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Quantitative analysis of immune response and erythropoiesis during rodent malarial infection.

ABSTRACT: Malarial infection is associated with complex immune and erythropoietic responses in the host. A quantitative understanding of these processes is essential to help inform malaria therapy and for the design of effective vaccines. In this study, we use a statistical model-fitting approach to investigate the immune and erythropoietic responses in Plasmodium chabaudi infections of mice. Three mouse phenotypes (wildtype, T-cell-deficient nude mice, and nude mice reconstituted with T-cells taken from wildtype mice) were infected with one of two parasite clones (AS or AJ). Under a Bayesian framework, we use an adaptive population-based Markov chain Monte Carlo method and fit a set of dynamical models to observed data on parasite and red blood cell (RBC) densities. Model fits are compared using Bayes' factors and parameter estimates obtained. We consider three independent immune mechanisms: clearance of parasitised RBCs (pRBC), clearance of unparasitised RBCs (uRBC), and clearance of parasites that burst from RBCs (merozoites). Our results suggest that the immune response of wildtype mice is associated with less destruction of uRBCs, compared to the immune response of nude mice. There is a greater degree of synchronisation between pRBC and uRBC clearance than between either mechanism and merozoite clearance. In all three mouse phenotypes, control of the peak of parasite density is associated with pRBC clearance. In wildtype mice and AS-infected nude mice, control of the peak is also associated with uRBC clearance. Our results suggest that uRBC clearance, rather than RBC infection, is the major determinant of RBC dynamics from approximately day 12 post-innoculation. During the first 2-3 weeks of blood-stage infection, immune-mediated clearance of pRBCs and uRBCs appears to have a much stronger effect than immune-mediated merozoite clearance. Upregulation of erythropoiesis is dependent on mouse phenotype and is greater in wildtype and reconstitited mice. Our study highlights the informative power of statistically rigorous model-fitting techniques in elucidating biological systems.

SUBMITTER: Miller MR

PROVIDER: S-EPMC2947982 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe emerging resistance of Plasmodium species to currently available anti-malarials remains a public health concern, hence the need for new effective, safe and affordable drugs. Natural products remain a reliable source of drugs. Nefang is a polyherbal anti-malarial of the Cameroonian folklore medicine with demonstrated in vitro antiplasmodial and antioxidant activities. It is composed of Mangifera indica (bark and leaf), Psidium guajava, Carica papaya, Cymbopogon citratus, Citrus sinensis, Ocimum gratissimum (leaves). This study aimed at investigating the suppressive, prophylactic and curative activities of Nefang in Plasmodium infected rodent models.MethodsSystemic acute oral toxicity of Nefang aqueous and ethanol extracts was assessed in mice up to a dose of 5,000 mgkg(-1) body weight. BALB/c mice and Wistar rats were inoculated with Plasmodium chabaudi chabaudi and Plasmodium berghei, respectively, and treated with Nefang, the Mangifera indica bark/Psidium guajava combination and a Psidium guajava leaf aqueous extracts (75, 150, 300 and 600 mgkg(-1) bwt). Their schizonticidal activity was then evaluated using the Peter's 4-day suppressive test). The prophylactic and curative (Rane's Test) activity of Nefang was also evaluated by determining the parasitaemia, survival time, body weight and temperature in pre-treated rodents.ResultsAcute oral toxicity of the extract did not cause any observed adverse effects. Percent suppressions of parasitaemia at 600 mgkg(-1) bwt were as follows (P. berghei/P. chabaudi): Nefang - 82.9/86.3, Mangifera indica bark/Psidium guajava leaf combination extract - 79.5/81.2 and Psidium guajava leaf - 58.9/67.4. Nefang exhibited a prophylactic activity of 79.5% and its chemotherapeutic effects ranged from 61.2 - 86.1% with maximum effect observed at the highest experimental dose.ConclusionThese results indicate that Nefang has excellent in vivo anti-malarial activities against P. berghei and P. chabaudi, upholding earlier in vitro antiplasmodial activities against multi-drug resistant P. falciparum parasites as well as its traditional use. Hence, Nefang represents a promising source of new anti-malarial agents.

