Plasmodium parasite-specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against Plasmodium takes many years and multiple rounds of infection and cure. Here we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center (GC) responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the GC reaction limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current paradigm describing the role and function of blood-stage Plasmodium -induced plasmablasts, but also reveal new targets and strategies to improve anti- Plasmodium humoral immunity.
Background M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers. MethodsThis first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo. A sentinel dosing strategy was used for each dose cohort whereby two participants (one assigned to M5717 and one assigned to placebo) were initially randomised and dosed. Randomisation schedules were generated electronically by independent, unblinded statisticians. Part two was an open-label, nonrandomised volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model in which participants were enrolled into three dose cohorts. Healthy men and women of non-childbearing potential aged 18-55 years were eligible for inclusion; individuals in the volunteer infection study were required to be malaria naive. Safety and tolerability (primary outcome of the single ascending dose study and secondary outcome of the volunteer infection study) were assessed by frequency and severity of adverse events. The pharmacokinetic profile of M5717 was also characterised (primary outcome of the volunteer infection study and secondary outcome of the single ascending dose study). Parasite clearance kinetics (primary outcome of the volunteer infection study) were assessed by the parasite reduction ratio and the corresponding parasite clearance half-life; the incidence of recrudescence up to day 28 was determined (secondary outcome of the volunteer infection study). Recrudescent parasites were tested for genetic mutations (exploratory outcome). The trial is registered with ClinicalTrials.gov (NCT03261401).
To determine the prevalence, associated factors, and relationships between symptoms of depression, symptoms of posttraumatic stress (PTS), and relationship distress in mothers and fathers of very preterm (VPT) infants (< 32 weeks). Mothers (n = 323) and fathers (n = 237) completed self-report measures on demographic and outcome variables at 38 days (SD = 23.1, range 9-116) postpartum while their infants were still hospitalised. Of mothers, 46.7% had a moderate to high likelihood of depression, 38.1% had moderate to severe symptoms of PTS, and 25.1% were in higher than average relationship distress. The corresponding percentages in fathers were 16.9, 23.7, and 27%. Depression was positively associated with having previous children (p = 0.01), speaking little or no English at home (p = 0.01), financial stress (p = 0.03), and recently accessing mental health services (p = 0.003) for mothers, and financial stress (p = 0.005) and not being the primary income earner (p = 0.04) for fathers. Similar associations were found for symptoms of PTS and relationship distress. Being in higher relationship distress increased the risk of depression in both mothers (p < .001) and fathers (p = 0.03), and PTS symptoms in mothers (p = 0.001). For both mothers and fathers, depression was associated with more severe PTS symptoms (p < .001). Fathers of VPT infants should be screened for mental health problems alongside mothers, and postpartum parent support programs for VPT infants should include strategies to improve the couple relationship.
Summary CD4 + T follicular helper cells (Tfh) are key drivers of antibody development. During Plasmodium falciparum malaria in children, the activation of Tfh is restricted to the Th1 subset and not associated with antibody levels. To identify Tfh subsets that are associated with antibody development in malaria, we assess Tfh and antibodies longitudinally in human volunteers with experimental P. falciparum infection. Tfh cells activate during infection, with distinct dynamics in different Tfh subsets. Th2-Tfh cells activate early, during peak infection, while Th1-Tfh cells activate 1 week after peak infection and treatment. Th2-Tfh cell activation is associated with the functional breadth and magnitude of parasite antibodies. In contrast, Th1-Tfh activation is not associated with antibody development but instead with plasma cells, which have previously been shown to play a detrimental role in the development of long-lived immunity. Thus, our study identifies the contrasting roles of Th2 and Th1-Tfh cells during experimental P. falciparum malaria.
Background Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines. Methods We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hour (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration. We compared these parameters to those from studies conducted elsewhere with infections induced by IBSM (n=66), sporozoites via mosquito bite (n=336) or injection (n=51). Results The parasite growth rate of 3D7 in QIMR Berghofer studies was 0.75/day (95% CI: 0.73–0.77/day), PMR48 was 31.9 (95% CI: 28.7–35.4), PMRLC was 16.4 (95% CI: 15.1–17.8) and parasite life-cycle was 38.8 hour (95% CI: 38.3–39.2 hour). These parameters were similar to estimates from IBSM studies elsewhere (0.71/day, 95% CI: 0.67–0.75/day; PMR48 26.6, 95% CI: 22.2–31.8), but significantly higher (P < 0.001) than in sporozoite studies (0.47/day, 95% CI: 0.43–0.50/day; PMR48 8.6, 95% CI: 7.3–10.1). Conclusion Parasite growth rates were similar across different IBSM studies and higher than infections induced by sporozoite.
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