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Mosquito Immunity ? Combating the Resurgence of Malaria and Dengue
17 Aug, 2007 11:41 am
The sequencing of the second mosquito genome, that of the dengue and yellow fever transmitting mosquito, Aedes aegypti, has enabled comprehensive comparative genomic studies with the malaria transmitting mosquito, Anopheles gambiae, whose genome was sequenced in 2002. In a three-way comparison with the well studied fruitfly, Drosophila melanogaster, our analysis of genes and gene families thought to be involved in insect immune responses revealed intriguing patterns which help to understand how immune systems may have evolved in response to varied challenges.
Why study mosquito immune systems?
Recent years have shown a global resurgence of human diseases transmitted by mosquitoes including malaria, dengue fever, lymphatic filariasis and arboviral encephalitides. This is due in part to the development of insecticide resistance in the vector mosquitoes and drug resistance in the pathogens, but also to changing socioeconomic conditions in disease-endemic countries which can disrupt disease control programmes. It has become increasingly acknowledged that new strategies must employ many different tactics to combat these devastating diseases – from physical interventions such as using bed nets to large-scale mosquito population control schemes. The fact that the parasites and viruses must pass through the mosquitoes in order to be transmitted to humans presents an additional opportunity for manipulation of the system, aiming to block this transmission step. Although insects do not possess an adaptive immune system as found in vertebrates, the versatility of the mechanisms of innate immunity in fighting infections is impressive. The development of new tools to study mosquito immunity has helped improve the understanding of these mechanisms and the results show that natural resistance to infection is mostly attributable to the action of components of the mosquito’s immune system. Thus the global battle against these diseases will be greatly strengthened by a comprehensive understanding of what makes some mosquitoes able to fight off infections while others remain susceptible and hence continue the cycle of disease transmission.
How similar/different are these mosquitoes?
To the casual observer most mosquitoes look very similar, and although several morphological differences between Anopheles and Aedes mosquitoes could be identified by a non-expert using a simple magnifying lens, they are in fact very different at the DNA level. These mosquitoes are believed to have diverged some 150 million years ago, but with insects evolving faster than vertebrates, they are by some genomic measures even more different than humans and chickens, which diverged about 300 million years ago. Focussing on genes and gene families implicated in insect immunity, our study aimed to identify related components in each of the two mosquitoes and the fruitfly, and to a more limited extent in other insect species such as the honeybee and the silkmoth. This involved a large collaborative effort with scientists from all over the world using their expertise to examine particular genes and gene families. For each gene family, our study examined the numbers of genes in each species, their phylogenetic relationships (which genes correspond to which among the three insects), and levels of divergence or conservation. The results from the analysis of insect immune signalling pathways and response modules revealed contrasting features evolving rapidly or conservatively which are related to different functional categories of genes and characteristics of immune reactions.
How do insect immune systems evolve?
On average, when looking at genes which have corresponding members in each of the three insects (orthologues), we found that immunity genes were significantly more divergent in terms of the protein sequences they encode than the rest of the genes in the genome. The most divergent of these were proteins involved in signalling pathways which effectively communicate the fact that a pathogen has been recognised and the immune system must respond. These signalling genes nevertheless, are strictly conserved in numbers with only one copy in each genome – unlike other categories of immunity genes which appear to have evolved through duplication events to produce multiple copies in each genome (paralogues), which nevertheless remain similar between species. This most likely reflects their different modes of action in the processes of recognition and producing effector responses. A collection of different recognition proteins is beneficial in terms of increasing the ability to recognise infectious agents. In a similar manner, a large selection of effector proteins means that when the immune response is switched on, the invaders can be quickly targeted for destruction. Another important class of immunity genes is that of the response modulators – they must ensure tight regulation so that the immune system is only triggered when needed. From large families of genes, evolution appears to have selected distinct modules in each species in a ‘mix and match’ manner which means that while the overall functions of modulation mechanisms are broadly maintained, employing phylogenetics to identify genes which may perform the same or very similar functions between species is very difficult. The appreciation of the diverse evolutionary modes that have shaped insect immune systems will help to guide future studies on the evolution of innate immune mechanisms in vertebrates and other animals.
Progress in the battle against devastating diseases.
Our study has highlighted important similarities and differences between two mosquitoes which together transmit some of the most devastating infectious diseases of humankind, and the insights gained will facilitate future studies of mosquito immunity. More generally, a better understanding of the evolution of innate immunity will assist research into other disease vector species such as the blood-sucking bug that transmits Chagas disease, or the Tsetse fly that transmits sleeping sickness.
Waterhouse M., Robert, et al , Evolutionary Dynamics of Immune-Related Genes and Pathways in Disease-Vector Mosquitoes, Science, 2007 Jun 22;316(5832):1738-43. PMID: 17588928