Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malaria is caused by the protozoan Plasmodium. The parasite Plasmodium completes its life cycle inside two hosts, i. e. human and mosquito. Among all known Plasmodium species, Plasmodium falciparum is known to cause maximum mortality. Various studies done on the mosquito stages of the parasite suggest that the proteins present on the parasite's surface are responsible for its survival under the adverse conditions prevailing in the mosquito midgut. When human blood containing Plasmodium gametocytes enters the mosquito gut, the gametocytes form gametes which then fuse to form zygotes. At this stage two closely related proteins, Pfs25 and Pfs28 are expressed on the surface of the parasite which continue to express up to the young oocyst stage. These proteins present on zygotes, ookinetes and young oocysts of Plasmodium are categorized in P25 and P28 families and are well known malaria vaccine candidate proteins. In this study, we have done sequence analysis, homology modeling and docking studies of a typical member of the P25 family of ookinete surface protein, i.e. Pfs25 from Plasmodium falciparum. We have built a 3D model of Pfs25 based on the X-ray crystallographic structure of Pvs25 from Plasmodium vivax. Also we have modeled the Fv region of the malaria transmission blocking monoclonal antibody 4B7. This antibody is the transmission blocking monoclonal antibody for Pfs25 protein. Pfs25 and 4B7 scFv (single chain variable fragment only) docking results indicate that EGF domain III of the Pfs25 protein interacts with the scFv region of modeled 4B7 antibody forming seven hydrogen bonds out of which six are formed with heavy chain of scFv region. Docking results of Pfs25 with gamma chain of laminin also suggest a possible role of Pfs25 protein in host parasite interaction.
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PMID:Structure and mechanism of a transmission blocking vaccine candidate protein Pfs25 from P. falciparum: a molecular modeling and docking study. 1903 56

Anopheles gambiae mosquitoes are the principal vectors of malaria. A major determinant of the capacity of these mosquitoes as disease vectors is their high reproductive rate. Reproduction depends on a single insemination, which profoundly changes the behavior and physiology of females. To identify factors and mechanisms relevant to the fertility of A. gambiae, we performed a comprehensive analysis of the molecular and cellular machinery associated with copulation in females. Initial whole-body microarray experiments comparing virgins with females at 2 h, 6 h, and 24 h after mating detected large transcriptional changes. Analysis of tissue localization identified a subset of genes whose expression was strikingly regulated by mating in the lower reproductive tract and, surprisingly, the gut. In the atrium of virgin females, where the male seminal fluid is received, our studies revealed a "mating machinery" consisting of molecular and structural components that are turned off or collapse after copulation, suggesting that this tissue loses its competence for further insemination. In the sperm storage organ, we detected a number of mating-responsive genes likely to have a role in the maintenance and function of stored sperm. These results identify genes and mechanisms regulating the reproductive biology of A. gambiae females, highlighting considerable differences with Drosophila melanogaster. Our data inform vector control strategies and reveal promising targets for the manipulation of fertility in field populations of these important disease vectors.
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PMID:Molecular and cellular components of the mating machinery in Anopheles gambiae females. 1903 21

New research has shown that mefloquine, an arylaminoalcohol used against malaria, is active against Schistosoma japonicum and Schistosoma mansoni in vivo. To enhance our understanding of the potential mechanism of action of mefloquine against schistosomiasis, we examined the dynamics of histopathological changes in adult S. japonicum. Mice infected with S. japonicum for 35 days were treated intragastrically with a single dose of mefloquine (400 mg/kg). One to 35 days after mefloquine administration, drug-induced histopathological alterations were studied. Twenty-four hours after treatment, S. japonicum showed signs of degeneration, including focal roughing and swelling of the tegument and/or muscles, dilatation of the gut, focal desquamation of gut epithelial cells, and a decrease in pigment particles. There was extensive degeneration of vitelline cells and appearance of pigment particles visible in the cytoplasm in female worms. The extent and severity of histopathological changes increased over time; 48 h posttreatment, two thirds of female worms and a quarter of male worms were classified as dead. Three to 14 days posttreatment, typical histological changes observed in surviving male worms were vesiculation, swelling of parenchymal tissues, and dilatation of gut. In females, there was disintegration and infiltration of inflammatory cells, forming dead worm abscesses and early stage of dead worm granuloma. Finally, 35 days posttreatment, only dead male and female worm granuloma were found. Our results provide further evidence of in vivo activity of mefloquine against adult schistosomes.
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PMID:Histopathological changes in adult Schistosoma japonicum harbored in mice treated with a single dose of mefloquine. 1922 97

