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Parasitic diseases cause ~500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the... more
Parasitic diseases cause ~500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase) and TRACK (Trypanosoma receptor for activated C-kinase). We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase), may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs.
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Chagas disease is a parasitic disease caused by the protozoan parasite Trypanosoma cruzi and about 230,000 persons are estimated to be infected in Ecuador. However, limited studies have been performed in the Amazon region, on the eastern... more
Chagas disease is a parasitic disease caused by the protozoan parasite Trypanosoma cruzi and about 230,000 persons are estimated to be infected in Ecuador. However, limited studies have been performed in the Amazon region, on the eastern side of the country. We evaluated here the seroprevalence of Trypanosoma cruzi infection in 12 rural villages of the Loreto canton, Orellana Province in schoolchildren aged 5-15 years and pregnant women. A total of 1,649 blood samples were tested for Trypanosoma cruzi antibodies by enzyme-linked immunosorbent assay and indirect hemaglutination, and discordant samples were tested by indirect immunofluorescence assay. We detected a seroprevalence of anti-Trypanosoma cruzi antibodies of 1.3% in schoolchildren aged 5-15 years, indicating the persistence of a constant and active vectorial transmission in the Loreto County and confirming the need of the implementation of nonconventional vector control. We also observed a seroprevalence of 3.8% in pregnant...
Penguins are able to maintain a high and constant body temperature despite a thermally constraining environment. Evidence for progressive adaptation to cold and marine life was sought by comparing body and peripheral skin temperatures,... more
Penguins are able to maintain a high and constant body temperature despite a thermally constraining environment. Evidence for progressive adaptation to cold and marine life was sought by comparing body and peripheral skin temperatures, metabolic rate, and thermal insulation in juvenile and adult Gentoo penguins exposed to various ambient temperatures in air (from -30 to +30 degrees C) and water (3-35 degrees C). Juvenile penguins in air showed metabolic and insulative capacities comparable with those displayed by adults. Both had a lower critical temperature (LCT) close to 0 degree C. In both adults and juveniles, the intercept of the metabolic curve with the abscissa at zero metabolic rate was far below body temperature. This was accompanied by a decrease in thermal insulation below LCT, allowing the preservation of a threshold temperature in the shell. However, this shell temperature maintenance was progressively abandoned in immersed penguins as adaptation to marine life develope...
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In the Yucatan peninsula, Mexico, the causative agent of Chagas disease Trypanosma cruzi is transmitted by the bug Triatoma dimidiata. While T. dimidiata invades and colonizes houses in other regions, this species has an intrusive... more
In the Yucatan peninsula, Mexico, the causative agent of Chagas disease Trypanosma cruzi is transmitted by the bug Triatoma dimidiata. While T. dimidiata invades and colonizes houses in other regions, this species has an intrusive behavior in Yucatan, likely attracted by artificial light and potential vertebrate hosts, but has limited ability to establish colonies. Bugs collected inside the homes also have a low nutritional status, suggesting that they cannot efficiently feed inside these houses. We hypothesized here that this low feeding status of T. dimidiata may be associated with the local practice in Mayan communities to sleep in hammocks instead of beds, as this sleeping habit could be an obstacle for triatomines to easily reach their host, particularly for nymphal instars which are unable to fly. To test this hypothesis, we used an experimental chamber of 100 cm x 50 cm x 50 cm in which we placed a miniature bed in one side and a miniature hammock on the other side. After pla...
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Chagas disease is one of the most important diseases in Latin America. Insecticides have been sprayed to control domiciliated vectors. However, some triatomine species are not strictly domiciliated, and the transmission risk posed by... more
Chagas disease is one of the most important diseases in Latin America. Insecticides have been sprayed to control domiciliated vectors. However, some triatomine species are not strictly domiciliated, and the transmission risk posed by immigrants is identified as a major challenge. The design of new control strategies requires disentangling the importance of demography and immigration in vector occurrence inside houses. Using a population dynamics model, we confirmed that dispersal can explain satisfactorily the domestic abundance of Triatoma dimidiata in Yucatan, Mexico. A surprisingly low fecundity was also required (no more than one to two female offspring per female per trimester). A wide range of survival probabilities was possible, although the best fit was obtained for a very low immature survival (< or = 0.01/trimester). Our model predicted that domestic populations are not sustainable, and up to 90% of the individuals found in houses are immigrants. We discuss the potentia...
