PLoS Neglected Tropical Diseases: New Articles

Genetic Characterization of Venezuelan Equine Encephalitis Virus from Bolivia, Ecuador and Peru: Identification of a New Subtype ID Lineage

2009-09-15T07:00:00Z

Author Summary

Venezuelan equine encephalitis virus (VEEV) has been responsible for hundreds of thousands of human and equine cases of severe disease in the Americas. In 2005–2007, cases of Venezuelan equine encephalitis (VEE) were diagnosed for the first time in residents of Bolivia; the patients did not report traveling, suggesting endemic circulation of VEEV in Bolivia. In 2001 and 2003, VEE cases were also identified in Ecuador. We characterize recent VEEV from Bolivia, Ecuador and Peru and compared their relationships to strains from other parts of South America. We found that most VEEV from Peru grouped within a particular genetic lineage known to circulate in Panama and Peru whereas the VEEV circulating in Ecuador belong to a genetic lineage that circulates in Colombia and Venezuela. Importantly, the VEEV from Madre de Dios, Peru and Cochabamba, Bolivia belong to a new genetic lineage. This finding could aid in the understanding of the emergence and evolution of VEEV in South America and underscores the need for continuous monitoring for VEEV activity.

Wolbachia Infection Reduces Blood-Feeding Success in the Dengue Fever Mosquito, Aedes aegypti

2009-09-15T07:00:00Z

Author Summary

The primary mosquito vector of dengue virus, Aedes aegypti, has recently been artificially infected with a symbiotic bacterium called Wolbachia pipientis. This bacterium occurs naturally inside the cells of ~66% of insect species. The Wolbachia used to infect A. aegypti shortens the insect's lifespan. Because only old mosquitoes are capable of transmitting dengue virus, the Wolbachia infection could theoretically reduce dengue virus transmission if infected mosquitoes were released into the wild. Here we have examined the effects of this Wolbachia infection on the mosquito's ability to obtain blood meals from human hosts. Blood is required for females to produce eggs, and so successful completion of this behaviour is necessary if Wolbachia-infected mosquitoes are to be competitive in the wild. Blood feeding on humans is also the time when viruses like dengue are transmitted, so changes in this behaviour can have consequences for the transmission rate of viruses. We show that Wolbachia-infected mosquitoes are less able to obtain blood meals, but only in old age. The reduced feeding success may be explained by a defect in the insect's proboscis. The finding is exciting as it may allow young mosquitoes to breed as normal but help reduce the lifespan and success of old mosquitoes, which are the primary transmitters of virus.

Polyparasite Helminth Infections and Their Association to Anaemia and Undernutrition in Northern Rwanda

2009-09-15T07:00:00Z

Author Summary

The helminth infections—schistosomiasis, hookworm, ascariasis and trichuriasis—are the main neglected tropical diseases (NTDs) to thrive in sub-Saharan Africa. Here we assess the distribution and the intensities of such polyparasite infections in two districts of the Northern Province in Rwanda and determine whether these are associated with anaemia, lowered haemoglobin levels and recent and/or chronic undernutrition. Rwanda is a small landlocked country in Central Africa where no research or control efforts on NTDs has been conducted since before the genocide in 1994. The current study aimed to elucidate, for the first time post-genocide, the burden of NTDs on the health of the Rwandan people and potential associated morbidity. Despite the fact that we observed low morbidity levels and intensities of polyparasite helminth infections, we recommend sustainable efforts for the deworming of the Rwandan people to be continued in order to offer a worm-free physical and cognitive development to the children of Rwanda and hence support the economic development of the country.

Profile of Central and Effector Memory T Cells in the Progression of Chronic Human Chagas Disease

2009-09-09T07:00:00Z

Author Summary

Chagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi that affects approximately 11 million people in Latin America. The involvement of the host's immune response on the development of severe forms of Chagas disease has not been fully elucidated. Studies on the immune response against T. cruzi infection show that the immunoregulatory mechanisms are necessary to prevent the deleterious effect of excessive immune response stimulation and consequently the fatal outcome of the disease. A recall response against parasite antigens observed in in vitro peripheral blood cell culture clearly demonstrates that memory response is generated during infection. Memory T cells are heterogeneous and differ in both the ability to migrate and exert their effector function. This heterogeneity is reflected in the definition of central (T_CM) and effector memory (T_EM) T cells. Our results suggest that a balance between regulatory and effectors T cells may be important for the progression and development of the disease. Furthermore, the high percentage of central memory CD4⁺ T cells in indeterminate patients after stimulation suggests that these cells may modulate host's inflammatory response by controlling cell migration to tissues and their effector role during chronic phase of the disease.

