can yet hardly be observed and therefore interpreted. In this work, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases such as high concentration drug treatments, nuclear translocation and golgi apparatus assays. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs or low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to the accessible discovery of biological and disease biomarkers.

bioinformatics↗

bioRxiv2021

LILRB1 and LILRB2 expression in peripheral blood immune cells at 18 and 24 months of age in infants born from mothers with placental malaria

BackgroundPlacental malaria (PM) is associated with a higher susceptibility of infants to Plasmodium falciparum (Pf) malaria. A hypothesis of immune tolerance has been suggested but no clear explanation has been provided so far. Our goal was to investigate the involvement of inhibitory receptors LILRB1 and LILRB2, known to drive immune evasion upon ligation with pathogen and/or host ligands, in PM-induced immune tolerance. MethodsInfants of mothers with or without PM were enrolled in Allada, southern Benin, and followed-up for 24 months. Antibodies with specificity for five blood stage parasite antigens were quantified by ELISA, and the frequency of immune cell subsets was quantified by flow cytometry. LILRB1 or LILRB2 expression was assessed on cells collected at 18 and 24 months of age. ResultsInfants born to PM-mothers had a higher risk of developing clinical malaria than those born to mothers without PM (IRR=1.53, p=0.040), and such infants displayed a lower frequency of non-classical monocytes (OR=0.74, p=0.01) that overexpressed LILRB2 (OR=1.36, p=0.002). Moreover, infants born to PM-mothers had lower levels of cytophilic IgG and higher levels of IL-10 during active infection. ConclusionModulation of IgG and IL-10 levels could impair monocyte functions (opsonisation/phagocytosis) in infants born to PM-mothers, possibly contributing to their higher susceptibility to malaria. The long-lasting effect of PM on infants monocytes was notable, raising questions about the capacity of ligands such as Rifins or HLA-I molecules to bind to LILRB1 and LILRB2 and to modulate immune responses, and about the reprogramming of neonatal monocytes/macrophages. KEY POINTSInfants of mothers with placental malaria were more susceptible to clinical malaria than those born to mothers without placental malaria and they displayed a lower frequency of non-classical monocytes that overexpressed LILRB2.

immunology↗

bioRxiv2021

Afucosylated Plasmodium falciparum-specific IgG is induced by infection but not by subunit vaccination

IgG specific for members of the Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1) family, which mediates receptor- and tissue-specific sequestration of infected erythrocytes (IEs), is a central component of naturally acquired malaria immunity. PfEMP1-specific IgG is thought to protect via inhibition of IE sequestration, and through IgG-Fc Receptor (Fc{gamma}R) mediated phagocytosis and killing of antibody-opsonized IEs. The affinity of afucosylated IgG to Fc{gamma}RIIIa is elevated up to 40-fold compared to fucosylated IgG, resulting in enhanced antibody-dependent cellular cytotoxicity. Most IgG in plasma is fully fucosylated, but afucosylated IgG is elicited in response to enveloped viruses and to paternal alloantigens during pregnancy. Here we show that naturally acquired PfEMP1-specific IgG is likewise markedly afucosylated in a stable and exposure-dependent manner, and efficiently induces Fc{gamma}RIIIa-dependent natural killer (NK) cell degranulation. In contrast, immunization with a soluble subunit vaccine based on VAR2CSA-type PfEMP1 resulted in fully fucosylated specific IgG. These results have implications for understanding natural and vaccine-induced antibody-mediated protective immunity to malaria. SummaryAfucosylated IgG has enhanced Fc-receptor affinity and functionality, and is formed specifically against membrane proteins of enveloped viruses. We show that this also applies to Plasmodium falciparum erythrocyte membrane-specific IgG induced by natural infection, but not by soluble PfEMP1 vaccination.

immunology↗

bioRxiv2018

First genome-wide association study of non-severe malaria in two birth cohorts in Benin: hints towards the involvement of the STAT3 pathway.

Recent research efforts to identify genes involved in the susceptibility to P. falciparum malaria have focused on severe forms of malaria, with several genome-wide association studies (GWAS) and multi-center analyses published this past decade. Here we present the first GWAS performed on mild malaria susceptibility in young children, designed to identify genetic variants involved in innate immunity or innate resistance mechanisms. Two cohorts of infants from southern Benin (525 and 250 individuals respectively), used as discovery and replication cohorts, were closely followed from birth to 18-24 months of age, with an assessment of a space-and time-dependent risk of exposure to vector bites. GWAS was performed on 15.5 million genotyped and imputed variants, with the susceptibility of infants to mild malaria attacks and to malaria infections as a whole (both symptomatic and asymptomatic). Infant susceptibility to malaria was assessed by considering all malaria events occurring during the follow-up using a Cox-model for recurrent events. We found strong statistical support for a role of PTPRT, a tyrosine phosphatase receptors involved in STAT3 pathway, with the protection against both mild malaria attacks and malaria infections (p=9.70x10-8 and p=1.78x10-7 respectively in the discovery cohort, and both p < 0.05 in the replication cohort). Furthermore, our study highlights several other genes, among them, UROC1, ACER3 and the PLAG2 cluster, whose biological functions are relevant in malaria infection. Results show that despite the difficulty of setting up such longitudinal field studies, GWAS on non-severe malaria can successfully identify new candidate genes and inform physiological mechanisms underlying natural protection against malaria.\n\nAUTHOR SUMMARYMalaria remains a major worldwide public health problem with circa 219 million cases and 435,000 deaths per year. As for many infectious diseases, the genetics of the host plays a role in the disease course. So far, most studies on such genetic factors focused on severe malaria forms. Our study aimed to find factors associated with simple forms (asymptomatic forms and uncomplicated clinical forms). We used dense genome-wide data of two cohorts of infants closely followed during two years in Benin, and we incorporated an environmental risk of exposure estimated at individual level from entomological, climatic, and environmental data. This allowed us to unravel several genes that appear to play a role in the susceptibility to malaria infection, thus demonstrating the feasibility of a genome-wide approach on non-severe forms. Functional studies are needed to confirm the role of the genetic factors highlighted here. Some of these genes represent interesting targets for future prevention strategies and drug development.

genetics↗