Browsing by Author "Doumtabe, Didier"

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    Creation of a non-Western humanized gnotobiotic mouse model through the transplantation of rural African fecal microbiota
    (American Society for Microbiology, 2023) Van Den Ham, Kristin M.; Little, Morgan R.; Bednarski, Olivia J.; Fusco, Elizabeth M.; Mandal, Rabindra K.; Mitra, Riten; Li, Shanping; Doumbo, Safiatou; Doumtabe, Didier; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Crompton, Peter D.; Schmidt, Nathan W.; Pediatrics, School of Medicine
    There is increasing evidence that microbes residing within the intestines (gut microbiota) play important roles in the well-being of humans. Yet, there are considerable challenges in determining the specific role of gut microbiota in human diseases owing to the complexity of diverse internal and environmental factors that can contribute to diseases. Mice devoid of all microorganisms (germ-free mice) can be colonized with human stool samples to examine the specific contribution of the gut microbiota to a disease. These approaches have been primarily focused on stool samples obtained from individuals in Western countries. Thus, there is limited understanding as to whether the same methods used to colonize germ-free mice with stool from Western individuals would apply to the colonization of germ-free mice with stool from non-Western individuals. Here, we report the results from colonizing germ-free mice with stool samples of Malian children.
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    Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season
    (Nature, 2020-12) Andrade, Carolina M.; Fleckenstein, Hannah; Thomson-Luque, Richard; Doumbo, Safiatou; Lima, Nathalia F.; Anderson, Carrie; Hibbert, Julia; Hopp, Christine S.; Tran, Tuan M.; Li, Shanping; Niangaly, Moussa; Cisse, Hamidou; Doumtabe, Didier; Skinner, Jeff; Sturdevant, Dan; Ricklefs, Stacy; Virtaneva, Kimmo; Asghar, Muhammad; Vafa Homann, Manijeh; Turner, Louise; Martins, Joana; Allman, Erik L.; N'Dri, Marie-Esther; Winkler, Volker; Llinás, Manuel; Lavazec, Catherine; Martens, Craig; Farnert, Anna; Kayentao, Kassoum; Ongoiba, Aissata; Lavstsen, Thomas; Osório, Nuno S.; Otto, Thomas D.; Recker, Mario; Traore, Boubacar; Crompton, Peter D.; Portugal, Silvia; Medicine, School of Medicine
    The dry season is a major challenge for Plasmodium falciparum parasites in many malaria endemic regions, where water availability limits mosquito vectors to only part of the year. How P. falciparum bridges two transmission seasons months apart, without being cleared by the human host or compromising host survival, is poorly understood. Here we show that low levels of P. falciparum parasites persist in the blood of asymptomatic Malian individuals during the 5- to 6-month dry season, rarely causing symptoms and minimally affecting the host immune response. Parasites isolated during the dry season are transcriptionally distinct from those of individuals with febrile malaria in the transmission season, coinciding with longer circulation within each replicative cycle of parasitized erythrocytes without adhering to the vascular endothelium. Low parasite levels during the dry season are not due to impaired replication but rather to increased splenic clearance of longer-circulating infected erythrocytes, which likely maintain parasitemias below clinical and immunological radar. We propose that P. falciparum virulence in areas of seasonal malaria transmission is regulated so that the parasite decreases its endothelial binding capacity, allowing increased splenic clearance and enabling several months of subclinical parasite persistence.
