Posts Tagged ‘Malaria’

Malaria infected mosquitoes are more attracted to human odor

Thursday, May 16th, 2013

Mosquito Mosquitoes infected with the malaria parasite Plasmodium falciparum are significantly more attracted to human odors than uninfected mosquitoes.

Researchers investigated the response of mosquitoes infected with P. falciparum malaria parasites and uninfected to human odor collected on fabric. Mosquitoes that were infected with the parasites landed and probed significantly more than uninfected mosquitoes in response to the odor. Previous research has already shown that the malarial parasite can alter mosquito behavior in ways that increase the rate of malaria transmission. For example, malaria-infected mosquitoes also consume larger, more frequent blood meals than their uninfected counterparts.

Studies of mosquito behavior in the context of malaria transmission usually use uninfected mosquito subjects. This study suggests that such behavioral studies may not always be representative of the behavior of infected mosquitoes. They conclude that understanding the olfactory changes underlying the behavior of these infected mosquitoes may help identify new compounds that could be used to develop mosquito traps for surveillance programs.

 

Malaria Infected Mosquitoes Express Enhanced Attraction to Human Odor. (2013) PLoS ONE 8(5): e63602. doi:10.1371/journal.pone.0063602
There is much evidence that some pathogens manipulate the behaviour of their mosquito hosts to enhance pathogen transmission. However, it is unknown whether this phenomenon exists in the interaction of Anopheles gambiae sensu stricto with the malaria parasite, Plasmodium falciparum – one of the most important interactions in the context of humanity, with malaria causing over 200 million human cases and over 770 thousand deaths each year. Here we demonstrate, for the first time, that infection with P. falciparum causes alterations in behavioural responses to host-derived olfactory stimuli in host- seeking female An. gambiae s.s. mosquitoes. In behavioural experiments we showed that P. falciparum-infected An. gambiae mosquitoes were significantly more attracted to human odors than uninfected mosquitoes. Both P. falciparum-infected and uninfected mosquitoes landed significantly more on a substrate emanating human skin odor compared to a clean substrate. However, significantly more infected mosquitoes landed and probed on a substrate emanating human skin odor than uninfected mosquitoes. This is the first demonstration of a change of An. gambiae behaviour in response to olfactory stimuli caused by infection with P. falciparum. The results of our study provide vital information that could be used to provide better predictions of how malaria is transmitted from human being to human being by An. gambiae s.s. females. Additionally, it highlights the urgent need to investigate this interaction further to determine the olfactory mechanisms that underlie the differential behavioural responses. In doing so, new attractive compounds could be identified which could be used to develop improved mosquito traps for surveillance or trapping programmes that may even specifically target P. falciparum-infected An. gambiae s.s. females.

 

Forcing your way in

Wednesday, December 12th, 2012

Apicomplexan Invasion Malaria, toxoplasmosis, and related diseases are caused by infection with unicellular parasites called Apicomplexa. Their name refers to the elaborate invasion machinery that occupies the apical end of the parasite cell. This apparatus allows the parasite to force its way into the cells of its host, and to deliver factors that will manipulate host cell structure, gene expression, and metabolism. Once in the host cell the parasite will begin to grow. The parasite replicates its genome and organelles numerous times and then loads these various elements into numerous daughter cells that will further spread the infection.

This paper describes a fibre that coordinates the daughter cell budding process. The fibre links the centrosome, which controls the mitotic spindle, and the genome with the microtubule organizing center of the budding daughter. Parasite mutants lacking the proteins that build the fiber fail to form daughter cells at the earliest step. The fiber and its components are remarkably similar to fibers that coordinate flagella in algae. While Apicomplexa are not flagelated (with the exception of certain gamete stages) they evolved from flagellated algae. The authors propose that elements of the invasion apparatus evolved from the flagellum or flagellum associated structures.

 

Cell Division in Apicomplexan Parasites Is Organized by a Homolog of the Striated Rootlet Fiber of Algal Flagella. (2012) PLoS Biol 10(12): e1001444. doi:10.1371/journal.pbio.1001444
Apicomplexa are intracellular parasites that cause important human diseases including malaria and toxoplasmosis. During host cell infection new parasites are formed through a budding process that parcels out nuclei and organelles into multiple daughters. Budding is remarkably flexible in output and can produce two to thousands of progeny cells. How genomes and daughters are counted and coordinated is unknown. Apicomplexa evolved from single celled flagellated algae, but with the exception of the gametes, lack flagella. Here we demonstrate that a structure that in the algal ancestor served as the rootlet of the flagellar basal bodies is required for parasite cell division. Parasite striated fiber assemblins (SFA) polymerize into a dynamic fiber that emerges from the centrosomes immediately after their duplication. The fiber grows in a polarized fashion and daughter cells form at its distal tip. As the daughter cell is further elaborated it remains physically tethered at its apical end, the conoid and polar ring. Genetic experiments in Toxoplasma gondii demonstrate two essential components of the fiber, TgSFA2 and 3. In the absence of either of these proteins cytokinesis is blocked at its earliest point, the initiation of the daughter microtubule organizing center (MTOC). Mitosis remains unimpeded and mutant cells accumulate numerous nuclei but fail to form daughter cells. The SFA fiber provides a robust spatial and temporal organizer of parasite cell division, a process that appears hard-wired to the centrosome by multiple tethers. Our findings have broader evolutionary implications. We propose that Apicomplexa abandoned flagella for most stages yet retained the organizing principle of the flagellar MTOC. Instead of ensuring appropriate numbers of flagella, the system now positions the apical invasion complexes. This suggests that elements of the invasion apparatus may be derived from flagella or flagellum associated structures.

