MicrobiologyBytes

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.

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Cellular movement is key to life and in the case of intracellular parasites, provides a vital mechanism to gain access to the protected niche they require. The parasite Toxoplasma gondii is a model for a group of parasites called apicomplexans, which move by an actin-dependent process referred to as gliding motility. This form of motility is distinct from that used by ciliated or flagellated cells, and from the crawling behavior of amoeba and many mammalian cells.

A new paper demonstrates that the normally highly conserved protein actin is divergent in these parasites and that it displays unusual kinetic properties that result in formation of short unstable filaments, in contrast to the highly stable nature of mammalian actin. The findings reveal that the short dynamic nature of parasite actins is due to a small number of amino acid differences that affect stability of the filament. These properties are essential to normal parasite motility since reversion of these residues to match those seen in mammalian cells was detrimental to gliding movement. The dependence of parasites on rapid turnover of highly unstable actins renders them extremely sensitive to toxins that stabilize actin filaments, thus providing a potential target for development of specific intervention.

Evolutionarily Divergent, Unstable Filamentous Actin Is Essential for Gliding Motility in Apicomplexan Parasites. (2011) PLoS Pathog 7(10): e1002280. doi:10.1371/journal.ppat.1002280
Apicomplexan parasites rely on a novel form of actin-based motility called gliding, which depends on parasite actin polymerization, to migrate through their hosts and invade cells. However, parasite actins are divergent both in sequence and function and only form short, unstable filaments in contrast to the stability of conventional actin filaments. The molecular basis for parasite actin filament instability and its relationship to gliding motility remain unresolved. We demonstrate that recombinant Toxoplasma (TgACTI) and Plasmodium (PfACTI and PfACTII) actins polymerized into very short filaments in vitro but were induced to form long, stable filaments by addition of equimolar levels of phalloidin. Parasite actins contain a conserved phalloidin-binding site as determined by molecular modeling and computational docking, yet vary in several residues that are predicted to impact filament stability. In particular, two residues were identified that form intermolecular contacts between different protomers in conventional actin filaments and these residues showed non-conservative differences in apicomplexan parasites. Substitution of divergent residues found in TgACTI with those from mammalian actin resulted in formation of longer, more stable filaments in vitro. Expression of these stabilized actins in T. gondii increased sensitivity to the actin-stabilizing compound jasplakinolide and disrupted normal gliding motility in the absence of treatment. These results identify the molecular basis for short, dynamic filaments in apicomplexan parasites and demonstrate that inherent instability of parasite actin filaments is a critical adaptation for gliding motility.

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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

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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.

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

• 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.

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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.

Leishmaniasis has been recognized since ancient times and, with at least 50,000 deaths a year due to this parasitic infection, it is certainly of current importance. In this article in Microbiology Today (pdf) Owain Millington asks is there any evidence to suggest that it can be considered as a re-emerging disease?

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Trypanosomes are single-celled parasites that cause sleeping sickness in humans and wasting diseases in livestock. They are transmitted by the tsetse fly and, until now, it was unclear whether they reproduce sexually or asexually, because this stage in their life cycle occurs inside the insect carrier. Sexual reproduction produces offspring that inherit half their genetic material from each parent. The alternative is asexual reproduction, where the offspring inherit all genetic material from a single parent. Sexual reproduction is important in organisms that cause diseases because it can spread genes that make them more virulent, or resistant to drugs used for treatment, as well as creating completely new strains with combinations of genes not previously encountered. Some time ago it was shown that genetic shuffling could occur when two different trypanosome strains were mixed in the tsetse fly, but it was far from clear that this was true sexual reproduction. It was difficult to visualise the process directly because it happened inside the insect. To get round this problem, Professor Wendy Gibson and colleagues used fluorescently tagged proteins to make trypanosomes light up like tiny lightbulbs. They tagged proteins that function only during meiosis, the process of cellular division at the core of sexual reproduction that shuffles the parental genes and deals them out in new combinations to the offspring.

Read more: Caught in the act: trypanosome sex visualised for the first time

Identification of the meiotic life cycle stage of Trypanosoma brucei in the tsetse fly. PNAS USA February 14 2011 doi: 10.1073/pnas.1019423108

Wolbachia pipientis is an intracellular maternally-inherited bacterial symbiont of invertebrates that is very common in insects, including a number of mosquito species. It can manipulate host reproduction in several ways, including cytoplasmic incompatibility, whereby certain crosses are rendered effectively sterile. Females that are uninfected produce infertile eggs when they mate with males that carry Wolbachia, while there is a “rescue” effect in Wolbachia-infected embryos such that infected females can reproduce successfully with any males. Therefore uninfected females suffer a frequency-dependent reproductive disadvantage. Wolbachia is able to rapidly invade populations using this powerful mechanism

Malaria is one of the world’s most devastating diseases, particularly in Africa, and new control strategies are desperately needed. Here we show that the presence of Wolbachia bacteria inhibits the development of a malaria parasite in the most important Anopheles mosquito species of Africa. In addition it shows that the presence of Wolbachia results in the switching on of immune genes that are known to affect development of many species of malaria parasite. When added to the lifespan-shortening effects of this particular strain of Wolbachia, and the general ability of Wolbachia to spread through insect populations, this study provides a stimulus for the development of Wolbachia-based malaria control methods. It also provides new insights into the wide range of effects of Wolbachia in insects.

Wolbachia Stimulates Immune Gene Expression and Inhibits Plasmodium Development in Anopheles gambiae. (2010) PLoS Pathog 6(10): e1001143. doi:10.1371/journal.ppat.1001143
The over-replicating wMelPop strain of the endosymbiont Wolbachia pipientis has recently been shown to be capable of inducing immune upregulation and inhibition of pathogen transmission in Aedes aegypti mosquitoes. In order to examine whether comparable effects would be seen in the malaria vector Anopheles gambiae, transient somatic infections of wMelPop were created by intrathoracic inoculation. Upregulation of six selected immune genes was observed compared to controls, at least two of which (LRIM1 and TEP1) influence the development of malaria parasites. A stably infected An. gambiae cell line also showed increased expression of malaria-related immune genes. Highly significant reductions in Plasmodium infection intensity were observed in the wMelPop-infected cohort, and using gene knockdown, evidence for the role of TEP1 in this phenotype was obtained. Comparing the levels of upregulation in somatic and stably inherited wMelPop infections in Ae. aegypti revealed that levels of upregulation were lower in the somatic infections than in the stably transinfected line; inhibition of development of Brugia filarial nematodes was nevertheless observed in the somatic wMelPop infected females. Thus we consider that the effects observed in An. gambiae are also likely to be more pronounced if stably inherited wMelPop transinfections can be created, and that somatic infections of Wolbachia provide a useful model for examining effects on pathogen development or dissemination. The data are discussed with respect to the comparative effects on malaria vectorial capacity of life shortening and direct inhibition of Plasmodium development that can be produced by Wolbachia.

Related:

• Wolbachia
• Wolbachia could combat dengue fever
• Bacterial sequences in invertebrate genomes