Mali International Center for Excellence in Research: Vectors and Hosts of Parasitic Infectious Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Ecology of Malaria Vectors Our major discovery published recently in Nature (Huestis et al. 2019) that many mosquito species use wind to migrate after taking a blood meal and thus may be spreading pathogens over hundreds of kilometers has been the focus of new studies. (1) Our paper describing that mosquitoes are able to withstand >11 hours high-altitude flight and subsequently reproduce and blood-feed on new hosts, thus potentially altering the gene pool at destination and transmitting pathogens there is published (Sanogo et al. 2021). 2) Comparing windborne flight activity of mosquitoes with that of other insects captured by nets (40-290 m above ground), we found that all species exhibited high seasonal and regional regularity, frequently flying on southerly winds, in accord with recolonization of the Sahel from southern source populations. Annually, the migrants crossing Mali at latitude 14N were in the billions/species, highlighting its impact on food security and public health (Florio et al. 2020). 3) We have been carrying out aerial sampling in three ecozones in Mali (Sahel, dry, and wet savannas) and two ecozones in Ghana (dry and equatorial forest) as part of our Gates Foundation GCE Award. Our initial results reveal that mosquitoes engage in high altitude flights across ecozones. Molecular identification of the species and infection status is at early stages. 4) A novel mosquito marking method we developed using DNA tag in fluorescent spray for rapid screening for marked individuals and was found to be highly effective (Faiman et al. 2021). New projects based on this marking methods are underway. 5) An epidemiological project entitled Evaluating the determinants of the spread of COVID-19 between and within rural communities in Mali, West Africa based on blood-fed mosquitoes is described separately in project AI001328-01. Impact of Iron Availability on Sickling Kinetics in Malian Children To address the Impact of iron availability on sickling kinetics in Malian Children, our specific aims are to: Assess alpha globin gene copy number and iron bioavailability; examine the distribution of intracellular hemoglobin concentration (mean corpuscular hemoglobin concentration, MCHC) and related RBC parameters; measure hemoglobin composition and oxygen affinity: quantify sickling kinetics of fresh RBCs ex vivo using an automated microscope; and determine rates of hemolysis and red cell turnover in vivo. Together, these measurements will provide the first comprehensive evaluation of naturally existing heterogeneity of hemoglobin composition in the red blood cell and its impact on the kinetics of sickling. In 2020, we have begun setting up the specialized equipment needed to conduct these studies in a new laboratory based in the sickle cell research center in Bamako, Mali. Comparison of anti-RH5 antibodies from human clinical trials in the UK with antibodies elicited by repeated malaria infection We have compared the concentration and characteristics of antibodies to P. falciparum RH5, a leading blood-stage malaria vaccine candidate, resulting from clinical trials in nave volunteers with those elicited by natural infection in Malian adults and children. To address this, we first conducted a serological study of PfRH5 antibodies in over 400 sera from Malian individuals of varying ages at the peak of the transmission season and stratified them into groups by age (Willcox et al., Cell Rep. Med.). While nearly all participants showed antibodies to the P. falciparum FVO parasite extract, antibody prevalence to PfRH5 was limited and the concentrations were very low; antibodies to the other antigens in the invasion complex (CyRPA and RIPR) were so low as to preclude further affinity purification. For additional characterization and comparison of the Malian antibodies, we compared the concentration of infection-induced anti-RH5 with titers induced by vaccination. The vaccination titers in nave volunteers in the UK were approximately 200-fold higher than those from Malians. This shows that PfRH5 is immunogenic when presented in a proper context. In addition, the infection-elicited RH5 antibodies differed in binding site specificity and avidity from the vaccine-elicited ones. We then tested the interaction of Malian IgGs with both human monoclonal and polyclonal antibodies; in general the interactions were additive or synergistic in a parasite growth inhibition assay and interference was not seen. Overall, the pre-existing antibodies to PfRH5 in those living in endemic areas are likely to interact positively with vaccine-induced antibodies, supporting the transition of PfRH5 to efficacy studies in the field (Willcox et al.). Naturally Occurring Wolbachia in Anopheline Mosquitoes from Mali Wolbachia is a bacterium commonly found in arthropods that is known to reduce susceptibility of culicine mosquitoes to several Arboviral infections. We identified a naturally-occurring strain of Wolbachia in An. gambiae s.l. mosquitoes in the Malian villages of Kenieroba and Dangassa, different from strains previously identified in Burkina Faso. Field and laboratory data indicate that Wolbachia infection reduces the prevalence and intensity of sporozoite infection. We carried out experimental P. falciparum infections and found that Wolbachia reduces the prevalence and intensity of sporozoite infection. More recently we have trained a Malian investigator to do genomic DNA extractions from field-caught desiccated mosquitoes, and we have optimized a new genomic DNA extraction protocol and a qRT-PCR assay to detect Wolbachia. We will examine the seasonal variation in prevalence of infection in Kenieroba and Dangassa and survey other villages in the area to establish the range of distribution of Wolbachia in this region, as well as different larval habitats, to establish whether Wolbachia infection is widespread or limited to specific larval breeding sites. We investigated the effect of continued exposure to sand fly bites on the human immune response and investigated it in the context of filariasis. We showed that repeated exposure to bites of the cutaneous leishmaniasis (CL) sand fly vector, Phlebotomus duboscqi, modulates the response of human monocytes. Monocytes of unexposed individuals selectively upregulated the production of IL-6 and CCL4 in response to Ph. duboscqi saliva, or to saliva of other vector sand fly species. In contrast, monocytes of individuals exposed to sand fly bites lost their responsiveness to saliva, microfilariae antigen and LPS, irrespective of co-infection with filaria. Nevertheless, infection with filaria significantly upregulated the frequency of CCL22+monocytes, IL-10+mDCs and regulatory T cells suggesting that repeated exposure to sand fly saliva alters human monocyte function towards a tolerized phenotype while co-infection with filaria favors a Leishmania-promoting Th2/regulatory response.