Dengue fever may be stopped before it is transmitted, says S.Ananthanarayanan.

Antibodies against many pathogens, which affect humans, are grown in animals and then transferred to humans. We now have a case of antibodies that arise in humans, and are transferred to mosquitoes to keep mosquitoes free of the dengue virus.

Anna Buchman, Stephanie GamezI, Ming Li, Igor Antoshechkin, Hsing-Han Li, Hsin-Wei Wang, Chun-Hong Chen, Melissa J. Klein, Jean-Bernard DucheminI, James E. Crowe, Jr., Prasad N. Paradkar, Omar S. Akbari, from University of California and Tata Institute for Genetics and Society, San Diego, California, Institute of Technology, Pasadena, National Tsing Hua University and National Health Research Institutes, Zhunan, Taiwan, Australian Animal Health Laboratory, Geelong, VIC, Australia and Vanderbilt University Medical Center, Nashville, Tennessee, describe in the journal, PLOS-Pathogens, their work of modifying the mosquito genome to make mosquitoes resistant to all four variations of the dengue virus. A small number of these dengue-resistant mosquitoes could then transform the mosquito population, worldwide, to be dengue-resistant, say the authors.

The interest, of course, is not the health of the mosquitoes. The interest is human health, for mosquitoes are not affected by dengue, they are the carriers of dengue. And very effective carriers, as 50% of the world’s human population is now at risk. There are 390 million documented cases of dengue fever in a year, the paper says, and the estimated economic losses amount to 40 billion USD. There are no specific methods of treatment or prevention and the sole commercially available vaccine, which is only partially effective, often cannot be used because it increases rather than mitigate the risk with some groups of people

The main carrier of the dengue virus is Aedes aegypti, or the yellow fever mosquito, and it is the vector that transmits dengue fever, chikungunya, Zika fever, Mayaro and yellow fever viruses, and other disease agents. The mosquito originated in Africa but has spread out, and is now found in tropical, subtropical and temperate regions throughout the world. .

It is difficult to control its breeding, as it develops resistance to insecticides and adopts evasive behavior, the paper says. There is hence need to think of other means, particularly genetic engineering, either to reduce mosquito populations or to reduce their ability to carry dengue. There has been some success in developing such strains of mosquitoes, but for these to be effective, it is necessary to release the strains in large numbers and frequently. This is laborious and expensive, the paper says

Researchers have therefore sought methods where the genetic modification of a few mosquitoes can rapidly spread into an entire population. This is achieved through a genetic engineering device known as a gene drive, where the probability of a gene in an organism being inherited by its offspring is altered. Usually, a gene is present in two versions in the pair of chromosomes and either one has a 50% chance of being inherited by the descendent. The gene drive technique is an insertion that cuts the chromosome at a specific place, and in the process of repair of the cut, the gene drive version, which consist of the drive and the altered gene, is copied. The cell then has two copies of the gene drive sequence, and the altered gene as well as the gene drive will occur in every descendent. The result is very rapid replication and the altered gene is soon present in a whole population.

While the gene drive is an effective way to spread a useful modified feature through most of the infecting population of mosquitoes, the work done so far has been able to target only one, or two, of the four major strains of the dengue virus, the paper says. As dengue epidemics affect large numbers and infection by one strain followed by infection by another can result in severe disease, it is necessary that the genetically altered mosquitoes block all kinds of the dengue virus.

Finding a broad-spectrum antibody, one that acts against all forms of dengue, in the mosquito, would thus be promising. Such an antibody has been synthetically developed for the mosquito to resist the parasite that causes malaria, the paper says, but not one that targets a virus. Nevertheless, antibodies against the dengue virus have been isolated in humans infected with dengue. Laboratory studies have shown that these antibodies were able to deal with the four versions of the dengue virus and were effective against two of the versions when used in a mouse model

The paper describes how the human antibody, which is capable of neutralizing all four version of the dengue virus, was modified so that it was compatible with mosquitoes and retained its effectiveness against dengue. Experiments were then carried out to verify that blood meals of infected blood did not lead to midgut infection of the mosquitoes, and that the procedure was effective with all four variations of the dengue virus.

The next assay was to see what effect the engineered antibody had on the fitness of the mosquito. This was to ensure that the genetically altered mosquitoes would be able to reproduce and spread their genetic content to progeny, for dissemination in the mosquito population. They assessed several parameters, like the time for development from the larva stage, male and female fecundity and fertility, male mating success and longevity. The results were that there was no significant effect on fitness and the ability to confer dengue resistance to progeny in good numbers.

“The strategy we describe here provides an efficient “cargo” gene that can be coupled with a gene-drive system to reduce or eliminate the risk of dengue transmission by mosquitoes,” the paper says. There is even a feature where the mosquito would keep in step with evolution of the dengue virus in reaction to being blocked by resistant mosquitoes. The paper goes on to say that the same methods, of synthesizing genetic solutions, coupled with gene-drive systems, could render mosquitoes resistant to other viruses, like those that cause ZIKA and chikungunya.

• Dengue is a mosquito-borne viral infection. • There are four types of the virus, which means that it is possible to be infected four times. • The global incidence has grown dramatically. About half of the world's population is now at risk. • Dengue is a leading cause of serious illness and death in some Asian and Latin American countries. • There is no specific treatment for dengue/severe dengue. Early detection and access to proper medical care lowers fatality rates to below 1%. • Dengue is found in tropical and sub-tropical climates worldwide, mostly in urban and semi-urban areas. • The mosquito vectors of dengue breed in and around human habitation. Their eggs can remain dry for months and hatch when in contact with water. • Dengue prevention and control depends on effective vector control and sustained community involvement.

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