Antibody-Mediated Growth Inhibition of Plasmodium falciparum: Relationship to Age and Protection from Parasitemia in Kenyan Children and Adults

BACKGROUND: Antibodies that impair Plasmodium falciparum merozoite invasion and intraerythrocytic development are one of several mechanisms that mediate naturally acquired immunity to malaria. Attempts to correlate anti-malaria antibodies with risk of infection and morbidity have yielded inconsistent results. Growth inhibition assays (GIA) offer a convenient method to quantify functional antibody activity against blood stage malaria. METHODS: A treatment-time-to-infection study was conducted over 12-weeks in a malaria holoendemic area of Kenya. Plasma collected from healthy individuals (98 children and 99 adults) before artemether-lumefantrine treatment was tested by GIA in three separate laboratories. RESULTS: Median GIA levels varied with P. falciparum line (D10, 8.8%; 3D7, 34.9%; FVO, 51.4% inhibition). The magnitude of growth inhibition decreased with age in all P. falciparum lines tested with the highest median levels among children \u3c4 years compared to adults (e.g. 3D7, 45.4% vs. 30.0% respectively, p = 0.0003). Time-to-infection measured by weekly blood smears was significantly associated with level of GIA controlling for age. Upper quartile inhibition activity was associated with less risk of infection compared to individuals with lower levels (e.g. 3D7, hazard ratio = 1.535, 95% CI = 1.012-2.329; p = 0.0438). Various GIA methodologies had little effect on measured parasite growth inhibition. CONCLUSION: Plasma antibody-mediated growth inhibition of blood stage P. falciparum decreases with age in residents of a malaria holoendemic area. Growth inhibition assay may be a useful surrogate of protection against infection when outcome is controlled for age

Is Task-Irrelevant Learning Really Task-Irrelevant?

In the present study we address the question of whether the learning of task-irrelevant stimuli found in the paradigm of task-irrelevant learning (TIPL) [1]–[9] is truly task irrelevant. To test the hypothesis that associations that are beneficial to task-performance may develop between the task-relevant and task-irrelevant stimuli, or the task-responses and the task-irrelevant stimuli, we designed a new procedure in which correlations between the presentation of task-irrelevant motion stimuli and the identity of task-targets or task-responses were manipulated. We found no evidence for associations developing between the learned (task-irrelevant) motion stimuli and the targets or responses to the letter identification task used during training. Furthermore, the conditions that had the greatest correlations between stimulus and response showed the least amount of TIPL. On the other hand, TIPL was found in conditions of greatest response uncertainty and with the greatest processing requirements for the task-relevant stimuli. This is in line with our previously published model that suggests that task-irrelevant stimuli benefit from the spill-over of learning signals that are released due to processing of task-relevant stimuli

Is Task-Irrelevant Learning Really Task-Irrelevant?

In the present study we address the question of whether the learning of task-irrelevant stimuli found in the paradigm of task-irrelevant learning (TIPL) [1]–[9] is truly task irrelevant. To test the hypothesis that associations that are beneficial to task-performance may develop between the task-relevant and task-irrelevant stimuli, or the task-responses and the task-irrelevant stimuli, we designed a new procedure in which correlations between the presentation of task-irrelevant motion stimuli and the identity of task-targets or task-responses were manipulated. We found no evidence for associations developing between the learned (task-irrelevant) motion stimuli and the targets or responses to the letter identification task used during training. Furthermore, the conditions that had the greatest correlations between stimulus and response showed the least amount of TIPL. On the other hand, TIPL was found in conditions of greatest response uncertainty and with the greatest processing requirements for the task-relevant stimuli. This is in line with our previously published model that suggests that task-irrelevant stimuli benefit from the spill-over of learning signals that are released due to processing of task-relevant stimuli

