Epigenetics and Malaria Susceptibility/Protection: A Missing Piece of the Puzzle

A better understanding of stable changes in regulation of gene expression that result from epigenetic events is of great relevance in the development of strategies to prevent and treat infectious diseases. Histone modification and DNA methylation are key epigenetic mechanisms that can be regarded as marks, which ensure an accurate transmission of the chromatin states and gene expression profiles over generations of cells. There is an increasing list of these modifications, and the complexity of their action is just beginning to be understood. It is clear that the epigenetic landscape plays a fundamental role in most biological processes that involve the manipulation and expression of DNA. Although the molecular mechanism of gene regulation is relatively well understood, the hierarchical order of events and dependencies that lead to protection against infection remain largely unknown. In this review, we propose that host epigenetics is an essential, though relatively under studied, factor in the protection or susceptibility to malaria

Analyse des facteurs qui modulent l'immunité anti-bilharzienne dans une population Dogon infectée par Schistosoma haematobium

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Eliminating Cervical Cancer in Mali and Senegal, Two Sub-Saharan Countries: Insights and Optimizing Solutions

Background: The number of cases with cervical cancer is rapidly increasing in Sub-Saharan Africa driven by inadequate rates of human papilloma virus (HPV) vaccination and screening programs and accompanied by poor health delivery systems. There are other factors to contend with such as lack of awareness, social myths, reluctance to vaccine acceptance and stigma with sexually transmitted diseases. Here, we formulate strategies to implement intervention programs against HPV infections and other risk factors for cervical cancer in these countries. Methods: We searched PubMed, Web of Science, and African Journals Online for this review. The current status of anti-HPV vaccination and precancerous screening programs in Mali and Senegal has been assessed by onsite visits. Collaborators from Mali and Senegal collected data and information concerning HPV vaccination and screening programs in these countries. Findings: We found that anti-HPV vaccination and cervical cancer screening have been conducted sporadically mainly in urban areas of Mali and Senegal. No known population-based programs are in progress in either of the two countries. We highlighted the advantages and drawbacks of currently available screening tests and proposed that screening by visual inspection with acetic acid (VIA) accompanied by self-sampling is the most cost-effective, culturally acceptable and most feasible strategy to implement in primary care settings. In addition, HPV DNA testing would be affordable, if local laboratory facilities could be established. We found that many of the factors that increase HPV acquisition and promote the oncogenic effect of the virus are largely widespread in both Senegal and Mali. These include infections with HIV and other sexually transmitted infections (STIs), immunosuppression, polygamous marriages, high parity, early sexual activities, early pregnancies, and multiple sexual partners. Interpretation: Neither vaccines nor screening tests are within the reach of the population in Mali and Senegal because of the high cost. The effective intervention measure would be to integrate anti-HPV vaccines into the Extended Program for Immunization (EPI), which has saved 3 million young lives per year in Africa with the support of GAVI, to implement cost control mechanisms for HPV vaccinations via price negotiations with manufacturing companies, as has recently been done by Rwanda. The collective efforts by local governments, researchers, private sector, and donors may lead to the introduction of affordable screening tests. A robust awareness campaign coupled with sustained and regular engagement of local communities about the prevention and risk factors is extremely important. The projected solutions may be well applicable to other Sub-Saharan countries that face similar challenges containing cervical cancer

