Chaperone expression profiles correlate with distinct physiological states of Plasmodium falciparum in malaria patients

<p>Abstract</p> <p>Background</p> <p>Molecular chaperones have been shown to be important in the growth of the malaria parasite <it>Plasmodium falciparum </it>and inhibition of chaperone function by pharmacological agents has been shown to abrogate parasite growth. A recent study has demonstrated that clinical isolates of the parasite have distinct physiological states, one of which resembles environmental stress response showing up-regulation of specific molecular chaperones.</p> <p>Methods</p> <p>Chaperone networks operational in the distinct physiological clusters in clinical malaria parasites were constructed using cytoscape by utilizing their clinical expression profiles.</p> <p>Results</p> <p>Molecular chaperones show distinct profiles in the previously defined physiologically distinct states. Further, expression profiles of the chaperones from different cellular compartments correlate with specific patient clusters. While cluster 1 parasites, representing a starvation response, show up-regulation of organellar chaperones, cluster 2 parasites, which resemble active growth based on glycolysis, show up-regulation of cytoplasmic chaperones. Interestingly, cytoplasmic Hsp90 and its co-chaperones, previously implicated as drug targets in malaria, cluster in the same group. Detailed analysis of chaperone expression in the patient cluster 2 reveals up-regulation of the entire Hsp90-dependent pro-survival circuitries. In addition, cluster 2 also shows up-regulation of <it>Plasmodium </it>export element (PEXEL)-containing Hsp40s thought to have regulatory and host remodeling roles in the infected erythrocyte.</p> <p>Conclusion</p> <p>In all, this study demonstrates an intimate involvement of parasite-encoded chaperones, PfHsp90 in particular, in defining pathogenesis of malaria.</p

Clinical Proteomics of the Neglected Human Malarial Parasite Plasmodium vivax

Recent reports highlight the severity and the morbidity of disease caused by the long neglected malaria parasite Plasmodium vivax. Due to inherent difficulties in the laboratory-propagation of P. vivax, the biology of this parasite has not been adequately explored. While the proteome of P. falciparum, the causative agent of cerebral malaria, has been extensively explored from several sources, there is limited information on the proteome of P. vivax. We have, for the first time, examined the proteome of P. vivax isolated directly from patients without adaptation to laboratory conditions. We have identified 153 proteins from clinical P. vivax, majority of which do not show homology to any previously known gene products. We also report 29 new proteins that were found to be expressed in P. vivax for the first time. In addition, several proteins previously implicated as anti-malarial targets, were also found in our analysis. Most importantly, we found several unique proteins expressed by P. vivax.This study is an important step in providing insight into physiology of the parasite under clinical settings

Chaperoning a cellular upheaval in malaria: heat shock proteins in Plasmodium falciparum

In addition to their ability to help newly synthesized proteins to fold, molecular chaperones are also recognized for their participation in cellular processes ranging from protein trafficking, signal transduction, differentiation and development. Novel roles for this group of proteins have come to light through studies on important human pathogens like Leishmania, Trypanosoma as well as Plasmodia species. This review analyzes our current state of knowledge on molecular chaperones in human malarial parasite Plasmodium falciparum. In addition to a comparative analysis of their structures, complexes, client proteins and functions, a discussion on their potential as vaccine candidates as well as drug targets is also presented. The major chaperone classes of Hsp90, Hsp70, Hsp60 and Hsp40 family are well represented in the malarial parasite. Genomic cataloguing of all the parasite chaperone homologs indicates that about 2% of the total number of genes are dedicated to this function. While Hsp90 and Hsp70 are the most abundantly expressed, the Hsp40 class appears to be the best represented among the 92 chaperones encoded by the parasite genome. Importantly PfHsp70 is considered a potential vaccine candidate and PfHsp90 has been implicated as a drug target against the parasite. Available information suggests fascinating roles for chaperones in the life cycle of the parasite. In addition to their value as therapeutic targets, the study of chaperones in parasitic systems may likely reveal new principles of chaperone function in biology

