Biology subjects

Achcar, F.

Publications and source records attributed to Achcar, F..

4 recordsLinked to original sources

bioRxiv2023

Repeated Plasmodium vivax blood stage infection provides sterile protection against homologous challenge in non-human primates

The malaria parasite Plasmodium vivax remains a major global public health challenge, causing major morbidity across tropical and subtropical regions. Several candidate vaccines are in preclinical and clinical trials, however no vaccine against P. vivax malaria is approved for use in humans. Here we assessed whether P. vivax strain-transcendent immunity can be achieved by repeated infection in Aotus monkeys. For this purpose, we repeatedly infected six animals with blood stages of the P. vivax Salvador 1 (SAL-1) strain until sterile immune, and then challenged with the AMRU-1 strain. Sterile immunity was achieved in 4/4 Aotus monkeys after two homologous infections with the SAL-1 strain, while partial protection against a heterologous AMRU-1 challenge (i.e., delay to infection and reduction in peak parasitemia compared to control) was achieved in 3/3 monkeys. IgG levels based on P. vivax lysate ELISA and protein microarray increased with repeated infections and correlated with the level of homologous protection. Analysis of parasite transcriptional profiles across inoculation levels provided no evidence of major antigenic switching upon homologous or heterologous challenge. In contrast, we observed significant transcriptional differences in the P. vivax core gene repertoire between SAL-1 and AMRU-1. Together with the strain-specific genetic diversity between SAL-1 and AMRU-1 these data suggest that the partial protection upon heterologous challenge is due to molecular differences between strains (at genome and transcriptome level) rather than immune evasion by antigenic switching. Our study demonstrates that sterile immunity against P. vivax can be achieved by repeated homologous blood stage infection in Aotus monkeys, thus providing a benchmark to test the efficacy of candidate blood stage P. vivax malaria vaccines. Author summaryPlasmodium vivax is the most widespread human malaria parasite. Elimination efforts are complicated due to the peculiar biology of P. vivax including dormant liver forms, cryptic reservoirs in bone marrow and spleen and a large asymptomatic infectious reservoir in affected populations. Currently there is no vaccine against malaria caused by P. vivax. Here we induce sterile immunity by repeated P. vivax infection with the SAL-1 strain in non-human primates. In contrast, heterologous challenge with the AMRU-1 strain only provided partial protection. Antibody levels against a crude antigen and a protein microarray correlated with the level of homologous protection. Parasite transcriptional profiles across inoculation levels failed to show major antigenic switching across SAL-1 infections or upon heterologous challenge, instead suggesting other mechanisms of immune evasion. Our study demonstrates that sterile immunity against P. vivax can be achieved by repeated blood stage infection in Aotus monkeys, thus providing a benchmark to test the efficacy of candidate blood stage P. vivax malaria vaccines.

microbiology↗

bioRxiv2022

FKBP35 secures ribosome homeostasis in Plasmodium falciparum

Plasmodium falciparum accounts for the majority of over 600000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with alternative modes of action is thus undoubted. The FK506-binding protein PfFKBP35 has gained attention as a promising drug target due to its high affinity to the macrolide compound FK506 (tacrolimus). Whilst there is considerable interest in targeting PfFKBP35 with small molecules, a genetic validation of this factor as a drug target is missing and its function in parasite biology remains elusive. Here, we show that limiting PfFKBP35 levels are lethal to P. falciparum and result in a delayed death-like phenotype that is characterized by defective ribosome homeostasis and stalled protein synthesis. Our data furthermore suggest that FK506, unlike the action of this drug in model organisms, exerts its anti-proliferative activity in a PfFKBP35-independent manner and, using cellular thermal shift assays, we identify putative FK506-targets beyond PfFKBP35. In addition to revealing first insights into the function of PfFKBP35, our results show that FKBP-binding drugs can adopt non-canonical modes of action - with major implications for the development of FK506-derived molecules active against Plasmodium parasites and other eukaryotic pathogens.

molecular biology↗

bioRxiv2022

Plasmodium falciparum adapts its investment into replication versus transmission according to the host environment

The malaria parasite life cycle includes asexual replication in human blood, with a proportion of parasites differentiating to gametocytes required for transmission to mosquitoes. Commitment to differentiate into gametocytes, which is marked by activation of the parasite transcription factor ap2-g, is known to be influenced by host factors but a comprehensive model remains uncertain. Here we analyze data from 828 children in Kilifi, Kenya with severe, uncomplicated, and asymptomatic malaria infection over 18 years of falling malaria transmission. We examine markers of host immunity and metabolism, and markers of parasite growth and transmission investment. We find that inflammatory responses and reduced plasma lysophosphatidylcholine levels are associated with markers of increased investment in parasite sexual reproduction (i.e., transmission investment) and reduced growth (i.e., asexual replication). This association becomes stronger with falling transmission and suggests that parasites can rapidly respond to the within-host environment, which in turn is subject to changing transmission.

microbiology↗

bioRxiv2019

P. falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers

Transmission of Plasmodium falciparum depends on the presence of mature gametocytes that can be ingested by mosquitoes taking a bloodmeal when feeding on human skin. It has long been hypothesised that skin sequestration contributes to efficient transmission. Although skin sequestration would have major implications for our understanding of transmission biology and the suitability of mosquito feeding methodologies to measure the human infectious reservoir, it has never been formally tested. In two populations of naturally infected gametocyte carriers from Burkina Faso, we assessed transmission potential to mosquitoes and directly quantified male and female gametocytes and asexual parasites in: i) finger prick blood, ii) venous blood, iii) skin biopsies, and in pools of mosquitoes that fed iv) on venous blood or, v) directly on the skin. Whilst more mosquitoes became infected when feeding directly on the skin compared to venous blood, concentrations of gametocytes in the subdermal skin vasculature were identical to that in other blood compartments. Asexual parasite densities, gametocyte densities and sex ratios were identical in the mosquito blood meals taken directly from the skin of parasite carriers and their venous blood.\n\nWe also observed sparse gametocytes in skin biopsies from legs and arms of gametocyte carriers by microscopy. Taken together, we provide conclusive evidence for the absence of significant skin sequestration of P. falciparum gametocytes. Gametocyte densities in peripheral blood are thus informative for predicting onward transmission potential to mosquitoes. Quantifying this human malaria transmission potential is of pivotal importance for the deployment and monitoring of malaria elimination initiatives.\n\nIMPORTANCEOur observations settle a long-standing question in the malaria field and close a major knowledge gap in the parasite cycle. By deploying mosquito feeding experiments and stage-specific molecular and immunofluorescence parasite detection methodologies in two populations of naturally infected parasite carriers, we conclusively reject the hypothesis of gametocyte skin sequestration. Our findings provide novel insights in parasite stage composition in human blood compartments, mosquito bloodmeals and their implications for transmission potential. We demonstrate that gametocyte levels in venous or finger prick blood can be used to predict onward transmission potential to mosquitoes. Our findings thus pave the way for methodologies to quantify the human infectious reservoir based on conventional blood sampling approaches to support the deployment and monitoring of malaria elimination efforts for maximum public health impact.

microbiology↗