At a glance
Cutting-edge research in public health
Our research focuses on vector-borne diseases, including those caused by parasites and viruses. We are particularly interested on the interactions between the innate immune system of disease vectors and the pathogens. Our central focus is malaria, which threatens almost half of the global population and kills about 700,000 people every year, mostly children below 5 in sub-Saharan Africa. It is caused by the protozoan parasite, Plasmodium, which is transmitted to humans through Anopheles mosquitoes. For our research we use the full suite of tools available to modern biological research including genomics, functional genomics, population genetics, reverse genetics, molecular and cell biology, biochemistry and bioinformatics, integrated in a systems biology framework.
Malaria transmission blocking
Enhanced indoor interventions for vector control have drastically reduced the number of malaria cases in recent years. However, these measures are reaching their capacity as mosquito resistance to them is increasing s. Our research programme aims to contribute to developing methods to block man-to-vector transmission. We strive to characterise the molecular framework of vector-parasite interactions during the critical early stages of mosquito infection and, based on that knowledge, develop translational paths to interventions. Such interventions include transmission-blocking vaccines and drugs, which although administered to humans function to stop the parasite in the mosquito or compromise the mosquito vectorial capacity.
Vector-borne diseases are emerging or resurging in northern territories with an accelerating pace. Major drivers are environmental change (including climate, travel, migration, and global trade); social and demographic drivers (including population aging, social inequalities, and life-styles); and public health system drivers (including antimicrobial resistance, health care capacity, animal health, and food safety). Among these, climate change is perhaps the most important and uncontrolled factor, as it is expected to aggravate existing local vulnerabilities by interacting with a complex web of these drivers. We investigate how climate change in combination with increases in global trade, urbanisation and travel could facilitate the introduction, establishment, and dispersal of new vectors and pathogens, and reservoir species.
A complement for mosquitoes
Disease transmission requires that microbes overcome the robust mosquito immune system. In the malaria vector mosquito, a protein homologous to mammalian complement factor C3, known as TEP1, plays a central role in defence against malaria parasites and bacteria. We investigate signals and biological processes leading to accumulation of TEP1 on the microbes, and how this can drive killing reactions such as lysis and melanization. Unravelling the molecular mechanisms regulating these evolutionary conserved innate immune responses could ultimately aid the design of novel therapeutics.
Mosquito gut homeostasis
Like our own intestinal tract, the mosquito gut is a complex ecosystem that involves many and diverse microorganisms. The numbers of bacteria in the mosquito gut increase drastically after ingestion of a bloodmeal but strong immune reactions triggered by this increase are important in restoring homeostasis. Disturbance of homeostasis has a drastic effect on infection with blood-borne pathogens such as malaria parasites and viruses. We are characterising the molecular mechanisms involved in the immune response versus tolerance to mosquito gut bacteria.
Innate immune response to viruses
In addition to transmitting parasitic diseases, mosquitoes are also vectors of viral diseases including Dengue and yellow fever, various encephalitides, West Nile and Chikungunya. We aim to dissect the insect responses to such viruses. Our findings reveal that the systemic response to viral infection is distinct from the response bacterial, fungal or parasitic infections, and similar to responses to double stranded RNA.
Learning from non-vector species
Different closely-related species of the Anopheles gambiae complex have profoundly different levels of permissiveness to malaria parasites. We are investigating the genetic and environmental basis of this phenomenon. Detail understanding of how mosquitoes and parasites co-adapt and co-evolve could inform interventions that aim to block malaria transmission in the vector.
Parasite in the vector
Linking defence and physiology
Our research has uncovered novel functional links between the vector defence responses to infection and physiology. They involve hormonal regulation of egg development, reproduction and digestion, nutrient trafficking machineries and behavioural responses such as food satiation and host seeking. We aim to dissect the molecular mechanisms that regulate this interesting interplay between defence and physiology, and study their impact on disease transmission.
Sexual and sporogonic development
We aim to understand the mechanisms that regulate the Plasmodium sexual development in the mosquito midgut and to identify genes and proteins that are involved in interactions with the vector, especially with the vector immune system. In particular, we are interested to dissect the regulatory mechanisms involved in the ookinete-to-oocyst transition that concurs with mosquito midgut invasion and the killing of a large fraction of the invading parasite population.
Male contribution to zygote development
Plasmodium male gametogenesis takes place within minutes inside the mosquito midgut, stimulated by mosquito metabolites and environmental factors. This involves three rounds of DNA replication rapidly followed by budding off of male gametes carrying haploid genomes. We are interested in understanding the male gamete contribution to parasite development in the mosquito, including cell cycle regulation and checkpoints, polarised protein secretion and epigenetic regulation of gene expression.
We have established a parasite dual co-infection system that permits investigation of the vector/parasite genotype*genotype interactions at a high throughput manner, using both mutant parasites and knockout mosquitoes. We currently use this system to examine putative genetic interactions between malaria parasite proteins and components of the mosquito immune system. We aim to extend this system to additional aspects of the vector-parasite interactions.
Genetics and genomics
We are part of VectorBase, an NIAID Bioinformatics Resource Centre dedicated to providing data and bioinformatics resources to the scientific community for Invertebrate Vectors of Human Pathogens. We provide a forum for the discussion and distribution of news and information relevant to invertebrate vectors, as well as access to tools to facilitate the querying and analysis of datasets related to vectors and vector-borne diseases. In particular, we gather and integrate community produced genomics and functional genomics data, host and analyse population genetics data, and develop tools to facilitate the study of host-pathogen interaction studies including large scale genotype by genotype interactions.
We aspire to decipher the genetic information encoded in the genomes of various disease vector mosquitoes, focusing on the evolutionary sculpting of the innate immune repertoires and the mosquito-pathogen interactions. We aim to provide new insights into vector host-seeking behaviour, capacity to invade new environments and interaction with pathogens. Our analyses so far reveal distinct and seemingly contrasting modes of evolution of genes involved in the different phases of an immune response, which reflects a continuous readjustment between accommodation and rejection of pathogens.
Antibiotics and malaria
Bacteria in the gut proliferate greatly after a bloodmeal, and this increase protects mosquitoes against infections with malaria parasites that are ingested upon a bite of an infected person. We are investigating whether ingestion of antibiotics-containing blood can disturb the mosquito gut homeostasis and render mosquitoes more permissive to malaria parasites. The results of this study will be informative to malaria elimination plans and also to guides and practices of antibiotic usage in controlling infectious diseases in malaria endemic countries.
We are pioneering development of novel technological platforms in malaria research, including genome-wide monitoring of gene expression, proteomic analyses, interrogation of natural variation and public health informatics. We use these technologies to investigate how the genetic and epigenetic makeup and natural variation of vectors and pathogens may affect disease transmission. We are also developing novel platforms that can be to screen for anti-mosquito and anti-malarial compounds, expanding the current assay portfolio for the discovery of new public health interventions.
Bridging field and lab research
We are extend our analyses to characterise at a genome-wide levels the interactions between field populations of mosquitoes and malaria parasites. So far, we are focusing our work on the African malaria system but we aim to soon expand this to include Latin American and Asian malaria. Our findings indicate that while the parasite tactics to infection appear to be rather conserved, mosquitoes have different mechanisms to deal with infection including varying immune responses. These data may imply that some of the proposed interventions must be tailored to each malaria setting.