How the malaria parasite eats lunch

Wednesday, June 20th, 2012

The food vacuole of Plasmodium falciparum The parasite Plasmodium falciparum is the causative agent of severe malaria in humans, killing somewhere between 600,000 and 1.2 million people each year. The complex life cycle includes an asexual proliferation within human erythrocytes, characterised by three distinct stages: rings, trophozoites and schizonts. Adaptations to the intra-erythrocytic lifestyle have created new and in some cases unique organelles, such as an endosomal/lysosomal-like organelle, the food vacuole. Haemoglobin degradation during the erythrocytic life stages is the major function of the food vacuole (FV) of Plasmodium falciparum and the target of several anti-malarial drugs that interfere with this metabolic pathway, killing the parasite. Two multi-spanning food vacuole membrane proteins are known, the multidrug resistance protein 1 (PfMDR1) and Chloroquine Resistance Transporter (PfCRT). Both modulate resistance to drugs that act in the food vacuole.

To investigate the formation and behaviour of the food vacuole membrane researchers generated inducible GFP fusions of chloroquine sensitive and resistant forms of the PfCRT protein. This inducible expression system them to follow newly-induced fusion proteins, and corroborated a previous report of a direct trafficking route from the ER/Golgi to the food vacuole membrane. These parasites also allowed the definition of a food vacuole compartment in ring stage parasites well before haemozoin crystals were apparent, as well as the elucidation of secondary PfCRT-labelled compartments adjacent to the food vacuole in late stage parasites.

In addition to previously demonstrated Brefeldin A sensitivity, the trafficking of PfCRT is disrupted by Dynasore, a non competitive inhibitor of dynamin-mediated vesicle formation. Chloroquine sensitivity was not altered in parasites over-expressing chloroquine resistant or sensitive forms of the PfCRT fused to GFP, suggesting that the PfCRT does not mediate chloroquine transport as a GFP fusion protein.

 

Investigation of the Plasmodium falciparum Food Vacuole through Inducible Expression of the Chloroquine Resistance Transporter (PfCRT). (2012) PLoS ONE 7(6): e38781. doi:10.1371/journal.pone.0038781

Effect of antimalarial drugs on the parasite life cycle

Thursday, February 23rd, 2012

Antimalarial drugs A paper in this week’s PLoS Medicine compares the activity of 50 current and experimental antimalarials against liver, sexual blood, and mosquito stages of selected human and nonhuman parasite species, including Plasmodium falciparum, Plasmodium berghei and Plasmodium yoelii. These results provide a valuable guide to help researchers decide which drugs and compounds show most promise as potential future antimalarial drugs for blocking the transmission of malaria.

 

The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium Life Cycle: A Comparative Study with Human and Rodent Parasites. (2012) PLoS Med 9(2): e1001169. doi:10.1371/journal.pmed.1001169
Background: Malaria remains a disease of devastating global impact, killing more than 800,000 people every year—the vast majority being children under the age of 5. While effective therapies are available, if malaria is to be eradicated a broader range of small molecule therapeutics that are able to target the liver and the transmissible sexual stages are required. These new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance.
Methods and Findings: Little is known about the wider stage-specific activities of current antimalarials that were primarily designed to alleviate symptoms of malaria in the blood stage. To overcome this critical gap, we developed assays to measure activity of antimalarials against all life stages of malaria parasites, using a diverse set of human and nonhuman parasite species, including male gamete production (exflagellation) in Plasmodium falciparum, ookinete development in P. berghei, oocyst development in P. berghei and P. falciparum, and the liver stage of P. yoelii. We then compared 50 current and experimental antimalarials in these assays. We show that endoperoxides such as OZ439, a stable synthetic molecule currently in clinical phase IIa trials, are strong inhibitors of gametocyte maturation/gamete formation and impact sporogony; lumefantrine impairs development in the vector; and NPC-1161B, a new 8-aminoquinoline, inhibits sporogony.
Conclusions: These data enable objective comparisons of the strengths and weaknesses of each chemical class at targeting each stage of the lifecycle. Noting that the activities of many compounds lie within achievable blood concentrations, these results offer an invaluable guide to decisions regarding which drugs to combine in the next-generation of antimalarial drugs. This study might reveal the potential of life-cycle–wide analyses of drugs for other pathogens with complex life cycles.