Rabies Situation in Cambodia

2009-09-08T07:00:00Z

Author Summary

In Cambodia, rabies still elicits fear in the communities. Since 1998 the Institut Pasteur in Cambodia (IPC), Phnom Penh has been the only source of free post-exposure prophylaxis (PEP) and post mortem diagnosis. During 1998–2007, on average ~12,400 patients received PEP annually at IPC (range 8,907–14,475) and 63 fatal human cases presenting with encephalitis following a dog bite were reported including 73% who tested positive by fluorescent-antibody test on brain samples or/and by reverse-transcriptase polymerase chain reaction on skin, cerebrospinal fluid, or urine. In 2007, 14,475 patients received PEP (100 PEP/100,000 people in Cambodia) including 95% who resided in Phnom Penh city (615 PEP/100,000) or five neighboring provinces. Using a step-by-step probability model, we estimated that 810 human rabies deaths would occur in 2007 (95% confidence interval [CI] 394–1,607); an incidence of 5.8/100,000 (95%CI 2.8–11.5). As a result, despite high attendance at the IPC's PEP center most Cambodians living in peripheral provinces in Cambodia may not have adequate access to PEP. Finally, the model generated one of the highest incidences of rabies worldwide. A national rabies control program is needed to improve surveillance and access to PEP, and to initiate vaccination campaigns in dogs.

Dynamics of Socioeconomic Risk Factors for Neglected Tropical Diseases and Malaria in an Armed Conflict

2009-09-08T07:00:00Z

Author Summary

Armed conflict and war and infectious diseases are globally among the leading causes of human suffering and premature death. Moreover, they are closely interlinked, as an adverse public health situation may spur violent conflict, and violent conflict may favor the spread of infectious diseases. The consequences of this vicious cycle are increasingly borne by civilians, often as a hidden and hence neglected burden. We analyzed household data that were collected before and after an armed conflict in a rural part of western Côte d'Ivoire, and investigated the dynamics of socioeconomic risk factors for neglected tropical diseases (NTDs) and malaria. We identified a worsening of the sanitation infrastructure, decreasing use of protective measures against mosquito bites, and increasing difficulties to reach public health care infrastructure. In contrast, household crowding, the availability of soap, and the accessibility of comparatively simple means of health care provision (e.g., traditional healers and community health workers) seemed to be more stable. Knowledge about such dynamics may help to increase crisis-proofness of critical infrastructure and public health systems, and hence mitigate human suffering due to armed conflict and war.

Skeeter Buster: A Stochastic, Spatially Explicit Modeling Tool for Studying Aedes aegypti Population Replacement and Population Suppression Strategies

2009-09-01T07:00:00Z

Author Summary

Dengue is a viral disease that affects approximately 50 million people annually, and is estimated to result in 12,500 fatalities. Dengue viruses are vectored by mosquitoes, predominantly by the species Aedes aegypti. Because there is currently no vaccine or specific treatment, the only available strategy to reduce dengue transmission is to control the populations of these mosquitoes. This can be achieved by traditional approaches such as insecticides, or by recently developed genetic methods that propose the release of mosquitoes genetically engineered to be unable to transmit dengue viruses. The expected outcome of different control strategies can be compared by simulating the population dynamics and genetics of mosquitoes at a given location. Development of optimal control strategies can then be guided by the modeling approach. To that end, we introduce a new modeling tool called Skeeter Buster. This model describes the dynamics and the genetics of Ae. aegypti populations at a very fine scale, simulating the contents of individual houses, and even the individual water-holding containers in which mosquito larvae reside. Skeeter Buster can be used to compare the predicted outcomes of multiple control strategies, traditional or genetic, making it an important tool in the fight against dengue.