Research Interests: Demography, Housing, Mexico, Humans, Female, and 5 moreAnimals, Chagas disease, Triatoma, MEXICO, and Insect Vectors
Leishmaniases represent an important public health problem in large parts of the world. In the south-east of Mexico, the major species isolated from patients is Leishmania mexicana mexicana, causing localised cutaneous leishmaniasis, and... more
Leishmaniases represent an important public health problem in large parts of the world. In the south-east of Mexico, the major species isolated from patients is Leishmania mexicana mexicana, causing localised cutaneous leishmaniasis, and the development of a vaccine is a key objective for the control of this parasite. We thus performed a comparative study of DNA vaccines encoding L. m. mexicana gp63 and CPb, L. m. amazonensis gp46, and L. major LACK to define the best antigen(s) candidate(s). cDNAs encoding these antigens were subcloned into the VR1012 plasmid, and susceptible BALB/c mice were immunised with two i.m. injections of 100 microg of plasmid DNA. All mice immunised with VR1012-GP46, VR1012-CPb and VR1012-GP63 showed increased IgG levels against L. m. mexicana, but not those immunised with VR1012-LACK. Two to three weeks after the last immunisation, mice were challenged by the injection of 4 x 10(6) L. m. mexicana parasites in the foot pad to evaluate protection. Measureme...
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Chagas disease is a tropical parasitic disease affecting about 10 million people, mostly in the Americas, and transmitted mainly by triatomine bugs. Insect vector control with indoor residual insecticides and the promotion of housing... more
Chagas disease is a tropical parasitic disease affecting about 10 million people, mostly in the Americas, and transmitted mainly by triatomine bugs. Insect vector control with indoor residual insecticides and the promotion of housing improvement is the main control intervention. The success of such interventions relies on their acceptance and appropriation by communities, which depends on their knowledge and perceptions of both the disease and the vector. In this study, we investigated school-aged children&amp;amp;amp;amp;amp;amp;#39;s knowledge and perception on triatomine vectors and Chagas disease to further understand how communities view this vector and the disease in Yucatan, Mexico. We performed an analysis of children&amp;amp;amp;amp;amp;amp;#39;s drawings on the theme of triatomines and their house in several rural villages, to explore in an open-ended manner their views, understanding and misconceptions. A total of 261 drawings were collected from children ages 6-12 from four villages. We found that children are very familiar with triatomine vectors, and know very well many aspects of their biology and ecology, and in particular their blood-feeding habits. On the other hand, their drawings suggest that the role of triatomines as vectors of a chronic and severe cardiac disease is less understood, and the main perceived health threat appears limited to the bite itself, as previously observed in adults. These results have important implications for the specific design of future education materials and campaigns, and for the promotion of the inclusion of children in raising Chagas disease awareness in these endemic communities.
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The health burden of Chagas' disease (resulting from Trypanosoma cruzi infection) in Latin America (estimated to outweigh that of malaria by 5-fold and affect 2-6 million people in Mexico alone) has motivated development of... more
The health burden of Chagas' disease (resulting from Trypanosoma cruzi infection) in Latin America (estimated to outweigh that of malaria by 5-fold and affect 2-6 million people in Mexico alone) has motivated development of therapeutic vaccines to prevent infection progression to severe disease. Our economic model for a Chagas' therapeutic vaccine in Mexico suggests that a vaccine would be highly cost-effective and in many cases economically dominant (providing both cost savings and health benefits) throughout a range of protection durations, severe adverse event risk, and dosing regimens and would be most likely to provide a positive return on investment if the vaccine prevented (rather than delayed) the onset of cardiomyopathy.