Social parasites

Wednesday, November 2nd, 2011

Trypanosoma brucei Social behaviors are most widely recognized in communication and cooperation observed in metazoans, ranging from navigation strategies and group hierarchies in insect communities to complex social networking in humans and other primates. However, communication and cooperation among individuals in a group also occurs at the cellular level, as illustrated in collective motility of migrating cells during wound healing, tissue morphogenesis and tumor metastases. Cell-cell communication and cooperative behavior is not restricted to higher animals and recent years have seen a surge in the study and understanding of social interactions and their underlying mechanisms in microbial systems.

Parasitic protozoa are etiologic agents of several major human maladies, including malaria, epidemic dysentery, Leishmaniasis and African sleeping sickness, that affect over half a billion people worldwide. Parasites also limit economic development in some of the poorest regions on the planet and are thus major contributors to the global human health and economic burden. Parasites have complex life cycles requiring transmission through multiple hosts, survival in diverse environments and a wide variety of cellular differentiation events. Hence there are numerous facets of parasite biology that may benefit from, or may even depend upon, social interactions. This review highlights recent work on social behavior in two well-studied parasites, Trypanosoma brucei that causes sleeping sickness and Plasmodium parasites that cause malaria. In addition to uncovering underappreciated aspects of parasite biology, these studies illustrate the potential for sociomicrobiology concepts to advance understanding of the biology, transmission and pathogenesis of parasitic protozoa.

 

Social parasites. Curr Opin Microbiol. Oct 21 2011
Protozoan parasites cause tremendous human suffering worldwide, but strategies for therapeutic intervention are limited. Recent studies illustrate that the paradigm of microbes as social organisms can be brought to bear on questions about parasite biology, transmission and pathogenesis. This review discusses recent work demonstrating adaptation of social behaviors by parasitic protozoa that cause African sleeping sickness and malaria. The recognition of social behavior and cell-cell communication as a ubiquitous property of bacteria has transformed our view of microbiology, but protozoan parasites have not generally been considered in this context. Works discussed illustrate the potential for concepts of sociomicrobiology to provide insight into parasite biology and should stimulate new approaches for thinking about parasites and parasite-host interactions.

What do human parasites do with a chloroplast?

Friday, September 30th, 2011

Plasmodium apicoplast Apicomplexans are an important group of pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. These single-celled eukaryotic parasites evolved from photosynthetic algae. A remnant chloroplast, called the apicoplast, is a hold-over from this more benign past in the ocean. The apicoplast is essential for parasite growth and development and therefore a potential target for drug therapy. The fact that humans and animals lack chloroplasts suggests that using approaches to target the apicoplast may provide parasite specificity. What are the critical functions of the apicoplast that should be targeted? In addition to the obvious medical relevance this question has broader biological implications. Why do organisms maintain an ancient symbiotic relationship when the initial rationale for this relationship has fallen by the evolutionary wayside?

A new study provides important clues. It demonstrates that antibiotic-induced loss of the apicoplast in cultured malaria parasites can be chemically rescued by providing isopentenyl-pyrophosphate (IPP) in the medium. IPP is generated by the apicoplast resident isoprenoid biosynthesis pathway and is apparently the one apicoplast metabolite that the parasite cannot live without in the red blood cell. This finding could be of great importance for the development of drugs and vaccines. The ability to produce and maintain parasite lines that lack the apicoplast also offers exciting experimental possibilities for the future.

 

What Do Human Parasites Do with a Chloroplast Anyway? (2011) PLoS Biol 9(8): e1001137. doi:10.1371/journal.pbio.1001137

The Next Opportunity for Anti-Malaria Drugs: The Liver

Monday, September 26th, 2011

Malaria life cycle Humans have suffered from the burden of malarial infections for thousands of years, and the disease has greatly influenced human evolution and history. Malaria remains a devastating disease, and in developing countries within Africa, South America, and Asia, the size of its burden has stifled economic growth and development. Despite successful eradication campaigns in North America and Europe, global cases of the disease show little decline, and current improvements rely on pyrethroid treated bed nets and combination therapeutics containing artemisinin derivatives, both of which are susceptible to emerging resistance. Our ability to counter these vulnerabilities with new agents is hampered by the modest number of fully validated drug targets and our limited understanding of many aspects of parasite biology.