Supplementary Table 7

<p>qPCR data for selected genes</p

Supplementary Table 3b

<p>MSigDB enrichment analysis based on genes which are down-regualted consistently in FDR</p

Non-Invasive Biomarkers for Celiac Disease

Once thought to be uncommon, celiac disease has now become a common disease globally. While avoidance of the gluten-containing diet is the only effective treatment so far, many new targets are being explored for the development of new drugs for its treatment. The endpoints of therapy include not only reversal of symptoms, normalization of immunological abnormalities and healing of mucosa, but also maintenance of remission of the disease by strict adherence of the gluten-free diet (GFD). There is no single gold standard test for the diagnosis of celiac disease and the diagnosis is based on the presence of a combination of characteristics including the presence of a celiac-specific antibody (anti-tissue transglutaminase antibody, anti-endomysial antibody or anti-deamidated gliadin peptide antibody) and demonstration of villous abnormalities. While the demonstration of enteropathy is an important criterion for a definite diagnosis of celiac disease, it requires endoscopic examination which is perceived as an invasive procedure. The capability of prediction of enteropathy by the presence of the high titer of anti-tissue transglutaminase antibody led to an option of making a diagnosis even without obtaining mucosal biopsies. While present day diagnostic tests are great, they, however, have certain limitations. Therefore, there is a need for biomarkers for screening of patients, prediction of enteropathy, and monitoring of patients for adherence of the gluten-free diet. Efforts are now being made to explore various biomarkers which reflect different changes that occur in the intestinal mucosa using modern day tools including transcriptomics, proteomics, and metabolomics. In the present review, we have discussed comprehensively the pros and cons of available biomarkers and also summarized the current status of emerging biomarkers for the screening, diagnosis, and monitoring of celiac disease

Host–Parasite Interactions in Human Malaria: Clinical Implications of Basic Research

The malaria parasite, Plasmodium, is one of the oldest parasites documented to infect humans and has proven particularly hard to eradicate. One of the major hurdles in designing an effective subunit vaccine against the malaria parasite is the insufficient understanding of host–parasite interactions within the human host during infections. The success of the parasite lies in its ability to evade the human immune system and recruit host responses as physiological cues to regulate its life cycle, leading to rapid acclimatization of the parasite to its immediate host environment. Hence understanding the environmental niche of the parasite is crucial in developing strategies to combat this deadly infectious disease. It has been increasingly recognized that interactions between parasite proteins and host factors are essential to establishing infection and virulence at every stage of the parasite life cycle. This review reassesses all of these interactions and discusses their clinical importance in designing therapeutic approaches such as design of novel vaccines. The interactions have been followed from the initial stages of introduction of the parasite under the human dermis until asexual and sexual blood stages which are essential for transmission of malaria. We further classify the interactions as “direct” or “indirect” depending upon their demonstrated ability to mediate direct physical interactions of the parasite with host factors or their indirect manipulation of the host immune system since both forms of interactions are known to have a crucial role during infections. We also discuss the many ways in which this understanding has been taken to the field and the success of these strategies in controlling human malaria

Effect of FeCl3 and diethyl ether as additives on compression ignition engine emissions

Improving the performance of internal combustion engines and ensuring the reduction of pollution by the application of an advanced technology constitutes one of the main keys for safe guarding nation's economy and health. In this context it is pertinent to note that in terms of brake thermal efficiency and brake specific fuel consumption, a single cylinder four stroke engine acquires a better performance with 15% diethyl ether (DEE) as an additive to diesel. Thus, the present investigation is motivated to compare the performance of the engine when run with diesel alone and when it is run with additives like ferric chloride (FeCl3) and diethyl ether. The experiments in the laboratory establish lowering emissions of CO, HC and smoke (excluding NO) with diesel and DEE additives compared to that with diesel and FeCl3 additives and diesel alone