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Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and activation of CD8(+) T cells is crucial for a protective immune response. Therefore, the identification of antigens with major histocompatibility complex class I... more
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and activation of CD8(+) T cells is crucial for a protective immune response. Therefore, the identification of antigens with major histocompatibility complex class I epitopes is a crucial step for vaccine development against T. cruzi. Our aim was to identify novel antigens and epitopes by immunoinformatics analysis of the parasite proteome (12 969 proteins) and to validate their immunotherapeutic potential in infected mice. We identified 172 predicted epitopes, using NetMHC and RANKPEP. The corresponding protein sequences were reanalyzed to generate a consensus prediction, and 26 epitopes were selected for in vivo validation. The interferon γ (IFN-γ) recall response of splenocytes from T. cruzi-infected mice confirmed that 10 of 26 epitopes (38%) induced IFN-γ production. The immunotherapeutic potential of a mixture of all 10 peptides was evaluated in infected mice. The therapeutic vaccine was able to control T. cruzi infection, as evidenced by reduced parasitemia, cardiac tissue inflammation, and parasite burden and increased survival. These findings illustrate the benefits of this approach for the rapid development of a vaccine against pathogens with large genomes. The identified peptides and the proteins from which they are derived are excellent candidates for the development of a vaccine against T. cruzi.
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Non-domiciliated (intrusive) triatomine vectors remain a challenge for the sustainability of Chagas disease vector control as these triatomines are able to transiently (re-)infest houses. One of the best-characterized examples is Triatoma... more
Non-domiciliated (intrusive) triatomine vectors remain a challenge for the sustainability of Chagas disease vector control as these triatomines are able to transiently (re-)infest houses. One of the best-characterized examples is Triatoma dimidiata from the Yucatan peninsula, Mexico, where adult insects seasonally infest houses between March and July. We focused our study on three rural villages in the state of Yucatan, Mexico, in which we performed a situation analysis as a first step before the implementation of an ecohealth (ecosystem approach to health) vector control intervention. The identification of the key determinants affecting the transient invasion of human dwellings by T. dimidiata was performed by exploring associations between bug presence and qualitative and quantitative variables describing the ecological, biological and social context of the communities. We then used a participatory action research approach for implementation and evaluation of a control strategy ba...
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American trypanosomiasis, or Chagas disease, is caused by Trypanosoma cruzi, and a vaccine would greatly improve disease control. While some studies in mice suggest that a vaccine is feasible, limited efficacy has been observed in dogs.... more
American trypanosomiasis, or Chagas disease, is caused by Trypanosoma cruzi, and a vaccine would greatly improve disease control. While some studies in mice suggest that a vaccine is feasible, limited efficacy has been observed in dogs. We evaluated here the safety and efficacy of a DNA vaccine encoding TSA-1 and Tc24 antigens in a dog model of acute T. cruzi infection. Mongrel dogs were immunized with two doses of 500 μg of DNA vaccine, two weeks apart, and infected with T. cruzi (SylvioX10/4 strain) two weeks after the second vaccine dose. Another group of dogs was infected first and treated with the vaccine. Disease progression was monitored for up to 70 days post-infection. The vaccine did not induce any critical change in blood parameters, nor exacerbation of disease in vaccinated animals. On the contrary, it prevented anemia and a decrease in lymphocyte counts following T. cruzi infection in vaccinated dogs. Both preventive and therapeutic vaccination significantly reduced parasitemia, cardiac inflammation and cardiac parasite burden, and tended to reduce the development of cardiac arrhythmias. These results indicate that a preventive or therapeutic DNA vaccine encoding TSA-1 and Tc24 antigens is safe and may reduce both parasite transmission and the clinical progression of Chagas disease in vaccinated dogs. This DNA vaccine may thus be an excellent veterinary vaccine candidate. These data also further strengthen the feasibility of a Chagas disease vaccine for humans.