Mosquito larvae use a digestive strategy that is relatively rare in nature. The anterior half of the larval mosquito midgut has a luminal pH that ranges between 10.5 and 11.5. Most other organisms, both large and small, initiate digestion in an acid medium. The relative uniqueness of the highly alkaline digestive strategy has been a long-standing research focus in larval lepidopterans. More recently, the disease vector potential of mosquitoes has fueled specific interest in larval mosquito biology and the alkaline digestive environment in the midgut. The probable principle anion influencing the highly alkaline gut lumen is bicarbonate/carbonate. Bicarbonate/carbonate is regulated at least in part by the activity of carbonic anhydrases. Hence, we have focused attention on the carbonic anhydrases of the mosquito larva. Anopheles gambiae, the major malaria mosquito of Africa, is an organism with a published genome which has facilitated molecular analyses of the 12 carbonic anhydrase genes annotated for this mosquito. Microarray expression analyses, tissue-specific quantitative RT-PCR, and antibody localization have been used to generate a picture of carbonic anhydrase distribution in the larval mosquito. Cytoplasmic, GPI-linked extracellular membrane-bound and soluble extracellular carbonic anhydrases have been located in the midgut and hindgut. The distribution of the enzymes is consistent with an anion regulatory system in which carbonic anhydrases provide a continuous source of bicarbonate/carbonate from the intracellular compartments of certain epithelial cells to the ectoperitrophic space between the epithelial cells and the acellular membrane separating the food bolus from the gut cells and finally into the gut lumen. Carbonic anhydrase in specialized cells of the hindgut (rectum) probably plays a final role in excretion of bicarbonate/carbonate into the aquatic environment of the larva. Detection and characterization of classic anion exchangers of the SLC4A family in the midgut has been problematic. The distribution of carbonic anhydrases in the system may obviate the requirement for such transporters, making the system more dependent on simple carbon dioxide diffusion and ionization via the activity of the enzyme.
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PMID:Carbonic anhydrases and anion transport in mosquito midgut pH regulation. 1944 76

Extracellular matrices in diverse biological systems are cross-linked by dityrosine covalent bonds catalyzed by the peroxidase/oxidase system. We show that a peroxidase, secreted by the Anopheles gambiae midgut, and dual oxidase form a dityrosine network that decreases gut permeability to immune elicitors. This network protects the microbiota by preventing activation of epithelial immunity. It also provides a suitable environment for malaria parasites to develop within the midgut lumen without inducing nitric oxide synthase expression. Disruption of this barrier results in strong and effective pathogen-specific immune responses.
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PMID:A peroxidase/dual oxidase system modulates midgut epithelial immunity in Anopheles gambiae. 2022 48

A repertoire of monoclonal antibodies (mAbs) was generated against the midgut proteins of Anopheles culicifacies mosquitoes. The mAbs AC-43 and AC-29 significantly inhibited Plasmodium vivax development inside the mosquito midgut. The number of oocysts that developed was reduced by 78.6% when mosquitoes ingested a combination of these two mAbs along with the blood meal. AC-43 mAb binds to the epitope common in 97, 80 and 43 kDa polypeptides from the midgut protein extract, as indicated by western blot analysis. Similarly, the mAb AC-29 recognized 52, 44, 40 and 29 kDa polypeptides. These female midgut-specific polypeptides are shared between An. culicifacies and An. stephensi, two major vectors of malaria in India. Deglycosylation assays revealed that O-linked carbohydrates are the major components in epitopes corresponding to AC-43 and AC-29. Gold particle labelling revealed that both these mAbs preferentially bind to glycoproteins at the apical microvilli and the microvillus-associated network present inside transverse sections of the gut epithelium. These regions are particularly known to have receptors for ookinetes, which enable them to cross this epithelial barrier and provide them with certain necessary chemicals or components for further development into oocysts. Therefore, these glycoproteins appear to be potential candidates for a vector-directed transmission-blocking vaccine (TBV).
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PMID:Monoclonal antibodies AC-43 and AC-29 disrupt Plasmodium vivax development in the Indian malaria vector Anopheles culicifacies (Diptera: Culicidae). 2041 13