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    Susceptibility to febrile malaria is associated with an inflammatory gut microbiome
    (Research Square, 2024-04-04) Schmidt, Nathan; Van Den Ham, Kristin; Bower, Layne; Li, Shanping; Lorenzi, Hernan; Doumbo, Safiatou; Doumtabe, Didier; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Crompton, Peter; Medicine, School of Medicine
    Malaria is a major public health problem, but many of the factors underlying the pathogenesis of this disease are not well understood. Here, we demonstrate in Malian children that susceptibility to febrile malaria following infection with Plasmodium falciparum is associated with the composition of the gut microbiome prior to the malaria season. Gnotobiotic mice colonized with the fecal samples of malaria-susceptible children had a significantly higher parasite burden following Plasmodium infection compared to gnotobiotic mice colonized with the fecal samples of malaria-resistant children. The fecal microbiome of the susceptible children was enriched for bacteria associated with inflammation, mucin degradation, gut permeability and inflammatory bowel disorders (e.g., Ruminococcus gauvreauii, Ruminococcus torques, Dorea formicigenerans, Dorea longicatena, Lachnoclostridium phocaeense and Lachnoclostridium sp. YL32). However, the susceptible children also had a greater abundance of bacteria known to produce anti-inflammatory short-chain fatty acids and those associated with favorable prognosis and remission following dysbiotic intestinal events (e.g., Anaerobutyricum hallii, Blautia producta and Sellimonas intestinalis). Metabolomics analysis of the human fecal samples corroborated the existence of inflammatory and recovery-associated features within the gut microbiome of the susceptible children. There was an enrichment of nitric oxide-derived DNA adducts (deoxyinosine and deoxyuridine) and long-chain fatty acids, the absorption of which has been shown to be inhibited by inflamed intestinal epithelial cells, and a decrease in the abundance of mucus phospholipids. Nevertheless, there were also increased levels of pseudouridine and hypoxanthine, which have been shown to be regulated in response to cellular stress and to promote recovery following injury or hypoxia. Overall, these results indicate that the gut microbiome may contribute malaria pathogenesis and suggest that therapies targeting intestinal inflammation could decrease malaria susceptibility.
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    Treatment of Chronic Asymptomatic Plasmodium falciparum Infection Does Not Increase the Risk of Clinical Malaria Upon Reinfection
    (Oxford, 2017-03) Portugal, Silvia; Tran, Tuan M.; Ongoiba, Aissata; Bathily, Abroudramane; Li, Shanping; Doumbo, Safiatou; Skinner, Jeff; Doumtabe, Didier; Kone, Younoussou; Sangala, Jules; Jain, Aarti; Davies, D. Huw; Hung, Christopher; Liang, Li; Ricklefs, Stacy; Homann, Manijeh Vafa; Felgner, Philip L.; Porcella, Stephen F.; Färnert, Anna; Doumbo, Ogobara K.; Kayentao, Kassoum; Greenwood, Brian M.; Traore, Boubacar; Crompton, Peter D.; Medicine, School of Medicine
    Background. Chronic asymptomatic Plasmodium falciparum infections are common in endemic areas and are thought to contribute to the maintenance of malaria immunity. Whether treatment of these infections increases the subsequent risk of clinical episodes of malaria is unclear. Methods. In a 3-year study in Mali, asymptomatic individuals with or without P. falciparum infection at the end of the 6-month dry season were identified by polymerase chain reaction (PCR), and clinical malaria risk was compared during the ensuing 6-month malaria transmission season. At the end of the second dry season, 3 groups of asymptomatic children were identified: (1) children infected with P. falciparum as detected by rapid diagnostic testing (RDT) who were treated with antimalarials (n = 104), (2) RDT-negative children whose untreated P. falciparum infections were detected retrospectively by PCR (n = 55), and (3) uninfected children (RDT/PCR negative) (n = 434). Clinical malaria risk during 2 subsequent malaria seasons was compared. Plasmodium falciparum–specific antibody kinetics during the dry season were compared in children who did or did not harbor asymptomatic P. falciparum infections. Results. Chronic asymptomatic P. falciparum infection predicted decreased clinical malaria risk during the subsequent malaria season(s); treatment of these infections did not alter this reduced risk. Plasmodium falciparum–specific antibodies declined similarly in children who did or did not harbor chronic asymptomatic P. falciparum infection during the dry season. Conclusions. These findings challenge the notion that chronic asymptomatic P. falciparum infection maintains malaria immunity and suggest that mass drug administration during the dry season should not increase the subsequent risk of clinical malaria.