Murine Models for Trypanosoma brucei gambiense Disease Progression—From Silent to Chronic Infections and Early Brain Tropism

2009-09-01T07:00:00Z

Author Summary

Trypanosoma brucei gambiense is responsible for more than 90% of reported cases of human African trypanosomosis (HAT). Infection can last for months or even years without major signs or symptoms of infection, but if left untreated, sleeping sickness is always fatal. In the present study, different T. b. gambiense field isolates from the cerebrospinal fluid of patients with HAT were adapted to growth in vitro. These isolates belong to the homogeneous Group 1 of T. b. gambiense, which is known to induce a chronic infection in humans. In spite of this, these isolates induced infections ranging from chronic to silent in mice, with variations in parasitaemia, mouse lifespan, their ability to invade the CNS and to elicit specific immune responses. In addition, during infection, an unexpected early tropism for the brain as well as the spleen and lungs was observed using bioluminescence analysis. The murine models presented in this work provide new insights into our understanding of HAT and allow further studies of parasite tropism during infection, which will be very useful for the treatment and the diagnosis of the disease.

Trypanosoma cruzi IIc: Phylogenetic and Phylogeographic Insights from Sequence and Microsatellite Analysis and Potential Impact on Emergent Chagas Disease

2009-09-01T07:00:00Z

Author Summary

Trypanosoma cruzi, the etiological agent of Chagas disease, infects over 10 million people in Latin America. Six major genetic lineages of the parasite have been identified with differential geographic distributions, ecological associations and epidemiological importance. With the advent of the T. cruzi genome sequence, it is possible to examine the micro-epidemiology of T. cruzi using high resolution genetic markers that assess diversity within these major types. Here we examine the genetic diversity of TcIIc, a poorly understood T. cruzi genetic lineage found predominantly among wild cycles of parasite transmission infecting terrestrial mammals and triatomine vectors, but also a potentially important emergent human disease agent. Amongst a number of findings, we show that TcIIc genetic diversity is comparable to other ancient T. cruzi lineages, highly spatially structured, and that a stringent co-evolutionary relationship with its principal reservoir host can be ruled out. Additionally, TcIIc is one of the two parents of hybrid lineages TcIId and TcIIe, which cause most of the Chagas disease that occurs in the Southern Cone of South America. The system we have developed will help to clarify the ecological circumstances around the emergence of these epidemiologically important hybrids, and perhaps help predict similar events in the future.

PLoS Neglected Tropical Diseases Issue Image | Vol. 3(8) August 2009

2009-08-25T07:00:00Z

RNAi-altered gene expression in larval schistosomes.

Confocal fluorescence micrograph of two in vitro-derived primary sporocysts of Schistosoma mansoni showing the somatic distribution of immunoreactive elongation factor 1a (EF1a) protein (green). Larvae are counterstained for actin (red) and DNA (blue) using Alexa-phalloidin and Hoechst dye, respectively. EF1a was one of 32 genes selected for larval phenotypic profiling by RNA interference (see article by de Moraes Mourão, et al. doi:10.1371/journal.pntd.0000502).

Image Credit: M. de Moraes Mourão, N. Dinguirard. Image was captured using a Nikon Eclipse TE2000 epifluorescent microscope equipped with a Bio-Rad Radiance 2100 MP Rainbow confocal imaging system (Keck Laboratory for Biological Imaging, University of Wisconsin).

Neglected Tropical Diseases in Sub-Saharan Africa: Review of Their Prevalence, Distribution, and Disease Burden