Certain cytokines, the prototype being the highly pleiotropic TNF, have many homeostatic physiological roles, are involved in innate immunity, and cause inflammation when in excess. These cytokines have long been accepted to have central roles in the pathogenesis of systemic or local non-cerebral disease states, whether acute or chronic, and whether or not caused by infectious agents. Over the last decade they have also been appreciated to be broadly important in brain physiology. As in other organs, excessive levels in brain are harmful, and its physiological complexity leads to correspondingly complex dysfunction. This review summarizes the burgeoning literature on this topic, and how the functions of these molecules, particularly TNF, are influencing the outlook of researchers on the pathophysiology of these diseases. Basic brain physiology is thus informing knowledge of the brain dysfunction that characterizes such apparently diverse states as Alzheimer's disease, trauma (mostly, but not only, to the brain), Parkinson's disease, and severe systemic infectious states, including malaria, sepsis, viral diseases and major depression. The implication is that the anti-cytokine therapies now in use, typically directed at TNF, warrant testing in these diseases in circumstances in which the therapeutic agent enters the cerebrospinal fluid. Routinely administering such drugs to patients exhibiting the neurological changes discussed in this review would simply add another organ system to what is already a very successful strategy in the treatment of inflammatory disease at other sites, such as joints, skin and gut. Clearly, the most relevant research is focussed on Alzheimer's disease, but the principles may also apply to other encephalopathies.
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PMID:The roles of TNF in brain dysfunction and disease. 2081 31

Mosquito midgut invasion by ookinetes of the malaria parasite Plasmodium disrupts the barriers that normally prevent the gut microbiota from coming in direct contact with epithelial cells. This triggers a long-lived response characterized by increased abundance of granulocytes, a subpopulation of hemocytes that circulates in the insect's hemocoel, and enhanced immunity to bacteria that indirectly reduces survival of Plasmodium parasites upon reinfection. In mosquitoes, differentiation of hemocytes was necessary and sufficient to confer innate immune memory.
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PMID:Hemocyte differentiation mediates innate immune memory in Anopheles gambiae mosquitoes. 2082 87

While symbiosis between bacteria and insects has been thoroughly investigated in the last two decades, investments on the study of yeasts associated with insects have been limited. Insect-associated yeasts are placed on different branches of the phylogenetic tree of fungi, indicating that these associations evolved independently on several occasions. Isolation of yeasts is frequently reported from insect habitats, and in some cases yeasts have been detected in the insect gut and in other organs/tissues. Here we show that the yeast Wickerhamomyces anomalus, previously known as Pichia anomala, is stably associated with the mosquito Anopheles stephensi, a main vector of malaria in Asia. Wickerhamomyces anomalus colonized pre-adult stages (larvae L(1)-L(4) and pupae) and adults of different sex and age and could be isolated in pure culture. By a combination of transmission electron microscopy and fluorescent in situ hybridization techniques, W. anomalus was shown to localize in the midgut and in both the male and female reproductive systems, suggesting multiple transmission patterns.
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PMID:The yeast Wickerhamomyces anomalus (Pichia anomala) inhabits the midgut and reproductive system of the Asian malaria vector Anopheles stephensi. 2120 55

The most deadly of the human malaria parasites, Plasmodium falciparum, has different stages specialized for invasion of hepatocytes, erythrocytes, and the mosquito gut wall. In each case, host cell invasion is powered by an actin-myosin motor complex that is linked to an inner membrane complex (IMC) via a membrane anchor called the glideosome-associated protein 50 (PfGAP50). We generated P. falciparum transfectants expressing green fluorescent protein (GFP) chimeras of PfGAP50 (PfGAP50-GFP). Using immunoprecipitation and fluorescence photobleaching, we show that C-terminally tagged PfGAP50-GFP can form a complex with endogenous copies of the linker protein PfGAP45 and the myosin A tail domain-interacting protein (MTIP). Full-length PfGAP50-GFP is located in the endoplasmic reticulum in early-stage parasites and then redistributes to apical caps during the formation of daughter merozoites. In the final stage of schizogony, the PfGAP50-GFP profile extends further around the merozoite surface. Three-dimensional (3D) structured illumination microscopy reveals the early-stage IMC as a doubly punctured flat ellipsoid that separates to form claw-shaped apposed structures. A GFP fusion of PfGAP50 lacking the C-terminal membrane anchor is misdirected to the parasitophorous vacuole. Replacement of the acid phosphatase homology domain of PfGAP50 with GFP appears to allow correct trafficking of the chimera but confers a growth disadvantage.
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PMID:Tracking Glideosome-associated protein 50 reveals the development and organization of the inner membrane complex of Plasmodium falciparum. 2123 23


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