Abstract:BackgroundIn the past decade, estimates of malaria infections have dropped from 500 million to 225 million per year; likewise, mortality rates have dropped from 3 million to 791,000 per year. However, approximately 90% of these deaths continue to occur in sub-Saharan Africa, and 85% involve children less than 5 years of age. Malaria mortality in children generally results from one or more of the following clinical syndromes: severe anemia, acidosis, and cerebral malaria. Although much is known about the clinic… Show more
“…We performed the analysis separately for patient samples from Senegal [25,29] and Malawi [26]. As the in vivo datasets include information about circulating parasites only, this comparison was restricted to clusters with a peak time ≤22 hours post-invasion [26]. A total of 24 clusters showed significant enrichment (q-value ≤0.05) in genes expressed in all the three field cohorts compared with in vitro ring stage parasites (Figure 2B), and a small subset of those was also differentially expressed between these cohorts (Figure 3A).Figure 3
Individual gene expression values from representative clusters associated with parasite phenotypes.…”
Section: Resultsmentioning
confidence: 99%
“…Stage distribution of genes in the two transcriptional groups (A and B) as defined by Milner et al . [26] is presented in the left panel. WBC, white blood cell.…”
BackgroundDuring intra-erythrocytic development, late asexually replicating Plasmodium falciparum parasites sequester from peripheral circulation. This facilitates chronic infection and is linked to severe disease and organ-specific pathology including cerebral and placental malaria. Immature gametocytes - sexual stage precursor cells - likewise disappear from circulation. Recent work has demonstrated that these sexual stage parasites are located in the hematopoietic system of the bone marrow before mature gametocytes are released into the bloodstream to facilitate mosquito transmission. However, as sequestration occurs only in vivo and not during in vitro culture, the mechanisms by which it is regulated and enacted (particularly by the gametocyte stage) remain poorly understood.ResultsWe generated the most comprehensive P. falciparum functional gene network to date by integrating global transcriptional data from a large set of asexual and sexual in vitro samples, patient-derived in vivo samples, and a new set of in vitro samples profiling sexual commitment. We defined more than 250 functional modules (clusters) of genes that are co-expressed primarily during the intra-erythrocytic parasite cycle, including 35 during sexual commitment and gametocyte development. Comparing the in vivo and in vitro datasets allowed us, for the first time, to map the time point of asexual parasite sequestration in patients to 22 hours post-invasion, confirming previous in vitro observations on the dynamics of host cell modification and cytoadherence. Moreover, we were able to define the properties of gametocyte sequestration, demonstrating the presence of two circulating gametocyte populations: gametocyte rings between 0 and approximately 30 hours post-invasion and mature gametocytes after around 7 days post-invasion.ConclusionsThis study provides a bioinformatics resource for the functional elucidation of parasite life cycle dynamics and specifically demonstrates the presence of the gametocyte ring stages in circulation, adding significantly to our understanding of the dynamics of gametocyte sequestration in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0133-7) contains supplementary material, which is available to authorized users.
“…We performed the analysis separately for patient samples from Senegal [25,29] and Malawi [26]. As the in vivo datasets include information about circulating parasites only, this comparison was restricted to clusters with a peak time ≤22 hours post-invasion [26]. A total of 24 clusters showed significant enrichment (q-value ≤0.05) in genes expressed in all the three field cohorts compared with in vitro ring stage parasites (Figure 2B), and a small subset of those was also differentially expressed between these cohorts (Figure 3A).Figure 3
Individual gene expression values from representative clusters associated with parasite phenotypes.…”
Section: Resultsmentioning
confidence: 99%
“…Stage distribution of genes in the two transcriptional groups (A and B) as defined by Milner et al . [26] is presented in the left panel. WBC, white blood cell.…”
BackgroundDuring intra-erythrocytic development, late asexually replicating Plasmodium falciparum parasites sequester from peripheral circulation. This facilitates chronic infection and is linked to severe disease and organ-specific pathology including cerebral and placental malaria. Immature gametocytes - sexual stage precursor cells - likewise disappear from circulation. Recent work has demonstrated that these sexual stage parasites are located in the hematopoietic system of the bone marrow before mature gametocytes are released into the bloodstream to facilitate mosquito transmission. However, as sequestration occurs only in vivo and not during in vitro culture, the mechanisms by which it is regulated and enacted (particularly by the gametocyte stage) remain poorly understood.ResultsWe generated the most comprehensive P. falciparum functional gene network to date by integrating global transcriptional data from a large set of asexual and sexual in vitro samples, patient-derived in vivo samples, and a new set of in vitro samples profiling sexual commitment. We defined more than 250 functional modules (clusters) of genes that are co-expressed primarily during the intra-erythrocytic parasite cycle, including 35 during sexual commitment and gametocyte development. Comparing the in vivo and in vitro datasets allowed us, for the first time, to map the time point of asexual parasite sequestration in patients to 22 hours post-invasion, confirming previous in vitro observations on the dynamics of host cell modification and cytoadherence. Moreover, we were able to define the properties of gametocyte sequestration, demonstrating the presence of two circulating gametocyte populations: gametocyte rings between 0 and approximately 30 hours post-invasion and mature gametocytes after around 7 days post-invasion.ConclusionsThis study provides a bioinformatics resource for the functional elucidation of parasite life cycle dynamics and specifically demonstrates the presence of the gametocyte ring stages in circulation, adding significantly to our understanding of the dynamics of gametocyte sequestration in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0133-7) contains supplementary material, which is available to authorized users.
“…However, we could not detect GCS activity. It is possible that the Plasmodium T-protein might play a GCS-independent moonlighting role under special circumstances since transcriptional profiling of low versus high parasitemia clusters of clinical samples from Malawi patients had revealed that the PfT gene is highly induced in low parasitemia cluster [17]. Also in the absence of a functional SHMT and GCS in the mitochondrion, it would be intriguing to investigate the strategies used by the parasite to generate mitochondrial pool of CH 2 -THF.…”
“…Further evidence for this lies, obviously, within the overall rarity of such events. Moreover, there are relatively few physiological states the parasite can achieve inside the human host-all of this biology is accomplished with a meager 6000 genes, most of which have no known function (Bozdech et al 2003a,b;Daily et al 2007;Milner et al 2012).…”
In the mosquito-human life cycle, the six species of malaria parasites infecting humans (, ,, ,, and ) undergo 10 or more morphological states, replicate from single to 10,000+ cells, and vary in total population from one to many more than 10 organisms. In the human host, only a small number of these morphological stages lead to clinical disease and the vast majority of all malaria-infected patients in the world produce few (if any) symptoms in the human. Human clinical disease (e.g., fever, anemia, coma) is the result of the parasite preprogrammed biology in concert with the human pathophysiological response. Caveats and corollaries that add variation to this host-parasite interaction include parasite genetic diversity of key proteins, coinfections, comorbidities, delays in treatment, human polymorphisms, and environmental determinants.
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