Global host metabolic response to Plasmodium vivax infection: a 1H NMR based urinary metabonomic study

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium vivax </it>is responsible for the majority of malarial infection in the Indian subcontinent. This species of the parasite is generally believed to cause a relatively benign form of the disease. However, recent reports from different parts of the world indicate that vivax malaria can also have severe manifestation. Host response to the parasite invasion is thought to be an important factor in determining the severity of manifestation. In this paper, attempt was made to determine the host metabolic response associated with <it>P. vivax </it>infection by means of NMR spectroscopy-based metabonomic techniques in an attempt to better understand the disease pathology.</p> <p>Methods</p> <p>NMR spectroscopy of urine samples from <it>P. vivax-</it>infected patients, healthy individuals and non-malarial fever patients were carried out followed by multivariate statistical analysis. Two data analysis techniques were employed, namely, Principal Component Analysis [PCA] and Orthogonal Projection to Latent Structure Discriminant Analysis [OPLS-DA]. Several NMR signals from the urinary metabolites were further selected for univariate comparison among the classes.</p> <p>Results</p> <p>The urine metabolic profiles of <it>P. vivax-</it>infected patients were distinct from those of healthy individuals as well as of non-malarial fever patients. A highly predictive model was constructed from urine profile of malarial and non-malarial fever patients. Several metabolites were found to be varying significantly across these cohorts. Urinary ornithine seems to have the potential to be used as biomarkers of vivax malaria. An increasing trend in pipecolic acid was also observed. The results suggest impairment in the functioning of liver as well as impairment in urea cycle.</p> <p>Conclusions</p> <p>The results open up a possibility of non-invasive analysis and diagnosis of <it>P. vivax </it>using urine metabolic profile. Distinct variations in certain metabolites were recorded, and amongst these, ornithine may have the potential of being used as biomarker of malaria. Pipecolic acid also showed increasing trend in the malaria patient compared to the other groups.</p

Malaria vaccine: a current perspective

The observation that inactivated Plasmodium sporozoites could protect against malaria is about a hundred years old. However, systematic demonstration of protection using irradiated sporozoites occurred in the nineteen-sixties, providing the impetus for the development of a malaria vaccine. In 1983, the circumsporozoite protein (CSP), a major sporozoite surface antigen, became the first Plasmodium gene to be cloned, and a CSP-based vaccine appeared imminent. Today, 25 years later, we are still without an effective malaria vaccine, despite considerable information regarding the genomics and proteomics of the malaria parasites. Although clinical immunity to malaria has been well-documented in adults living in malaria endemic areas, our understanding of the host-immune responses operating in such malaria immune persons remains poor, and limits the development of immune control of the disease. Currently, several antigen and adjuvant combinations have entered clinical trials, in which efficacy against experimental sporozoite challenge and/or exposure to natural infection is evaluated. This review collates information on the recent status of the field. Unresolved challenges facing the development of a malaria vaccine are also discussed

Development of SMEDDS using natural lipophile: application to β-Artemether delivery

The objective of the present investigation was to formulate self-microemulsifying drug delivery systems (SMEDDS) using a novel, indigenous natural lipophile (N-LCT) as an oily phase. SMEDDS based on N-LCT and commercially available modified oil (Capryol 90) were formulated and their application in improving the delivery of a lipophilic anti-malarial drug, β-Artemether (BAM) was also evaluated. BAM-loaded SMEDDS were characterized with respect to mean globule size and in vitro drug release profile in comparison to the marketed formulation (Larither®). Comparative in vivo anti-malarial performance of the developed SMEDDS was evaluated against the (Larither®) in Swiss male mice infected with lethal ANKA strain of Plasmodium berghei. The parameters studied were percent parasitemia, activity against time and animal survival period. Both the BAM-SMEDDS showed excellent self-microemulsification efficiency and released &gt;98% of the drug in just 15 min whereas (Larither®) showed only 46% drug release at the end of 1 h. The mean globule size for optimized BAM-SMEDDS was &lt;100 nm. The anti-malarial studies revealed that BAM-SMEDDS resulted in significant improvement in the anti-malarial activity (P &lt; 0.05) as compared to that of (Larither®) and BAM solubilized in the oily phases and surfactant. The developed SMEDDS highlight safety for use and potential applications of indigenous natural lipophile in the development of novel colloidal drug carriers

Age-Dependent Sex Bias in Clinical Malarial Disease in Hypoendemic Regions

<div><h3>Background and Objectives</h3><p>Experimental models show a male bias in murine malaria; however, extant literature on biases in human clinical malaria is inconclusive. Studies in hyperendemic areas document an absence of sexual dimorphism in clinical malaria. Data on sex bias in clinical malaria in hypoendemic areas is ambiguous—some reports note a male bias but do not investigate the role of differential mosquito exposure in that bias. Moreover, these studies do not examine whether the bias is age related. This study investigates whether clinical malaria in hypoendemic regions exhibits a sex bias and whether this bias is age-dependent. We also consider the role of vector exposure in this bias.</p> <h3>Methods</h3><p>Retrospective passive clinical malaria datasets (2002–2007) and active surveillance datasets (2000–2009) were captured for the hypoendemic Mumbai region in Western India. To validate findings, passive retrospective data was captured from a primary malaria clinic (2006–2007) in hypoendemic Rourkela (Eastern India). Data was normalized by determining percent slide-positivity rates (SPRs) for males and females, and parasite-positivity distributions were established across age groups. The Mann–Whitney test, Wilcoxon Signed Rank test, and Chi-square analysis were used to determine statistical significances.</p> <h3>Results</h3><p>In both the Mumbai and Rourkela regions, clinical malaria exhibited an adult male bias (p<0.01). A sex bias was not observed in children aged ≤10. Post-puberty, male SPRs were significantly greater than females SPRs (p<0.01). This adult male bias was observed for both vivax and falciparum clinical disease. Analysis of active surveillance data did not reveal an age or sex bias in the frequency of parasite positivity.</p> <h3>Conclusion</h3><p>This study demonstrates an age-dependent sex bias in clinical malaria in hypoendemic regions and enhanced incidence of clinical malaria in males following puberty. Possible roles of sex hormones, vector exposure, co-infections, and other factors in this enhanced susceptibility are discussed.</p> </div

Age distributions of differences between male and female SPRs in the clinical malaria and active surveillance datasets in the Mumbai region.

<p>A,C, Box plot showing the 25th and 75th percentiles, together with the median, with whiskers showing the minimum and maximum difference in the percent slide-positivity rates between males and females across age groups in the clinical malaria dataset for vivax (A) and falciparum (C) malaria. B,D, Box plots as in A showing the difference in the percent slide-positivity rates between males and females across age groups who tested positive for <i>P. vivax</i> (B) and <i>P. falciparum</i> (D) in the active surveillance programme. Data were compared with the difference of male/female SPRs expected under the hypothesis of neutrality (0, red line) and were analyzed with the Mann–Whitney test. Statistically significant values are shown in black. Numbers in red indicate statistically significant p values obtained by Wilcoxon Signed Rank test under the hypothesis that the median of the group did not differ significantly from zero. The test could not be applied to the falciparum data in the active surveillance dataset.</p

Active surveillance datasets (Mumbai region).

<p>Active surveillance datasets (Mumbai region).</p