Variant Surface Glycoprotein gene repertoires in Trypanosoma brucei have diverged to become strain-specific

Background: In a mammalian host, the cell surface of African trypanosomes is protected by a monolayer of a single variant surface glycoprotein (VSG). The VSG is central to antigenic variation; one VSG gene is expressed at any one time and there is a low frequency stochastic switch to expression of a different VSG gene. The genome of Trypanosoma brucei contains a repertoire of > 1000 VSG sequences. The degree of conservation of the genomic VSG repertoire in different strains has not been investigated in detail.|Results: Eighteen expressed VSGs from Ugandan isolates were compared with homologues (> 40 % sequence identity) in the two available T. brucei genome sequences. Fourteen homologues were present in the genome of Trypanosoma brucei brucei TREU927 from Kenya and fourteen in the genome of T. b. gambiense Dal972 from Cote d'Ivoire. The Ugandan VSGs averaged 71% and 73 % identity to homologues in T. b. brucei and T. b. gambiense respectively. The sequence divergence between homologous VSGs from the three different strains was not random but was more prevalent in the parts of the VSG believed to interact with the host immune system on the living trypanosome.|Conclusion: It is probable that the VSG repertoires in the different isolates contain many common VSG genes. The location of divergence between VSGs is consistent with selection for strain-specific VSG repertoires, possibly to allow superinfection of an animal by a second strain. A consequence of strain-specific VSG repertoires is that any vaccine based on large numbers of VSGs from a single strain will only provide partial protection against other strains

Patterns in Age-Seroprevalence Consistent with Acquired Immunity against Trypanosoma brucei in Serengeti Lions

Trypanosomes cause disease in humans and livestock throughout sub-Saharan Africa. Although various species show evidence of clinical tolerance to trypanosomes, until now there has been no evidence of acquired immunity to natural infections. We discovered a distinct peak and decrease in age prevalence of T. brucei s.l. infection in wild African lions that is consistent with being driven by an exposure-dependent increase in cross-immunity following infections with the more genetically diverse species, T. congolense sensu latu. The causative agent of human sleeping sickness, T. brucei rhodesiense, disappears by 6 years of age apparently in response to cross-immunity from other trypanosomes, including the non-pathogenic subspecies, T. brucei brucei. These findings may suggest novel pathways for vaccinations against trypanosomiasis despite the notoriously complex antigenic surface proteins in these parasites

Patterns in Age-Seroprevalence Consistent with Acquired Immunity against Trypanosoma brucei in Serengeti Lions

Trypanosomes cause disease in humans and livestock throughout sub-Saharan Africa. Although various species show evidence of clinical tolerance to trypanosomes, until now there has been no evidence of acquired immunity to natural infections. We discovered a distinct peak and decrease in age prevalence of T. brucei s.l. infection in wild African lions that is consistent with being driven by an exposure-dependent increase in cross-immunity following infections with the more genetically diverse species, T. congolense sensu latu. The causative agent of human sleeping sickness, T. brucei rhodesiense, disappears by 6 years of age apparently in response to cross-immunity from other trypanosomes, including the non-pathogenic subspecies, T. brucei brucei. These findings may suggest novel pathways for vaccinations against trypanosomiasis despite the notoriously complex antigenic surface proteins in these parasites

The genome sequence of <i>Trypanosoma brucei gambiense</i>, causative agent of chronic Human African Trypanosomiasis

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; &lt;i&gt;Trypanosoma brucei gambiense&lt;/i&gt; is the causative agent of chronic Human African Trypanosomiasis or sleeping sickness, a disease endemic across often poor and rural areas of Western and Central Africa. We have previously published the genome sequence of a &lt;i&gt;T. b. brucei&lt;/i&gt; isolate, and have now employed a comparative genomics approach to understand the scale of genomic variation between &lt;i&gt;T. b. gambiense&lt;/i&gt; and the reference genome. We sought to identify features that were uniquely associated with &lt;i&gt;T. b. gambiense&lt;/i&gt; and its ability to infect humans.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods and findings:&lt;/b&gt; An improved high-quality draft genome sequence for the group 1 &lt;i&gt;T. b. gambiense&lt;/i&gt; DAL 972 isolate was produced using a whole-genome shotgun strategy. Comparison with &lt;i&gt;T. b. brucei&lt;/i&gt; showed that sequence identity averages 99.2% in coding regions, and gene order is largely collinear. However, variation associated with segmental duplications and tandem gene arrays suggests some reduction of functional repertoire in &lt;i&gt;T. b. gambiense&lt;/i&gt; DAL 972. A comparison of the variant surface glycoproteins (VSG) in &lt;i&gt;T. b. brucei&lt;/i&gt; with all &lt;i&gt;T. b. gambiense&lt;/i&gt; sequence reads showed that the essential structural repertoire of VSG domains is conserved across &lt;i&gt;T. brucei&lt;/i&gt;.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; This study provides the first estimate of intraspecific genomic variation within &lt;i&gt;T. brucei&lt;/i&gt;, and so has important consequences for future population genomics studies. We have shown that the &lt;i&gt;T. b. gambiense&lt;/i&gt; genome corresponds closely with the reference, which should therefore be an effective scaffold for any &lt;i&gt;T. brucei&lt;/i&gt; genome sequence data. As VSG repertoire is also well conserved, it may be feasible to describe the total diversity of variant antigens. While we describe several as yet uncharacterized gene families with predicted cell surface roles that were expanded in number in &lt;i&gt;T. b. brucei&lt;/i&gt;, no &lt;i&gt;T. b. gambiense&lt;/i&gt;-specific gene was identified outside of the subtelomeres that could explain the ability to infect humans.&lt;/p&gt