 

The Next Opportunity in Anti-Malaria Drug Discovery: The Liver Stage. (2011) PLoS Pathog 7(9): e1002178. doi:10.1371/journal.ppat.1002178
Malaria afflicts 350–500 million people annually, and this debilitating and deadly infectious disease exacts a heavy toll on susceptible populations around the globe. Efforts to find effective, safe, and low-cost drugs for malaria have sharply increased in recent years. Almost all of these efforts have focused on the cyclic blood stage of the disease, partly because the parasites can be easily maintained in culture through addition of human red blood cells to the growth medium, and partly because blood stage infection causes malaria’s characteristic symptoms. However, the asymptomatic liver stage, which the parasite goes through only once in its life history, presents the best opportunity for developing drugs that both hit new targets and also could be used in highly desirable eradication campaigns. Recent research, especially on the frequency of differentially expressed genes in blood and liver stage parasites, supports the feasibility of discovering stage-specific drugs. Discovering these drugs will require a high-throughput liver stage phenotypic screen comparable to the existing blood stage screens, and the basic tools for such a screen have recently been created.

Off on your hols soon?

Monday, June 6th, 2011

Going somewhere exotic? If you are, make sure to look at the Malaria Hotspots website, full of essential information for travellers:

Malaria Hotspots

  • Between 1990-2009, every year approximately 1,800 British travellers return home with malaria. The UK is one of the biggest importers of malaria in Europe.
  • The most severe form of malaria (Plasmodium falciparum) accounted for 79% of cases amongst British travellers in 2009.
  • Malaria is a preventable infection but can be fatal if left untreated – an average of nine people die each year from malaria in the UK.
  • Malaria is transmitted by infected mosquitos. It only takes one bite from an infected mosquito to contract malaria.

The Malaria Hotspots website is an educational initiative organised and funded by GlaxoSmithKline Travel Health.

This week’s Wednesday Wolbachia

Wednesday, May 25th, 2011

Mosquito Bacterial associates are ubiquitous among insects, including mosquitoes. Wolbachia are obligate endosymbiotic bacteria that infect numerous insects, many of which are vectors of pathogenic microorganisms. Interest has centered around Wolbachia as a means of reducing arthropod-borne disease due to the capacity of the bacteria to manipulate the reproduction of the insect host, which in turn favors their own transmission.

Recent studies show that Wolbachia can directly cause pathogen interference (PI) in their invertebrate hosts, whereby infected insects are less susceptible to pathogens. Infection with Wolbachia bacteria has been shown to reduce pathogen levels in multiple mosquito species. Anopheles mosquitoes (the obligate vectors of human malaria) are naturally uninfected with Wolbachia, and stable artificial infections have not yet succeeded in this genus; however somatic infections can be established that can be used to assess the effect of Wolbachia infection in Anopheles. Here, we show that infection with two different Wolbachia strains can significantly reduce levels of the human malaria parasite Plasmodium falciparum in Anopheles gambiae. After infection, Wolbachia disseminate throughout the mosquito but are notably absent from the gut and ovaries. The mosquito immune system is first induced in response to Wolbachia infection, but is then suppressed as the infection progresses. The Wolbachia strain wMelPop is highly virulent to Anopheles only after blood feeding. If stable infections can be established in Anopheles, and they act in a similar manner to somatic infections, Wolbachia could potentially be used as part of a strategy to control malaria.

 

Wolbachia Infections Are Virulent and Inhibit the Human Malaria Parasite Plasmodium Falciparum in Anopheles Gambiae. 2011 PLoS Pathog 7(5): e1002043. doi:10.1371/journal.ppat.1002043
Endosymbiotic Wolbachia bacteria are potent modulators of pathogen infection and transmission in multiple naturally and artificially infected insect species, including important vectors of human pathogens. Anopheles mosquitoes are naturally uninfected with Wolbachia, and stable artificial infections have not yet succeeded in this genus. Recent techniques have enabled establishment of somatic Wolbachia infections in Anopheles. Here, we characterize somatic infections of two diverse Wolbachia strains (wMelPop and wAlbB) in Anopheles gambiae, the major vector of human malaria. After infection, wMelPop disseminates widely in the mosquito, infecting the fat body, head, sensory organs and other tissues but is notably absent from the midgut and ovaries. Wolbachia initially induces the mosquito immune system, coincident with initial clearing of the infection, but then suppresses expression of immune genes, coincident with Wolbachia replication in the mosquito. Both wMelPop and wAlbB significantly inhibit Plasmodium falciparum oocyst levels in the mosquito midgut. Although not virulent in non-bloodfed mosquitoes, wMelPop exhibits a novel phenotype and is extremely virulent for approximately 12–24 hours post-bloodmeal, after which surviving mosquitoes exhibit similar mortality trajectories to control mosquitoes. The data suggest that if stable transinfections act in a similar manner to somatic infections, Wolbachia could potentially be used as part of a strategy to control the Anopheles mosquitoes that transmit malaria.