2009-08-25T07:00:00Z

The neglected tropical diseases (NTDs) are the most common conditions affecting the poorest 500 million people living in sub-Saharan Africa (SSA), and together produce a burden of disease that may be equivalent to up to one-half of SSA's malaria disease burden and more than double that caused by tuberculosis. Approximately 85% of the NTD disease burden results from helminth infections. Hookworm infection occurs in almost half of SSA's poorest people, including 40–50 million school-aged children and 7 million pregnant women in whom it is a leading cause of anemia. Schistosomiasis is the second most prevalent NTD after hookworm (192 million cases), accounting for 93% of the world's number of cases and possibly associated with increased horizontal transmission of HIV/AIDS. Lymphatic filariasis (46–51 million cases) and onchocerciasis (37 million cases) are also widespread in SSA, each disease representing a significant cause of disability and reduction in the region's agricultural productivity. There is a dearth of information on Africa's non-helminth NTDs. The protozoan infections, human African trypanosomiasis and visceral leishmaniasis, affect almost 100,000 people, primarily in areas of conflict in SSA where they cause high mortality, and where trachoma is the most prevalent bacterial NTD (30 million cases). However, there are little or no data on some very important protozoan infections, e.g., amebiasis and toxoplasmosis; bacterial infections, e.g., typhoid fever and non-typhoidal salmonellosis, the tick-borne bacterial zoonoses, and non-tuberculosis mycobaterial infections; and arboviral infections. Thus, the overall burden of Africa's NTDs may be severely underestimated. A full assessment is an important step for disease control priorities, particularly in Nigeria and the Democratic Republic of Congo, where the greatest number of NTDs may occur.

Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression

2009-08-25T07:00:00Z

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North–South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts.

Assessing the Impact of a Missed Mass Drug Administration in Haiti

2009-08-25T07:00:00Z

A Constitutional Amendment for Deworming

2009-08-25T07:00:00Z

A Schistosome cAMP-Dependent Protein Kinase Catalytic Subunit Is Essential for Parasite Viability

2009-08-25T07:00:00Z

Author Summary

Schistosomes are parasitic flatworms that inhabit the circulatory system and are the cause of a debilitating and insidious disease for millions of people worldwide. Like other complex organisms, schistosomes and other parasitic worms regulate their cell biology through extensive use of enzymes called protein kinases that phosphorylate other proteins to alter their function. One such protein kinase, cAMP-dependent protein kinase (PKA), has been proposed as a therapeutic target for the treatment of parasitic infections and cancer. Here we use biochemical techniques to show that schistosome worms possess a functional PKA pathway that is required for survival of the parasites. We also identify a parasite gene that encodes a functional PKA enzyme and show that silencing this gene results in both significant loss of PKA activity in schistosome worms and parasite death. These findings suggest that the gene we have identified is critically important to schistosomes and that its protein product may represent a target for the development of much-needed new drugs to treat schistosome infections.

Adenosine Kinase of T. b. rhodesiense Identified as the Putative Target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine Using Chemical Proteomics

2009-08-25T07:00:00Z

Author Summary

Human African trypanosomiasis (HAT), a devastating and fatal parasitic disease endemic in sub-Saharan Africa, urgently needs novel targets and efficacious chemotherapeutic agents. Recently, we discovered that 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine exhibits specific antitrypanosomal activity toward T. b. rhodesiense, the causative agent of the acute form of HAT. Here we applied a chemical proteomics approach to find the cellular target of this compound. Adenosine kinase, a key enzyme of the parasite purine salvage pathway, was isolated and identified as compound binding partner. Direct binding assays using recombinant protein, and tests on an adenosine kinase knock-down mutant of the parasite produced by RNA interference confirmed TbrAK as the putative target. Kinetic analyses showed that the title compound is an activator of adenosine kinase and that the observed hyperactivation of TbrAK is due to the abolishment of the intrinsic substrate-inhibition. Whereas hyperactivation as a mechanism of action is well known from drugs targeting cell signaling, this is a novel and hitherto unexplored concept for compounds targeting metabolic enzymes, suggesting that hyperactivation of TbrAK may represent a novel therapeutic strategy for the development of trypanocides.

Importance of Coverage and Endemicity on the Return of Infectious Trachoma after a Single Mass Antibiotic Distribution

2009-08-25T07:00:00Z

Author Summary

Trachoma, caused by ocular chlamydia infection, is the most common infectious cause of blindness in the world. The World Health Organization (WHO) recommends the SAFE strategy (eyelid surgery, antibiotics, facial hygiene, environmental improvements) for trachoma control. Oral antibiotics reduce the transmission of ocular chlamydia, but re-infection of treated individuals is common. Therefore, the WHO recommends annual mass antibiotic treatments to the entire village. The success of treatment is likely based on many factors, including the antibiotic coverage, or percentage of villagers who receive antibiotics. However, no studies have analyzed the importance of antibiotic coverage for the reduction of ocular chlamydia. Here, we performed multivariate regression analyses on data from a clinical trial of mass oral antibiotics for trachoma in a severely affected area of Ethiopia. At the relatively high levels of antibiotic coverage in our study, coverage was associated with post-treatment infection at two months, but not at six months. The amount of infection at baseline was strongly correlated with post-treatment infection at both two and six months. These results suggest that in areas with severe trachoma treated with relatively high antibiotic coverage, increasing coverage even further may have only a short-term benefit.