Malaria severity: Possible influence of the E670G PCSK9 polymorphism: A preliminary case-control study in Malian children.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promotes the degradation of low-density lipoprotein receptors leading to reduced hepatic uptake of plasma cholesterol. Non-synonymous single-nucleotide polymorphisms in its gene have been linked to hypo- or hyper- cholesterolemia, depending on whether they decrease or increase PCSK9 activity, respectively. Since the proliferation and the infectivity of Plasmodium spp. partially depend on cholesterol from the host, we hypothesize that these PCSK9 genetic polymorphisms could influence the course of malaria infection in individuals who carry them. Here we examined the frequency distribution of one dominant (C679X) and two recessive (A443T, I474V) hypocholesterolemic polymorphisms as well as that of one recessive hypercholesterolemic polymorphism (E670G) among healthy and malaria-infected Malian children.Dried blood spots were collected in Bandiagara, Mali, from 752 age, residence and ethnicity-matched children: 253 healthy controls, 246 uncomplicated malaria patients and 253 severe malaria patients. Their genomic DNA was extracted and genotyped for the above PCSK9 polymorphisms using Taqman assays. Associations of genotype distributions and allele frequencies with malaria were evaluated.The minor allele frequency of the A443T, I474V, E670G, and C679X polymorphisms in the study population sample was 0.12, 0.20, 0.26, and 0.02, respectively. For each polymorphism, the genotype distribution among the three health conditions was statistically insignificant, but for the hypercholesterolemic E670G polymorphism, a trend towards association of the minor allele with malaria severity was observed (P = 0.035). The association proved to be stronger when allele frequencies between healthy controls and severe malaria cases were compared (Odd Ratio: 1.34; 95% Confidence Intervals: 1.04-1.83); P = 0.031).Carriers of the minor allele of the E670G PCSK9 polymorphism might be more susceptible to severe malaria. Further investigation of the cholesterol regulating function of PCSK9 in the pathophysiology of malaria is needed

Author Correction: Model-based assessment of Chikungunya and O’nyong-nyong virus circulation in Mali in a serological cross-reactivity context

International audienc

Protection of Malian children from clinical malaria is associated with recognition of multiple antigens

Contains fulltext : 153754.pdf (publisher's version ) (Open Access)BACKGROUND: Naturally acquired immunity to clinical malaria is thought to be mainly antibody-mediated, but reports on antigen targets are contradictory. Recognition of multiple antigens may be crucial for protection. In this study, the magnitude of antibody responses and their temporal stability was assessed for a panel of malaria antigens in relation to protection against clinical Plasmodium falciparum malaria. METHODS: Malian children aged two to 14 years were enrolled in a longitudinal study and followed up by passive and active case detection for seven months. Plasma was collected at enrolment and at the beginning, in the middle and after the end of the transmission season. Antibody titres to the P. falciparum-antigens apical membrane protein (AMA)-1, merozoite surface protein (MSP)-1(1)(9), MSP-3, glutamine-rich protein (GLURP-R0) and circumsporozoite antigen (CSP) were assessed by enzyme-linked immunosorbent assay (ELISA) for 99 children with plasma available at all time points. Parasite carriage was determined by microscopy and nested PCR. RESULTS: Antibody titres to all antigens, except MSP-1(1)(9), and the number of antigens recognized increased with age. After malaria exposure, antibody titres increased in children that had low titres at baseline, but decreased in those with high baseline responses. No significant differences were found between antibody titers for individual antigens between children remaining symptomatic or asymptomatic after exposure, after adjustment for age. Instead, children remaining asymptomatic following parasite exposure had a broader repertoire of antigen recognition. CONCLUSIONS: The present study provides immune-epidemiological evidence from a limited cohort of Malian children that strong recognition of multiple antigens, rather than antibody titres for individual antigens, is associated with protection from clinical malaria

Model-based assessment of Chikungunya and O’nyong-nyong virus circulation in Mali in a serological cross-reactivity context

International audienceSerological surveys are essential to quantify immunity in a population but serological cross-reactivity often impairs estimates of the seroprevalence. Here, we show that modeling helps addressing this key challenge by considering the important cross-reactivity between Chikungunya (CHIKV) and O’nyong-nyong virus (ONNV) as a case study. We develop a statistical model to assess the epidemiology of these viruses in Mali. We additionally calibrate the model with paired virus neutralization titers in the French West Indies, a region with known CHIKV circulation but no ONNV. In Mali, the model estimate of ONNV and CHIKV prevalence is 30% and 13%, respectively, versus 27% and 2% in non-adjusted estimates. While a CHIKV infection induces an ONNV response in 80% of cases, an ONNV infection leads to a cross-reactive CHIKV response in only 22% of cases. Our study shows the importance of conducting serological assays on multiple cross-reactive pathogens to estimate levels of virus circulation

<i>PCSK9</i> SNPs under study.

<p><i>PCSK9</i> SNPs under study.</p

Genotype distribution among healthy and malaria children.

<p>Genotype distribution among healthy and malaria children.</p

Association analysis of PCSK9 SNPs and severe malaria.

<p>Association analysis of PCSK9 SNPs and severe malaria.</p