Atlas of Science

Tag: Dengue

  • How to use machine learning to discover relevant aspects in the Dengue Virus protease and guide the drug discovery process?

    How to use machine learning to discover relevant aspects in the Dengue Virus protease and guide the drug discovery process?

    Dengue Virus (DENV) is perhaps one of the most relevant viral pathogens in tropical and sub-tropical areas. A World Health Organization (WHO) report indicates that DENV related infections have increased 30-fold in the last 50 years. DENV circulates as four different serological groups, between 50 and 100 million people are affected by DENV every year, and 2.5 billion people live in an area of risk. The many people at risk is highly relevant to assess the impact of the virus since some DENV related infections as Dengue hemorrhagic fever and Dengue Shock Syndrome could have a mortality rate as high as 2.5%.

    Fig. 1. In red, Dengue virus NS3 protease, and in cyan its NS2b cofactor. Machine learning methods were used to characterize novel sites in the protein complex as susceptible targets or anchor points for drugs against all four serotypes of Dengue virus.

    Since November 2015 there is a vaccine available to prevent DENV infection. However, there is currently no antiviral drug available for DENV infection treatment. Many experts have indicated that an antiviral drug could be helpful to manage infections in vulnerable groups like children and the elderly. Also, it could be beneficial to slow down DENV spreading and treatment of severe cases. In the past decade, there have been many efforts to discover new DENV inhibitors with little success partly because the known targets that are being used to guide the antiviral drug development face different challenges to the discovery process.

    Dengue virus belongs the Flavivirus genus, same as Zika Virus and West Nile Virus. As part of its life-cycle, it produces a single protein (polyprotein) that after cleavage creates all the viral proteins needed to accomplish its function inside the infected cell and to assemble the new viruses. Cleavage is essential for the virus to generate functional proteins. The Viral Ns2b-NS3 Protease complex and host cell enzymes oversee cleaving the polyprotein. Therefore, DENV Ns2b-NS3 Protease is an excellent candidate to guide the drug discovery process.

    In structure-based drug design, a known target is required to guide the discovery process. However, it is not enough to know the 3D structure of the target, in this case, the protein. It is essential to know the specific residues that have a functional relevance to discover a molecule that can bind them. In the case of the Ns2b-NS3 Protease, only a few functional relevant residues were known, and they were all related directly to the active site and therefore the catalytic role of the enzyme. Many authors have stated that because of the active site nature, it is hard to develop an adequate drug. Within this scenario, our team decided to use computational methods to discover new functionally relevant residues in the DENV Ns2b-NS3 Protease that could guide the drug discovery process.

    In this case, we described a step by step process to build a machine learning algorithm capable of identifying new functionally relevant residues in the DENV Ns2b-NS3 Protease. We fed our algorithm with published experimental data available and different residue-based molecular descriptors (computationally calculated). It is worth noting that some of these molecular descriptors were obtained with other publicly accessible Machine Learning methods. Moreover, the methodology described in this work could virtually be applied to any biological system. Therefore, we identified some residues that clustered together outside the active site of the protease. These residues could be useful to guide the development of noncompetitive inhibitors for the Ns2b-NS3 protease and therefore a potential drug to treat DENV infections. Finding functionally relevant sites outside the active site is relevant since DENV nonstructural proteins have different non-canonical roles different than their catalytic functions directly related to the viral cycle.

    Daniel Aguilera-Pesantes, Miguel A. Mendez
    Universidad San Francisco de Quito, Instituto de Simulacion Computacional, Ecuador

     

    Publication

    Discovering key residues of dengue virus NS2b-NS3-protease: New binding sites for antiviral inhibitors design.
    Aguilera-Pesantes D, Robayo LE, Méndez PE, Mollocana D, Marrero-Ponce Y, Torres FJ, Méndez M
    Biochem Biophys Res Commun. 2017 Oct 28

  • Genetic information of mosquito blood cells decoded

    Genetic information of mosquito blood cells decoded

    Mosquitoes are most dangerous tiny animal killing 7.25 million peoples in the world annually, as they transmit many deadliest pathogens causing malaria, dengue, chikungunya, zika virus infection etc. Despite of the strong innate and adaptive immune system in humans, these pathogens are able to defeat the immune power of specialized blood cells, but surprisingly the same pathogens fail to cause severe disease conditions in the mosquitoes.  For the last few decades scientists are trying hard to know that how these small flies manage to fight against these microbial pathogens. Although, it is known that mosquitoes rely on the germ line encoded innate immune system, but the biology of mosquito blood cells is unknown.

    Fig. 1. Schematic overview of mosquito blood cells encoded molecular information.
    Fig. 1. Schematic overview of mosquito blood cells encoded molecular information.