Project description:Salmonella enterica serovar Typhimurium causes enteric disease and compromises food safety. In pigs, the molecular response of the intestine to S. typhimurium has been traditionally characterized by in vitro models that do not reflect the actual immunological competence of the intestinal mucosa. In this work, we performed an oral S. typhimurium infection study to obtain insight into the in vitro response in three different sections (jejunum, ileum and colon) of the porcine intestine. For this, samples from one-month-old infected piglets were collected during a time course comprising 1, 2, and 6 days post inoculation to evaluate the intestinal response by quantifying the mRNA expression of gene coding for 28 innate immune system molecules using quantitative real-time PCR assays. In addition, samples from non-infected control animals were also employed to establish differences in the steady state gene expression between intestinal sections. The panel of quantified molecules included an assortment of cytokines, chemokines, pattern-recognition receptors, intracellular signaling molecules, transcription factors and antimicrobial molecules. Changes in gene expression occurred in the three different parts of the intestine and during the course of the S. typhimurium infection. Moreover, the high variation observed in expression patterns of genes coding for inflammatory mediators could indicate that each intestinal section responds differently to the infection. Thus, on the contrary to findings in the jejunum and colon, a down-regulation and lack of induction of some proinflammatory cytokine transcripts was observed in the ileum. Nevertheless, all chemoattractant cytokines assayed were up-regulated in the ileum and jejunum whereas only interleukin-8 and MIP-1alpha mRNA were over expressed in the colon. In conclusion, our results reveal regional differences in gene expression profiles along the porcine intestinal gut as well as regional differences in the inflammatory response to S. typhimurium infection. Taken together, these data should provide a basis for a complete understanding of the porcine intestinal response to bacterial infection.

Project description:BackgroundThe contribution of pro-inflammatory cytokines to the pathogenesis of malarial anemia has been studied extensively but the roles of Th2 cytokines remain unknown. Here, we investigated the role of signal transducer and activator of transcription (STAT)6-mediated responses in erythropoietic suppression during acute malaria infection in mice.Design and methodsNaïve and/or erythropoietin-treated wild-type and STAT6(-/-) mice were infected with Plasmodium chabaudi AS (P. chabaudi), and the effects parasitemia, hematologic parameters, erythropoietin receptor, TER119, and CD71 expression, in vitro erythropoietin-stimulated proliferation of splenic erythroid precursors, and serum cytokine levels were analyzed. To explore the role of interleukin-4 in STAT6-dependent erythropoietic suppression, mice were treated in vivo with a monoclonal antibody to interleukin-4 and the effects on parasitemia, hematologic parameters, and cytokine levels were analyzed.ResultsInfected STAT6(-/-) mice developed enhanced reticulocytosis compared to wild-type mice despite higher parasitemia and a similar course of anemia. Enhanced reticulocytosis in infected STAT6(-/-) mice was associated with an increased frequency of late-stage erythroblasts, fewer leukocytes expressing CD71, and increased erythropoietin-stimulated proliferation of splenocytes compared to infected wild-type mice. Interleukin-4-depleted wild-type mice had increased levels of parasitemia and a course of reticulocytosis similar to responses observed in infected STAT6(-/-) mice. Determination of serum cytokine levels in STAT6(-/-) and wild-type mice depleted of interleukin-4 by treatment with mAb revealed significantly lower levels of interferon-gamma compared to control wild-type mice during infection.ConclusionsTogether, these findings provide evidence for a STAT6-dependent mechanism in mediating erythropoietic suppression during acute blood-stage malaria and indicate a role for interleukin-4 and possibly interferon-gammain STAT6-induced erythropoietic suppression.

Project description:Immune response genes play an important role during acute HIV and SIV infection. Using an SIV macaque model of AIDS and CNS disease, our overall goal was to assess how the expression of genes associated with immune and inflammatory responses are longitudinally changed in different organs or cells during SIV infection. To compare RNA expression of a panel of 88 immune-related genes across time points and among three tissues - spleen, mesenteric lymph nodes (MLN) and peripheral blood mononuclear cells (PBMC) - we designed a set of Nanostring probes. To identify significant genes during acute SIV infection and to investigate whether these genes are tissue-specific or have global roles, we introduce a novel multiplexed component analysis (MCA) method. This combines multivariate analysis methods with multiple preprocessing methods to create a set of 12 "judges"; each judge emphasizes particular types of change in gene expression to which cells could respond, for example, the absolute or relative size of expression change from baseline. Compared to bivariate analysis methods, our MCA method improved classification rates. This analysis allows us to identify three categories of genes: (a) consensus genes likely to contribute highly to the immune response; (b) genes that would contribute highly to the immune response only if certain assumptions are met - e.g. that the cell responds to relative expression change rather than absolute expression change; and (c) genes whose contribution to immune response appears to be modest. We then compared the results across the three tissues of interest; some genes are consistently highly-contributing in all tissues, while others are specific for certain tissues. Our analysis identified CCL8, CXCL10, CXCL11, MxA, OAS2, and OAS1 as top contributing genes, all of which are stimulated by type I interferon. This suggests that the cytokine storm during acute SIV infection is a systemic innate immune response against viral replication. Furthermore, these genes have approximately equal contributions to all tissues, making them possible candidates to be used as non-invasive biomarkers in studying PBMCs instead of MLN and spleen during acute SIV infection experiments. We identified clusters of genes that co-vary together and studied their correlation with regard to other gene clusters. We also developed novel methods to faithfully visualize multi-gene correlations on two-dimensional polar plots, and to visualize tissue specificity of gene expression responses.

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Quantitative analysis of immune response and erythropoiesis during rodent malarial infection.

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