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Research Interests: Housing, Population Dynamics, Tropical medicine (Health Sciences), Mexico, Rural Health, and 13 moreFemale, Animals, Male, Host-parasite interactions, Chagas disease, Trypanosoma Cruzi, Public health systems and services research, Sex Factors, Triatoma, MEXICO, Seasons, Geographic Information Systems, and Insect Vectors
Dirofilariasis (Dirofilaria immitis) and American trypanosomiasis (Trypanosoma cruzi) are zoonotic parasitic diseases affecting the hearts of a variety of mammalian host species, including dogs. In this study, some of the... more
Dirofilariasis (Dirofilaria immitis) and American trypanosomiasis (Trypanosoma cruzi) are zoonotic parasitic diseases affecting the hearts of a variety of mammalian host species, including dogs. In this study, some of the immunopathological characteristics of natural co-infection by these two parasites were compared with T. cruzi infection in dogs from Mexico. Antibody analysis in serum indicated significantly lower anti-T. cruzi IgG levels in co-infected dogs (n = 4) compared to those with T. cruzi infection alone (n = 9), together with a somewhat lower IgG2/IgG1 ratio. Cardiac tissue inflammation was limited and focal in co-infected animals whereas T. cruzi infected dogs had extensive and diffuse tissue inflammation. Three out of nine T. cruzi infected dogs and 1/4 of T. cruzi and D. immitis co-infected dogs showed cardiac alterations. The results showed that co-infections may interfere with host responses, and their significant prevalence (4/13 T. cruzi infected dogs) suggests that they should be taken into account by researchers and clinicians.
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Chagas&#39; disease, caused by the protozoan parasite Trypanosoma cruzi, represents a major public health problem in most of the American continent. As transmission of the parasite is being interrupted in most of South America, the... more
Chagas&#39; disease, caused by the protozoan parasite Trypanosoma cruzi, represents a major public health problem in most of the American continent. As transmission of the parasite is being interrupted in most of South America, the disease remains endemic in various areas of Mexico. We review here some of the information gathered in recent years. Seroprevalence of T. cruzi infection in humans remains relatively high in some areas, and there has been a general increase in the number of chronic cases reported to health authorities in recent years. In fact, chronic chagasic cardiomyopathy appears to be affecting a large number of patients with heart disease, but many cases may be misreported because of the unspecific nature of the clinical symptoms. Epidemiological monitoring of vector and reservoir populations, as well as of human cases is helping focus on endemic areas, but a better coordination and development of these efforts is still needed. Recent studies of parasite biology are in agreement with previous work showing the great diversity of parasite characteristics, and support the need for a regional approach to this zoonosis. Strong and continuing support from health and academic authorities is thus still needed to further improve our understanding of Chagas&#39; disease in Mexico and implement efficient control programs.