Wave interaction with defects in pressurised composite structures

There exists a great variety of structural failure modes which must be frequently inspected to ensure continuous structural integrity of composite structures. This work presents a Finite Element (FE) based method for calculating wave interaction with damage within structures of arbitrary layering and geometric complexity. The principal novelty is the investigation of pre-stress effect on wave propagation and scattering in layered structures. A Wave Finite Element (WFE) method, which combines FE analysis with periodic structure theory (PST), is used to predict the wave propagation properties along periodic waveguides of the structural system. This is then coupled to the full FE model of a coupling joint within which structural damage is modelled, in order to quantify wave interaction coeffcients through the joint. Pre-stress impact is quantified by comparison of results under pressurised and non-pressurised scenarios. The results show that including these pressurisation effects in calculations is essential. This is of specific relevance to aircraft structures being intensely pressurised while on air. Numerical case studies are exhibited for different forms of damage type. The exhibited results are validated against available analytical and experimental results

Identification of Trypanosome Proteins in Plasma from African Sleeping Sickness Patients Infected with T. b. rhodesiense

Control of human African sleeping sickness, caused by subspecies of the protozoan parasite Trypanosoma brucei, is based on preventing transmission by elimination of the tsetse vector and by active diagnostic screening and treatment of infected patients. To identify trypanosome proteins that have potential as biomarkers for detection and monitoring of African sleeping sickness, we have used a ‘deep-mining” proteomics approach to identify trypanosome proteins in human plasma. Abundant human plasma proteins were removed by immunodepletion. Depleted plasma samples were then digested to peptides with trypsin, fractionated by basic reversed phase and each fraction analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This sample processing and analysis method enabled identification of low levels of trypanosome proteins in pooled plasma from late stage sleeping sickness patients infected with Trypanosoma brucei rhodesiense. A total of 254 trypanosome proteins were confidently identified. Many of the parasite proteins identified were of unknown function, although metabolic enzymes, chaperones, proteases and ubiquitin-related/acting proteins were found. This approach to the identification of conserved, soluble trypanosome proteins in human plasma offers a possible route to improved disease diagnosis and monitoring, since these molecules are potential biomarkers for the development of a new generation of antigen-detection assays. The combined immuno-depletion/mass spectrometric approach can be applied to a variety of infectious diseases for unbiased biomarker identification

Humans and Insects Decide in Similar Ways

Behavioral ecologists assume that animals use a motivational mechanism for decisions such as action selection and time allocation, allowing the maximization of their fitness. They consider both the proximate and ultimate causes of behavior in order to understand this type of decision-making in animals. Experimental psychologists and neuroeconomists also study how agents make decisions but they consider the proximate causes of the behavior. In the case of patch-leaving, motivation-based decision-making remains simple speculation. In contrast to other animals, human beings can assess and evaluate their own motivation by an introspection process. It is then possible to study the declared motivation of humans during decision-making and discuss the mechanism used as well as its evolutionary significance. In this study, we combine both the proximate and ultimate causes of behavior for a better understanding of the human decision-making process. We show for the first time ever that human subjects use a motivational mechanism similar to small insects such as parasitoids [1] and bumblebees [2] to decide when to leave a patch. This result is relevant for behavioral ecologists as it supports the biological realism of this mechanism. Humans seem to use a motivational mechanism of decision making known to be adaptive to a heterogeneously distributed resource. As hypothesized by Hutchinson et al. [3] and Wilke and Todd [4], our results are consistent with the evolutionary shaping of decision making because hominoids were hunters and gatherers on food patches for more than two million years. We discuss the plausibility of a neural basis for the motivation mechanism highlighted here, bridging the gap between behavioral ecology and neuroeconomy. Thus, both the motivational mechanism observed here and the neuroeconomy findings are most likely adaptations that were selected for during ancestral times