Patterns of co-speciation and host switching in primate malaria parasites

<p>Abstract</p> <p>Background</p> <p>The evolutionary history of many parasites is dependent on the evolution of their hosts, leading to an association between host and parasite phylogenies. However, frequent host switches across broad phylogenetic distances may weaken this close evolutionary link, especially when vectors are involved in parasites transmission, as is the case for malaria pathogens. Several studies suggested that the evolution of the primate-infective malaria lineages may be constrained by the phylogenetic relationships of their hosts, and that lateral switches between distantly related hosts may have been occurred. However, no systematic analysis has been quantified the degree of phylogenetic association between primates and their malaria parasites.</p> <p>Methods</p> <p>Here phylogenetic approaches have been used to discriminate statistically between events due to co-divergence, duplication, extinction and host switches that can potentially cause historical association between <it>Plasmodium </it>parasites and their primate hosts. A Bayesian reconstruction of parasite phylogeny based on genetic information for six genes served as basis for the analyses, which could account for uncertainties about the evolutionary hypotheses of malaria parasites.</p> <p>Results</p> <p>Related lineages of primate-infective <it>Plasmodium </it>tend to infect hosts within the same taxonomic family. Different analyses testing for congruence between host and parasite phylogenies unanimously revealed a significant association between the corresponding evolutionary trees. The most important factor that resulted in this association was host switching, but depending on the parasite phylogeny considered, co-speciation and duplication may have also played some additional role. Sorting seemed to be a relatively infrequent event, and can occur only under extreme co-evolutionary scenarios. The concordance between host and parasite phylogenies is heterogeneous: while the evolution of some malaria pathogens is strongly dependent on the phylogenetic history of their primate hosts, the congruent evolution is less emphasized for other parasite lineages (e.g. for human malaria parasites). Estimation of ancestral states of host use along the phylogenetic tree of parasites revealed that lateral transfers across distantly related hosts were likely to occur in several cases. Parasites cannot infect all available hosts, and they should preferentially infect hosts that provide a similar environment for reproduction. Marginally significant evidence suggested that there might be a consistent variation within host ranges in terms of physiology.</p> <p>Conclusion</p> <p>The evolution of primate malarias is constrained by the phylogenetic associations of their hosts. Some parasites can preserve a great flexibility to infect hosts across a large phylogenetic distance, thus host switching can be an important factor in mediating host ranges observed in nature. Due to this inherent flexibility and the potential exposure to various vectors, the emergence of new malaria disease in primates including humans cannot be predicted from the phylogeny of parasites.</p

Regulation of immunity during visceral Leishmania infection

Unicellular eukaryotes of the genus Leishmania are collectively responsible for a heterogeneous group of diseases known as leishmaniasis. The visceral form of leishmaniasis, caused by L. donovani or L. infantum, is a devastating condition, claiming 20,000 to 40,000 lives annually, with particular incidence in some of the poorest regions of the world. Immunity to Leishmania depends on the development of protective type I immune responses capable of activating infected phagocytes to kill intracellular amastigotes. However, despite the induction of protective responses, disease progresses due to a multitude of factors that impede an optimal response. These include the action of suppressive cytokines, exhaustion of specific T cells, loss of lymphoid tissue architecture and a defective humoral response. We will review how these responses are orchestrated during the course of infection, including both early and chronic stages, focusing on the spleen and the liver, which are the main target organs of visceral Leishmania in the host. A comprehensive understanding of the immune events that occur during visceral Leishmania infection is crucial for the implementation of immunotherapeutic approaches that complement the current anti-Leishmania chemotherapy and the development of effective vaccines to prevent disease.The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement No.602773 (Project KINDRED). VR is supported by a post-doctoral fellowship granted by the KINDReD consortium. RS thanks the Foundation for Science and Technology (FCT) for an Investigator Grant (IF/00021/2014). This work was supported by grants to JE from ANR (LEISH-APO, France), Partenariat Hubert Curien (PHC) (program Volubilis, MA/11/262). JE acknowledges the support of the Canada Research Chair Program

Reduced conditioned fear response in mice that lack Dlx1 and show subtype-specific loss of interneurons

The inhibitory GABAergic system has been implicated in multiple neuropsychiatric diseases such as schizophrenia and autism. The Dlx homeobox transcription factor family is essential for development and function of GABAergic interneurons. Mice lacking the Dlx1 gene have postnatal subtype-specific loss of interneurons and reduced IPSCs in their cortex and hippocampus. To ascertain consequences of these changes in the GABAergic system, we performed a battery of behavioral assays on the Dlx1 mutant mice, including zero maze, open field, locomotor activity, food intake, rotarod, tail suspension, fear conditioning assays (context and trace), prepulse inhibition, and working memory related tasks (spontaneous alteration task and spatial working memory task). Dlx1 mutant mice displayed elevated activity levels in open field, locomotor activity, and tail suspension tests. These mice also showed deficits in contextual and trace fear conditioning, and possibly in prepulse inhibition. Their learning deficits were not global, as the mutant mice did not differ from the wild-type controls in tests of working memory. Our findings demonstrate a critical role for the Dlx1 gene, and likely the subclasses of interneurons that are affected by the lack of this gene, in behavioral inhibition and associative fear learning. These observations support the involvement of particular components of the GABAergic system in specific behavioral phenotypes related to complex neuropsychiatric diseases