Co-authorship Network Analysis: A Powerful Tool for Strategic Planning of Research, Development and Capacity Building Programs on Neglected Diseases

2009-08-18T07:00:00Z

Author Summary

The selection and prioritization of research proposals is always a challenge, particularly when addressing neglected tropical diseases, as the scientific communities are relatively small, funding is usually limited and the disparity between the science and technology capacity of different countries and regions is enormous. When the Ministry of Health and the Ministry of Science and Technology of Brazil decided to launch an R&D program on neglected diseases for which at least 30% of the Program's resources were supposed to be invested in institutions and authors from the poorest regions of Brazil, it became clear to us that new strategies and approaches would be required. Social network analysis of co-authorship networks is one of the new approaches we are exploring to develop new tools to help policy-/decision-makers and academia jointly plan, implement, monitor and evaluate investments in this area. Publications retrieved from international databases provide the starting material. After standardization of names and addresses of authors and institutions with text mining tools, networks are assembled and visualized using social network analysis software. This study enabled the development of innovative criteria and parameters, allowing better strategic planning, smooth implementation and strong support and endorsement of the Program by key stakeholders.

Cooperative Blood-feeding and the Function and Implications of Feeding Aggregations in the Sand Fly, Lutzomyia longipalpis (Diptera: Psychodidae)

2009-08-18T07:00:00Z

Author Summary

Understanding the processes that promote cooperation amongst animals in nature is a fundamental question in evolutionary biology with ramifications in the social sciences. In insects, cooperative or altruistic interactions are usually observed amongst genetically related social insects (kin selection). Here we provide evidence that in Lutzomia longipalpis, a small biting fly and an important vector of disease in the New World, cooperative blood-feeding occurs in groups of non-kin individuals. Groups of 20 flies and single flies were fed on hamster hosts and we compared their salivary gland usage as well as the time taken to initiate a bloodmeal, its duration, and the number of eggs they produced. Our results show that flies feeding in aggregations benefit from decreased saliva expenditure and greatly enhanced blood intake and egg production. These effects were particularly strong on older hamsters pre-exposed to sand fly bites, suggesting that group-feeding flies may better overcome their stronger immune response. These experiments demonstrate that, in L. longipalpis, feeding cooperatively maximizes the effects of saliva injected into hosts to facilitate blood intake and to counteract the host immune defences, resulting in much increased fecundity. This constitutes the first explanation for the function of feeding aggregations in hematophagous insects and a fascinating example of cooperation amongst individuals in a non-social organism.

Reduced Susceptibility to Praziquantel among Naturally Occurring Kenyan Isolates of Schistosoma mansoni

2009-08-18T07:00:00Z

Author Summary

The emergence of drug resistant pathogens is a great challenge to the control of infectious diseases. Schistosomiasis is one of the world's greatest neglected tropical diseases, and it is primarily controlled with the drug praziquantel. This drug is often used by repeatedly treating patients to maintain reduced worm burdens, an ideal situation to encourage the evolution of resistant worms. Although drug based control programs are increasing, monitoring efforts for drug resistance remain rare. We measured drug susceptibility of schistosomes from a cohort of patients in Kenya who are enrolled in a longitudinal study in which they are repeatedly treated with praziquantel. We found that schistosomes from previously treated patients were significantly less susceptible than those that were not. Also, schistosomes derived from a single patient who had been treated with praziquantel 18 times showed marked resistance. Although the findings of this study indicated that reduced drug susceptibility occurs in this population of schistosomes, this trait does not seem to be spreading widely or creating clinical levels of resistance. We hypothesize that the trait remains at low frequency because of the large population of schistosomes that are not exposed to the drug and/or potential fitness costs associated with reduced susceptibility.