Evaluation of antibody response to Plasmodium falciparum in children according to exposure of Anopheles gambiae s.l or Anopheles funestus vectors

<p>Abstract</p> <p>Background</p> <p>In sub-Saharan areas, malaria transmission was mainly ensured by <it>Anopheles. gambiae </it>s.l. and <it>Anopheles. funestus </it>vectors. The immune response status to <it>Plasmodium falciparum </it>was evaluated in children living in two villages where malaria transmission was ensured by dissimilar species of <it>Anopheles </it>vectors (<it>An. funestus vs An. gambiae </it>s.l.).</p> <p>Methods</p> <p>A multi-disciplinary study was performed in villages located in Northern Senegal. Two villages were selected: Mboula village where transmission is strictly ensured by <it>An. gambiae </it>s.l. and Gankette Balla village which is exposed to several <it>Anopheles </it>species but where <it>An. funestus </it>is the only infected vector found. In each village, a cohort of 150 children aged from one to nine years was followed during one year and IgG response directed to schizont extract was determined by ELISA.</p> <p>Results</p> <p>Similar results of specific IgG responses according to age and <it>P. falciparum </it>infection were observed in both villages. Specific IgG response increased progressively from one-year to 5-year old children and then stayed high in children from five to nine years old. The children with <it>P. falciparum </it>infection had higher specific antibody responses compared to negative infection children, suggesting a strong relationship between production of specific antibodies and malaria transmission, rather than protective immunity. In contrast, higher variation of antibody levels according to malaria transmission periods were found in Mboula compared to Gankette Balla. In Mboula, the peak of malaria transmission was followed by a considerable increase in antibody levels, whereas low and constant anti-malaria IgG response was observed throughout the year in Gankette Balla.</p> <p>Conclusion</p> <p>This study shows that the development of anti-malaria antibody response was profoundly different according to areas where malaria exposure is dependent with different <it>Anopheles </it>species. These results are discussed according to i) the use of immunological tool for the evaluation of malaria transmission and ii) the influence of <it>Anopheles </it>vectors species on the regulation of antibody responses to <it>P. falciparum</it>.</p

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Re-engagement in care of people living with HIV lost to follow-up after initiation of antiretroviral therapy in Mali: Who returns to care?

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Risk factors for loss to follow-up, transfer or death among people living with HIV on their first antiretroviral therapy regimen in Mali

International audienceOBJECTIVES: Risk factors for loss to follow-up (LTFU) were assessed for people living with HIV (PLHIV) at various reference out-patient clinics (expertise level II) and hospitals (expertise level III) in Mali.METHODS: HIV-1-positive adults starting antiretroviral therapy (ART) in 2006-2013 were eligible for inclusion. Risk factors for LTFU, defined as no visit in the 6 months preceding the last database update, were assessed with the Cox model, taking into account the competing risks of transfer and death. Potential risk factors at the start of ART were demographic and socioeconomic variables, World Health Organization (WHO) stage, CD4 count, period of ART initiation, type of ART, region of care, expertise level and distance from home.RESULTS: We included 9821 PLHIV, 33% of whom were male, starting ART at nine out-patient clinics and seven hospitals [five and two in the capital Bamako and four and five in the 'regions' (i.e. districts outside the capital), respectively] with a median (interquartile range) CD4 count of 153 (56-270) cells/μL. Five-year cumulative incidences of LTFU, transfer and death were 35.2, 9.7 and 6.7%, respectively. People followed at Bamako hospitals > 5 km from home, at regional hospitals or at regional out-patient clinics < 5 km from home were at higher risk of LTFU than people followed at Bamako out-patient clinics, whereas people followed at regional out-patient clinics 5-50 km away from home were at lower risk for LTFU. Deaths were less frequent at hospitals, whether in Bamako or in the regions, than at Bamako out-patient clinics, and more frequent at regional out-patient clinics.CONCLUSIONS: Expertise level and distance to care were associated with LTFU. Stigmatization may play a role for PLHIV living close to the centres in the regions

Myeloma Cell Self-Renewal Depends on JAG2 Expression and Is Mediated by IGF1 or SCF Loop