The Origin of Intraspecific Variation of Virulence in an Eukaryotic Immune Suppressive Parasite

Occurrence of intraspecific variation in parasite virulence, a prerequisite for coevolution of hosts and parasites, has largely been reported. However, surprisingly little is known of the molecular bases of this variation in eukaryotic parasites, with the exception of the antigenic variation used by immune-evading parasites of mammals. The present work aims to address this question in immune suppressive eukaryotic parasites. In Leptopilina boulardi, a parasitic wasp of Drosophila melanogaster, well-defined virulent and avirulent strains have been characterized. The success of virulent females is due to a major immune suppressive factor, LbGAP, a RacGAP protein present in the venom and injected into the host at oviposition. Here, we show that an homologous protein, named LbGAPy, is present in the venom of the avirulent strain. We then question whether the difference in virulence between strains originates from qualitative or quantitative differences in LbGAP and LbGAPy proteins. Results show that the recombinant LbGAPy protein has an in vitro GAP activity equivalent to that of recombinant LbGAP and similarly targets Drosophila Rac1 and Rac2 GTPases. In contrast, a much higher level of both mRNA and protein is found in venom-producing tissues of virulent parasitoids. The F1 offspring between virulent and avirulent strains show an intermediate level of LbGAP in their venom but a full success of parasitism. Interestingly, they express almost exclusively the virulent LbGAP allele in venom-producing tissues. Altogether, our results demonstrate that the major virulence factor in the wasp L. boulardi differs only quantitatively between virulent and avirulent strains, and suggest the existence of a threshold effect of this molecule on parasitoid virulence. We propose that regulation of gene expression might be a major mechanism at the origin of intraspecific variation of virulence in immune suppressive eukaryotic parasites. Understanding this variation would improve our knowledge of the mechanisms of transcriptional evolution currently under active investigation

Civil conflict and sleeping sickness in Africa in general and Uganda in particular

Conflict and war have long been recognized as determinants of infectious disease risk. Re-emergence of epidemic sleeping sickness in sub-Saharan Africa since the 1970s has coincided with extensive civil conflict in affected regions. Sleeping sickness incidence has placed increasing pressure on the health resources of countries already burdened by malaria, HIV/AIDS, and tuberculosis. In areas of Sudan, the Democratic Republic of the Congo, and Angola, sleeping sickness occurs in epidemic proportions, and is the first or second greatest cause of mortality in some areas, ahead of HIV/AIDS. In Uganda, there is evidence of increasing spread and establishment of new foci in central districts. Conflict is an important determinant of sleeping sickness outbreaks, and has contributed to disease resurgence. This paper presents a review and characterization of the processes by which conflict has contributed to the occurrence of sleeping sickness in Africa. Conflict contributes to disease risk by affecting the transmission potential of sleeping sickness via economic impacts, degradation of health systems and services, internal displacement of populations, regional insecurity, and reduced access for humanitarian support. Particular focus is given to the case of sleeping sickness in south-eastern Uganda, where incidence increase is expected to continue. Disease intervention is constrained in regions with high insecurity; in these areas, political stabilization, localized deployment of health resources, increased administrative integration and national capacity are required to mitigate incidence. Conflict-related variables should be explicitly integrated into risk mapping and prioritization of targeted sleeping sickness research and mitigation initiatives

Polyandry Is a Common Event in Wild Populations of the Tsetse Fly Glossina fuscipes fuscipes and May Impact Population Reduction Measures

Glossina fuscipes fuscipes is the most common tsetse species in Uganda where it is responsible for transmitting Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense parasites causing sleeping sickness in humans in addition to related trypanosomes that cause Nagana in cattle. An understanding of the reproductive biology of this vector is essential for the application of sustainable control/eradication methods such as Sterile Insect Technique (SIT). We have analysed the number of times a female mates in the wild as this aspect of the reproductive behaviour may affect the stability and size of populations. We provide evidence that remating is a common event in the wild and females store sperm from multiple males, which may potentially be used for insemination. In vector eradication programmes, re-infestation of cleared areas and/or in cases of residual populations, the occurrence of remating may unfortunately enhance the reproductive potential of the re-invading propagules. We suggest that population age structure may influence remating frequency. Considering the seasonal demographic changes that this fly undergoes during the dry and wet seasons, control programmes based on SIT should release large numbers of sterile males, even in residual surviving target populations, in the dry season