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 Expanding the scope of our investigation of windborne Anopheles (Huestis et al. 2019: Nature), we 1) describe high altitude migration across 7 mosquito genera comprising of 50 mosquito species. At altitude, females outnumbered males 6:1, and 93% of the females have taken at least one blood meal on a vertebrate host prior to their departure. Coinciding with peak disease transmission and the engagement of millions of mosquitoes across Mali alone - the case for windborne mosquitoes as carriers of mosquito-borne pathogens (MBPs) is bolstered. Fourteen of the windborne mosquito species had been reported as vectors to 25 MBPs in West Africa, which represent 32% of the MBPs known in that region and include those that inflict the heaviest burden on human and animal health, such as malaria, dengue, and Rift Valley fever (Yaro et al. 2022: preprint). 2) Metagenomics analysis of mosquitoes collected at altitude indicated infection with viruses e.g., Araticum virus, bacteria e.g., Asaia spp., and eukaryotes e.g., Trypanosoma spp. and Plasmodium spp. Targeted pathogen detection using pan-Plasmodium primers revealed 49 infected mosquitoes of 1,003 tested, and subsequently confirmed using primers targeting the 18S rDNA. Infectiousness rate measured as thoracic infection was 2.8%. Fourteen species of avian plasmodia were identified by sequencing. Early results also revealed infection of high-altitude mosquitoes with filariid nematodes (0.7% N=300) and several infected mosquitoes for for flaviviruses. For the first time, we report here the detection of arboviruses, bacteria, and eukaryotic pathogens in high-altitude mosquitoes, thus providing proof of concept for their long-distance spread by windborne mosquitoes. 3) Aerial sampling across 5 ecozones from the Sahel to the equatorial forest yielded 36 mosquito species (ongoing). Diversity and abundance were higher above perennial ecozones, i.e., equatorial forest than above the Sahel. Low ecozone specificity indicated that most species move between neighboring ecozones, but movement between the equatorial forest to the Sahel >750 km also occurs. 4) Tracking mosquitoes marked by deuterium (2H) from the end of the wet season until the beginning of the subsequent wet season supported that aestivation is a major persistence mechanism of An. coluzzii, contributing at least 20% of the adults at the onset of rain (Faiman et al. 2022: In press). 5) Using our novel mosquito marking method (Faiman et al. 2021), we have measured extensive movement of mosquitoes across the entire village that undermined assessment of transmission blocking vaccine. In a subsequent study, we measured movement between villages up to 12 km away. 6) 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. Establishing Clinical and Laboratory Research Infrastructure at the Centre de Recherche et de Lutte Contre la Drepanocytose (CRLD) for studies of Hemoglobinopathies in Malian Children and Adults The CRLD is a clinic, day hospital, and research center in Bamako, Mali that provides specialized care for more than 12,000 children and adults with sickle cell disease. The LMVR has established a collaboration with the CRLD to conduct clinical observational studies into the pathophysiology of sickle cell disease and the underlying mechanisms by which genetic and acquired hemoglobinopathies such as HbS, HbC, alpha thalassemia, and iron deficiency protect against severe malaria. To support this goal, we are building capacity to conduct clinical and laboratory research at the CRLD. We opened a new clinical research protocol Amlioration de la prise en charge de la drpanocytose au Mali travers lengagement et la participation au rseau Panafricain de lutte contre la drpanocytose for the purpose of collecting clinical data and biospecimens from 2,000 children and 2,000 adults with sickle cell disease over the next 3 years for observational studies of sickle cell disease pathophysiology. We outfitted a new laboratory space with electricity, water, air conditioning, and benches to support studies of red cell sickling and vascular biology. We have purchased and installed clinical equipment for complete blood counts, reticulocyte studies, hemoglobin HPLC, and biochemical studies. We have obtained funding for the CRLD to engage with a Pan-African network through an NHLBI U01 mechanism reported separately at the NIH Reporter under 1U01HL157007. This funding will also support a study introducing monthly malaria chemoprophylaxis for children with sickle cell disease. Working together, LMVR and CRLD have increased clinical and basic research capacity to enable studies of sickle cell disease and its interactions with malaria. 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 We previously identified Wolbachia, an intracellular symbiont, which was present at low levels in wild-caught mosquitoes from Mali. Furthermore, Wolbachia-infected mosquitoes in Mali, as well as colonized mosquitoes challenged in the laboratory had lower intensity and prevalence of P. falciparum sporozoite infections. In recent collections in the same Malian villages, we were no longer able to detect Wolbachia in natural populations. We are currently investigating whether microbiota (bacterial and fungal) or microsporidia present in natural mosquito populations affect their capacity to transmit malaria. Evaluation of the occurrence of P. vivax near Bamako is ongoing. So far, one infected individual was identified. We are continuing to investigate new emerging foci of cutaneous leishmaniasis in Mali and studies are ongoing to determine the incidence of disease, and the infection rate in the sand fly vector. We are investigating vector gut microbiota in field populations.