    A team of researchers led by Dr. Rajnikant Dixit, at India’s National Institute of Malaria Research, used an advanced molecular technology to dig out the genetic information of the mosquito blood cells. To do this investigation, cold anesthetized adult mosquito was bedded on the microscopic slide to pool the mosquito’s water like blood using specialized micro-syringe. Following deep sequencing technology, the team was successful to capture at least 3025 genes from the minute cells. To decode the biological information ‘locked in’ the mosquito’s blood cells scientist used specialize tools of bioinformatics.

    To the surprise scientists found many interesting information valuing that blood cells may be tiny, but carries ability to do diverse functions. Researchers identified many hemocyte genes capable of immune functions equivalent to vertebrate blood cells. To demonstrate that how mosquito hemocytes manage to fight against any pathogen, experiment was planned in two directions to give immune challenge to the mosquitoes. In one strategy live bacterial soup was injected with the help of micro-syringe into the thorax, expecting a direct interaction of bacteria with circulating hemocytes. Other way, researchers gave oral supplement of the bacterial soup to the mosquitoes, to track indirect response via gut tissue. The result of this study conveyed that hemocytes are specialized to recognize, discriminate and may rapidly clear the foreign invaders, as in humans. In addition to this, researchers were surprised to know that mosquito hemocytes are able to code for many unusual proteins which not only make them metabolically active, but also important for their communication, attachment, movement, signalling and nutritional supply throughout the body of the mosquitoes (Fig. 1.).

    A future challenge for the researcher remains to know whether hemocytes carries any long term immune memory, like vertebrates and how these cells fights against real pathogens of malaria, dengue etc.

    Tina Thomas, Punita Sharma, Tanwee Das De and Rajnikant Dixit
    National Institute of Malaria Research, India

     

    Publication

    Hemocytome: deep sequencing analysis of mosquito blood cells in Indian malarial vector Anopheles stephensi.
    Thomas T, De TD, Sharma P, Lata S, Saraswat P, Pandey KC, Dixit R.
    Gene. 2016 Jul 10

  • Review of ten-years presence of Aedes albopictus in Spain

    Review of ten-years presence of Aedes albopictus in Spain

    The tiger mosquito was first detected in 2004 near Barcelona, although maybe it had arrived one or two years before. Since then, its distribution has been spreading and, in 2014, it has been found in almost all provinces of the Spanish Mediterranean coast and Gipuzkoa province (Basque Country). The most affected region is Catalonia, maybe just because it is where it has been longer, and the second one, the Valencian Comunity.

    From the beginning, the number of positive municipalities continually has increased year by year. The pattern of occupation has combined a progressive increase, in the periphery of distribution, with long jumps to remote areas. Illustrative examples of long jumps were the detection in Altafulla (Tarragona province) 44 km from the first record and, above all, in the coast of Orihuela (Alicante province) 300 km. Likewise, detections in Balearic Islands (200 km from mainland) or in Alhaurín de la Torre (Malaga province), 280 km from the nearest known point (Águilas, Murcia province).

    Historical record of positive municipalities by years (2004–2014).
    Historical record of positive municipalities by years (2004–2014).

    Along of this time, none systematic study has been made in Spain but rather the known data are result of partial studies made by different research teams with diverse aims or interests. So, the main objective was to compile all published and unpublished information about tiger mosquito in Spain and show them as a whole. And to offer the most updated data, the results of 2014 samplings were incorporated.

    Information about biology of Ae. albopictus is included, as altitude range and the seasonal variations as pseudo-phenologies. Because the most used sampling method is the oviposition traps (where the females lay eggs), the data are really not about the amount of caught adults but the amount of layed eggs. The pseudo-phenologies really show the reproductive activity variations which would be related to populational variations.

    Pseudo-phenologies from Catalonia, Balearic Islands and the Region of Murcia are shown. Assuming latitudinal variations, the oviposition begins about the end of April/early May. The populational peak is placed about the end of August in northern places and it shifts to September/October in the southern ones. The activity finishes between the end of October/end of November, although in Murcia the reproductive activity does not end completely and few positives, with few eggs, have been recorded in winter.

    About public health impact, although, at present, no autochthonous cases of dengue and chikungunya have happened, the presence of tiger mosquito in Spain has created a new scenario of epidemiological risk since imported cases of these diseases are regularly detected in Spain. Above all since the establishment of chikungunya in the Americas, in 2013, because the high connections between both Latin America and Spain.

    So, the current incidence of the tiger mosquito on Spanish public health is restricted to the biting nuisance, although few studies have been carried on about.