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Research Interests: Mexico, Biological Sciences, Humans, Animals, Ecosystem, and 3 moreTriatoma, MEXICO, and Insect Vectors
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Research Interests: Genetics, Gene Flow, Fluctuating asymmetry, Mexico, Infectious Disease, and 14 moreFemale, Animals, Male, Genetic Association Studies, Chagas disease, Morphological Variation, Animals and disease transmission, Genotype, Trypanosoma Cruzi, Triatoma, Sibling Species, Genetic variation, MEXICO, and Wing
Research Interests: Genetics, Geography, Mexico, Seasonality, Humans, and 16 moreFemale, Animals, Male, Polymerase Chain Reaction, Chagas disease, Yucatan Peninsula, Cytochrome B, Geographic distribution, Trypanosoma Cruzi, Group, Triatoma, Sibling Species, Genetic variation, MEXICO, Species Specificity, and Insect Vectors
Research Interests: Evolutionary Biology, Genetics, Phylogeography, Population Genetics, Molecular Evolution, and 13 moreHeredity, Phylogeny, Population structure, Humans, Animals, Host-parasite interactions, Chagas disease, Vector control, Animals and disease transmission, Trypanosoma Cruzi, Triatominae, Host Pathogen Interactions, and Insect Vectors
Several studies have documented that helminth infections can interfere with the development of the immune response of vaccines against different diseases, although some results have been contradictory. The mechanisms involved in the... more
Several studies have documented that helminth infections can interfere with the development of the immune response of vaccines against different diseases, although some results have been contradictory. The mechanisms involved in the inhibition of the immune response to vaccination by helminth are still unclear, and murine models of helminth-malaria coinfections have proven helpful in investigating some aspects of the interactions involved. The study evaluated here focuses on the effect of helminth infection in mice on the immunogenicity and protective efficacy of two distinct malaria vaccine candidates, a transmission-blocking DNA vaccine based on Pfs25 antigen and a pre-erythrocytic vaccine based on irradiated sporozoites. Interestingly, the authors found that helminth infection dramatically reduced DNA vaccine immunogenicity, while immunization with irradiated sporozoites was able to induce a high level of antibodies and protection, independently of helminth infection. Immune suppression by helminth infection affected all IgG isotypes, suggesting no particular polarization of the immune response, but the generation of memory B cells was not affected. It will be of key interest to understand the mechanisms underlying the efficacy of the sporozoite vaccine, and its ability to overcome helminth immunosuppression, as this may help in the design of more effective vaccines.
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Chagas disease is a leading cause of heart disease affecting approximately 10 million people in Latin America and elsewhere worldwide. The two major drugs available for the treatment of Chagas disease have limited efficacy in Trypanosoma... more
Chagas disease is a leading cause of heart disease affecting approximately 10 million people in Latin America and elsewhere worldwide. The two major drugs available for the treatment of Chagas disease have limited efficacy in Trypanosoma cruzi-infected adults with indeterminate (patients who have seroconverted but do not yet show signs or symptoms) and determinate (patients who have both seroconverted and have clinical disease) status; they require prolonged treatment courses and are poorly tolerated and expensive. As an alternative to chemotherapy, an injectable therapeutic Chagas disease vaccine is under development to prevent or delay Chagasic cardiomyopathy in patients with indeterminate or determinate status. The bivalent vaccine will be comprised of two recombinant T. cruzi antigens, Tc24 and TSA-1, formulated on alum together with the Toll-like receptor 4 agonist, E6020. Proof-of-concept for the efficacy of these antigens was obtained in preclinical testing at the Autonomous University of Yucatan. Here the authors discuss the potential for a therapeutic Chagas vaccine as well as the progress made towards such a vaccine, and the authors articulate a roadmap for the development of the vaccine as planned by the nonprofit Sabin Vaccine Institute Product Development Partnership and Texas Children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Hospital Center for Vaccine Development in collaboration with an international consortium of academic and industrial partners in Mexico, Germany, Japan, and the USA.
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Chagas&amp;amp;amp;amp;amp;amp;#39; disease is an important health problem in most Latin American countries, and a concern in dog populations, which act as a reservoir. We showed in previous studies that a therapeutic DNA vaccine... more
Chagas&amp;amp;amp;amp;amp;amp;#39; disease is an important health problem in most Latin American countries, and a concern in dog populations, which act as a reservoir. We showed in previous studies that a therapeutic DNA vaccine could partially control the pathology after Trypanosoma cruzi infection in mice, and this vaccine may represent an alternative treatment for Chagas&amp;amp;amp;amp;amp;amp;#39; disease. Here we evaluated the therapeutic efficacy of this vaccine in experimentally infected dogs for up to 2 months after infection. Our results suggest that DNA vaccine treatment may affect the immune response and delay Chagas&amp;amp;amp;amp;amp;amp;#39; disease progression in T. cruzi-infected dogs, and confirm the potential of this novel treatment.