International audienceThe purpose of this study was to identify the pathways associated with the ability of human myeloma cells (HMCLs) to spontaneous self-renew in a serum-free semi-solid human collagen-based assay. Among 32 HMCLs analyzed, 8 were able to grow spontaneously (from 5% to 35% of seeded cells) without any addition of cytokines or growth factors and this capacity to grow correlated with the presence of RAS mutations (p=0.04). Gene expression profile analysis of HMCLs identified one gene, JAG2, overexpressed in HMCLs that are able to self-renew. Interestingly, flow cytometry analysis of JAG2 expression showed that the level of membrane JAG2 expression positively correlated (r=0.87) to the percentage of colony formation (p=0.004). Blocking Jag-Notch interactions with Notch-Fc chimeric molecules impaired self-colony formation underlying a role for Jag-Notch pathway in colony formation. Furthermore, direct JAG2 silencing in two independent HMCLs (KMM1 and JJN3) prevented colony formation. Moreover, xenografts in SCID mice showed that JAG2 silencing fully impaired tumor growth of both KMM1 and JJN3. RT-PCR evaluation of JAG2 expression showed that 20 of 30 CD138+ purified primary myeloma cells expressed JAG2 and a Jag2+ subpopulation was identified by flow cytometry within primary CD138+ MM cells of patients at diagnosis or relapse.We further identified the growth factors involved in the self-renewal. By using blocking anti-IGF1R Ab or C-KIT inhibitor (imatinib mesylate), we showed that self-renewal of HMCLs was dependent on IGF1/IGF1R (5 of 8) or on C-KIT/SCF (1) or on both loops (2 of 8). Of note, C-KIT+ HMCLs expressed high JAG2 level at the cell membrane that was decreased by imatinib mesylate. Interestingly, none HMCL self-renewal was dependent on IL6/IL6R loop despite the high efficiency of paracrine IL6 to induce colony formation in most HMCLs. To address expression of C-KIT/SCF and IGF1R/IGF1 in primary myeloma cells, we used public data from patients at diagnosis published by Arkansas University. Expression of C-KIT and IGF1R was found in 56% and 50% of patients at diagnosis, respectively: 53% of patients express one or the other receptor, 27% express both and 20% express none. Expression of receptors is not similar with regard to the molecular classification of patients as previously shown by cytometry: indeed, MS patients underexpress C-KIT (p<0.001) but overexpress IGF1R (p<0.001), in full contrast to HY patients who overexpress C-KIT (p<0.001) but underexpress IGF1R (p<0.001). Moreover, IGF1R expression is lower on C-KIT+ patients as compared with C-KIT− ones (p=0.049). Of note, CD-1 and CD-2 patients underexpress both C-KIT (p=0.039) and IGF1R (p<0.001). IGF1 and SCF are produced by the microenvironment although IGF1 (but not SCF) mRNA was found in myeloma cells too. Altogether, these data suggest that IGF1 and SCF could be the main growth factors for 80% of the patients. Blocking these two tyrosine kinase receptors (in good agreement with their expression in patients) as well as Jag2/Notch interactions could decrease myeloma progression and/or relapse and thus increase survival

Primaquine as a Candidate for HHV-8-Associated Primary Effusion Lymphoma and Kaposi’s Sarcoma Treatment

International audienceHuman Herpesvirus 8 (HHV-8) is associated with three main severe orphan malignancies, Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD), and primary effusion lymphoma (PEL), which present few therapeutic options. We identified the antimalarial primaquine diphosphate (PQ) as a promising therapeutic candidate for HHV-8-associated PEL and KS. Indeed, PQ strongly reduced cell viability through caspase-dependent apoptosis, specifically in HHV-8-infected PEL cells. Reactive oxygen species (ROS)- and endoplasmic reticulum (ER) stress-mediated apoptosis signaling pathways were found to be part of the in vitro cytotoxic effect of PQ. Moreover, PQ treatment had a clinically positive effect in a nonobese diabetic (NOD)/SCID xenograft PEL mouse model, showing a reduction in tumor growth and an improvement in survival. Finally, an exploratory proof-of-concept clinical trial in four patients harboring severe KS was conducted, with the main objectives to assess the efficacy, the safety, and the tolerability of PQ, and which demonstrated a positive efficacy on Kaposi’s sarcoma-related lesions and lymphedema

Decitabine and Melphalan Fail to Reactivate p73 in p53 Deficient Myeloma Cells

(1) Background: TP53 deficiency remains a major adverse event in Multiple Myeloma (MM) despite therapeutic progresses. As it is not possible to target TP53 deficiency with pharmacological agents, we explored the possibility of activating another p53 family member, p73, which has not been well studied in myeloma. (2) Methods: Using human myeloma cell lines (HMCLs) with normal or abnormal TP53 status, we assessed TP73 methylation and expression. (3) Results: Using microarray data, we reported that TP73 is weakly expressed in 47 HMCLs and mostly in TP53 wild type (TP53wt) HMCLs (p = 0.0029). Q-RT-PCR assays showed that TP73 was expressed in 57% of TP53wt HMCLs (4 out of 7) and 11% of TP53 abnormal (TP53abn) HMCLs (2 out of 18) (p = 0.0463). We showed that TP73 is silenced by methylation in TP53abn HMCLs and that decitabine increased its expression, which, however, remained insufficient for significant protein expression. Alkylating drugs increased expression of TP73 only in TP53wt HMCLs but failed to synergize with decitabine in TP53abn HMCLs. (4) Conclusions: Decitabine and melphalan does not appear as a promising combination for inducing p73 and bypassing p53 deficiency in myeloma cells

A simple flow cytometry-based barcode for routine authentication of multiple myeloma and mantle cell lymphoma cell lines

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