    The legal situation of the tiger mosquito is complicated because it is included in the official list of invasive species and any related action (even control) on these kind of species depends of the environmental authorities since they are framed in the environmental laws. Then, the higher authorities have eluded the responsibility of control and, in the last instance, the local authorities (municipal governments) have had to face the problem, since they are more directly pressed by citizens.

    As conclusion, on one hand, the distribution has been increased and many types of environments and geographical areas have been occupied, contrary to earlier risk models. On the other hand, urgent policies are needed from central, regional and local governments for proposing measures to avoid the occupation of large part of Spanish territory.

    Francisco Collantes
    Departamento de Zoología y Antropología Física, Facultad de Biología,
    Universidad de Murcia, Murcia, Spain

     

    Publication

    Review of ten-years presence of Aedes albopictus in Spain 2004-2014: known distribution and public health concerns.
    Collantes F, Delacour S, Alarcón-Elbal PM, Ruiz-Arrondo I, Delgado JA, Torrell-Sorio A, Bengoa M, Eritja R, Miranda MÁ, Molina R, Lucientes J.
    Parasit Vectors. 2015 Dec 23

  • Will dengue vaccination be cost-effective for an epidemic country? The case of Argentina

    Will dengue vaccination be cost-effective for an epidemic country? The case of Argentina

    Dengue is one of the major tropical diseases, causing a huge burden in terms of suffering, deaths and economic costs globally. Many research institutions and pharmaceutical companies throughout the world have been trying to develop a vaccine against this disease. The two candidate vaccines that have demonstrated the highest level of progress are the Dengvaxia® from the Sanofi-Pasteur company and the Tetravax-DV from the National Institute of Health (NIH) and the Butantan Institute of Brazil. In early 2016 the vaccine from Sanofi-Pasteur was authorized to be commercialized in Philippines and in three countries of Latin America, while the vaccine from the NIH and the Butantan Institute would be available as soon as within the next two years. The most important issues to be considered for these and others new vaccines are safety, efficacy, and cost-effectiveness. This last factor can be understood as an evaluation of whether the cost of acquiring the vaccines are outweighed by the gain in health benefits and the saving of medical costs associated with treating the disease. Our recent study published in Vaccine in 2016 was designed to answer this third question.

    Fig. 1. Map of South America showing dengue endemic countries (red vertical lines) and the area of Argentina with documented autochthonous transmission of dengue (red fill).

    From the Argentina’s point of view, the problem with the Dengvaxia® is that this vaccine was evaluated and licensed in dengue endemic countries, whereas Argentina is currently considered as epidemic and non-endemic. This is because the autochthonous transmission does not occur every year in the same places and is restricted to the months of November to April. What happens then with Argentina? On one hand, a high proportion of its population is exposed to a low risk of dengue infection. On the other hand, several provinces are at risk of autochthonous dengue transmission and outbreaks, but not every year. Moreover, many cities are bordering endemic regions of neighbor countries (Bolivia, Paraguay and Brazil), share climatic and socio-cultural characteristics, intense local border traffic and have suffered several dengue outbreaks. In this context, it is crucial for public health decision-makers making the best choice of whether or not to incorporate this vaccine into the immunization programs for large groups or targeted populations.

    Given the aforementioned situation, the results of our paper indicate us two things. The first one being that in a real-life situation, if the vaccination program is targeted to those areas showing the highest risk of dengue transmission, a relative small proportion of the whole population of the country, the price of the vaccine had to be equal or lower than US$28 for the strategy being considered as cost-effective. The second concept is more theoretical but equally important: in a hypothetical situation in which countries could produce their own vaccines or in which the acquisition prices were similar from the production costs of these vaccines, according to these prices, the dengue vaccination would be cost-effective for the entire country, mainly for the populations living in the area with any risk of vectorial transmission. Although hard to interpret, this second analysis gives us a clear idea of how important these new vaccines and technologies are for the whole society. Overall, the conclusion is that the dengue vaccination would probably be cost-effective in Argentina, a country considered as epidemic.

    Even if our paper sheds light over the cost-effectiveness relationship of these vaccines in a currently considered non-endemic country, more research should be undertaken in the near future regarding the efficacy and safety of the Dengvaxia®, the TetraVax-DV and other candidate dengue vaccines in hyperendemic, endemic, low-endemic and epidemic countries.

    Pablo W. Orellano1 and Oscar D. Salomon2
    1Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)
    Universidad Tecnologica Nacional, Facultad Regional San Nicolas, Argentina
    2Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)
    Instituto Nacional de Medicina Tropical, Puerto Iguazu, Argentina

     

    Publication

    Cost-utility analysis of dengue vaccination in a country with heterogeneous risk of dengue transmission.
    Orellano PW, Reynoso JI, Stahl HC, Salomon OD.
    Vaccine. 2016 Jan 27