Fighting Zika Virus with Mosquito Genetics

 

By  John McLaughlin

 

The Zika virus burst into the news last year when a dramatic increase in microcephaly cases was reported throughout several states in Brazil. This frightening birth defect quickly became associated with the mosquito-borne virus, carried by Aedes mosquitos; Aedes aegypti, which also carries Dengue, is the main vector in the current Zika outbreak. While Zika virus usually affects adults with fairly mild symptoms such as fever, rash, and joint pain, it can have severe or fatal consequences for the fetuses being carried by infected females. In fact, The World Health Organization (WHO) has recently reported a scientific consensus on the theory that Zika is the cause of the large number of Brazilian microcephaly cases.

 

In January of 2016, a Hawaiian baby born with microcephaly became the first case of Zika reported in the United States. And the U.S. National Institute of Allergy and Infectious Diseases has recently stated that a wider outbreak of the virus within the United States will likely occur soon. Naturally, mosquito containment has become a top priority for health officials in both infected areas and those likely to be impacted by the virus. The standard list of mosquito control protocols includes pesticide repellents, mosquito nets, eliminating stagnant open water sources, and long-sleeved clothing to limit skin exposure. In addition to these, health authorities are considering a number of new strategies based on genetic engineering technologies.

 

One such technique employs the concept of gene drive, the fact that some “selfish” gene alleles can segregate into gametes at frequencies higher than the expected Mendelian ratios. In this scenario, gene drive can be exploited to spread a disease resistance gene quickly throughout a population of mosquitoes. Recently, a team at the University of California tested this idea by using CRISPR technology to engineer the mosquito Anopheles stephensi with a malarial resistance gene drive. After integration of the resistance gene cassette and DNA targeting with CRISPR, this gene was successfully copied onto the homologous chromosome with high efficiency, thus ensuring that close to 100% of its offspring will bear resistance. Possibly, similar techniques could be exploited to engineer Zika resistance in Aedes mosquitoes.

 

In contrast to engineering disease resistance, an alternative defense strategy is to simply reduce the population of a specific mosquito species, in the case of a Zika outbreak, Aedes aegypti. The WHO has recently approved a GM mosquito which, after breeding, produces offspring that die before reaching adulthood. This technique can dramatically reduce an insect population when applied in strategic locations. The British biotech firm Oxitech has also developed its own strain of sterile Aedes aegypti males. In laboratory testing, these GM mosquitoes compete effectively with wild males for female breeding partners. The short-term goal is receiving approval to test these sterile males in the wild; ultimately, a targeted release of these mosquitoes will reduce the Aedes aegypti population in Zika hot spots without affecting other species.

 

In parallel to mosquito engineering, other work has focused on studying the mechanisms underlying Zika’s dramatic affects on the brain. To study the process of Zika infection in vitro, scientists at Johns Hopkins cultured 3-D printed brain organoids and demonstrated that the virus preferentially infects neural stem cells, resulting in reduced cortical thickness owing to the loss of differentiated neurons. This neural cell death may explain the frequent microcephaly observed in fetuses carried by infected mothers.

 

Much like the recent outbreak of Ebola in several African countries, this event helps underscores the importance of basic research. A recent New York Times article drew attention to this fact by highlighting the need for more complete genome sequences of the mosquito species that carry Zika. With a complete genome sequence at hand, researchers might be able to piece together information in answering questions such as: why are some Aedes mosquitoes vectors for Zika and others aren’t? Species differences in genome sequence may provide some answers. Nevertheless, greater knowledge of the mosquito’s biology will yield more options for human intervention. This is an excellent case study in how ‘basic’ and ‘translational’ research projects can co-evolve in special situations.