Browsing by Author "Schmidt, Nathan W."
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Item Characterizing the Formation and Functionality of Immune Memory Cells in Response to Plasmodium Infection(2025-05) Fusco, Elizabeth Michelle; Schmidt, Nathan W.; Absalon, Sabrina; Bauer, Margaret; Longtin, Krista; Luo, Wei; Richer, MartinMalaria is an infectious disease caused by Plasmodium parasites. Over 40% of the world lives in malaria endemic regions, and children under the age of 5 in Sub-Saharan Africa face the highest burden of this disease. The clinical symptoms of malaria are caused by the cyclical infection and rupture of red blood cells by Plasmodium, and these parasites are cleared from the blood by the immune system. Plasmodium infection does not induce sterilizing immunity; however, individuals can generate clinical immunity to malaria after repeated exposures, but the factors that regulate this process are poorly understood. An emerging modulator of the immune response is the gut microbiome. We previously identified that the composition of the gut microbiome correlates with the outcome of Plasmodium infections in African children and impacts ability of the immune system to fight a Plasmodium infection in mice. We next investigated how the gut microbiome impacts the immune memory response in mice. We determined that the gut microbiome influences the formation of memory B cells and memory T cells during primary Plasmodium yoelii infection. Furthermore, the gut microbiome governs the ability of these immune memory cells to mount a secondary germinal center (GC) response to a Plasmodium berghei ANKA challenge. Curiously, the gut microbiome did not affect the accumulation of plasma cells (PCs) in the bone marrow following P. yoelii infection, and we observed that antigen-specific PC accumulation was poor. It is hypothesized that PCs are important for protection against reinfection with Plasmodium due to their ability to secrete high-affinity antibodies. We next characterized how P. yoelii infection impacted the generation and maintenance of PCs. We discovered that P. yoelii infection impairs the ability of the GC to produce long-lived PCs (LLPCs). Additionally, P. yoelii alters the composition of the bone marrow, negatively impacting the ability of PCs to engraft in the bone marrow as LLPCs. These defects in the generation and maintenance of P. yoelii-induced LLPCs likely impairs the ability of the immune system to protect against future Plasmodium infections.Item 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 MedicineThere 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.Item Decreased Natural Killer Cell Function in Pediatric Severe Malaria in Areas of Higher Transmission(2025-05) Turyasingura, Grace; John, Chandy C.; Kaplan, Mark H.; Schmidt, Nathan W.; Absalon, SabrinaNatural killer (NK) cells inhibit Plasmodium falciparum parasite growth through antibody-dependent cellular cytotoxicity (ADCC) in vitro. Research conducted in malaria-endemic regions has demonstrated that memory-like NK cells are elevated in individuals exposed to malaria, exhibit enhanced ADCC activity, and correlate with reduced parasitemia and protection against uncomplicated malaria. However, the role of NK cells in pediatric severe malaria (SM) is not known. To evaluate the NK cell phenotype and function in SM, we used flow cytometry to evaluate CD56 bright, CD56 dim, and CD56 neg NK cell subsets in Ugandan children 6 months – 4 years of age with SM (cerebral malaria (CM), n=11), severe malarial anemia (SMA), n=10) and asymptomatic community children as controls (CC, n=19). Children were enrolled from sites of moderate (Jinja) and low (Kampala) malaria transmission. Analysis revealed that children with SM had a lower proportion of total NK cells and CD56 bright NK cells; however, absolute counts of NK cells per ml did not differ. In addition, LILRB1, an inhibitory receptor, was the only phenotypic marker whose proportions were significantly increased in children with SM compared to CC. Functionally, children with SM had a higher proportion of degranulating (CD107a+, IFN-γ-) memory-like NK cells. However, memory-like NK cell subsets from children with SM had a lower proportion of interferon-γ only (CD107a-, IFN-γ+)-production than CC. In addition, when comparing malaria transmission intensities with NK cell function, NK cells of children with SM in moderate transmission area exhibited a lower proportion of degranulation compared to the area of low transmission. Conversely, in low malaria transmission areas, NK cells of children with SM demonstrated a higher proportion of degranulation compared to CC. These findings elucidate distinct functional differences in NK cells among children with SM in areas of low versus moderate malaria transmission.Item Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium infection(Cell Press, 2021-05-11) Mandal, Rabindra K.; Denny, Joshua E.; Namazzi, Ruth; Opoka, Robert O.; Datta, Dibyadyuti; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of MedicineGut microbiota educate the local and distal immune system in early life to imprint long-term immunological outcomes while maintaining the capacity to dynamically modulate the local mucosal immune system throughout life. It is unknown whether gut microbiota provide signals that dynamically regulate distal immune responses following an extra-gastrointestinal infection. We show here that gut bacteria composition correlated with the severity of malaria in children. Using the murine model of malaria, we demonstrate that parasite burden and spleen germinal center reactions are malleable to dynamic cues provided by gut bacteria. Whereas antibiotic-induced changes in gut bacteria have been associated with immunopathology or impairment of immunity, the data demonstrate that antibiotic-induced changes in gut bacteria can enhance immunity to Plasmodium. This effect is not universal but depends on baseline gut bacteria composition. These data demonstrate the dynamic communications that exist among gut bacteria, the gut-distal immune system, and control of Plasmodium infection.Item Dysbiotic lung microbial communities of neonates from allergic mothers confer neonate responsiveness to suboptimal allergen(Frontiers Media, 2023-03-10) Bloodworth, Jeffery C.; Hoji, Aki; Wolff, Garen; Mandal, Rabindra K.; Schmidt, Nathan W.; Deshane, Jessy S.; Morrow, Casey D.; Kloepfer, Kirsten M.; Cook-Mills, Joan M.; Pediatrics, School of MedicineIn humans and animals, offspring of allergic mothers have increased responsiveness to allergens. This is blocked in mice by maternal supplementation with α-tocopherol (αT). Also, adults and children with allergic asthma have airway microbiome dysbiosis with increased Proteobacteria and may have decreased Bacteroidota. It is not known whether αT alters neonate development of lung microbiome dysbiosis or whether neonate lung dysbiosis modifies development of allergy. To address this, the bronchoalveolar lavage was analyzed by 16S rRNA gene analysis (bacterial microbiome) from pups of allergic and non-allergic mothers with a basal diet or αT-supplemented diet. Before and after allergen challenge, pups of allergic mothers had dysbiosis in lung microbial composition with increased Proteobacteria and decreased Bacteroidota and this was blocked by αT supplementation. We determined whether intratracheal transfer of pup lung dysbiotic microbial communities modifies the development of allergy in recipient pups early in life. Interestingly, transfer of dysbiotic lung microbial communities from neonates of allergic mothers to neonates of non-allergic mothers was sufficient to confer responsiveness to allergen in the recipient pups. In contrast, neonates of allergic mothers were not protected from development of allergy by transfer of donor lung microbial communities from either neonates of non-allergic mothers or neonates of αT-supplemented allergic mothers. These data suggest that the dysbiotic lung microbiota is dominant and sufficient for enhanced neonate responsiveness to allergen. Importantly, infants within the INHANCE cohort with an anti-inflammatory profile of tocopherol isoforms had an altered microbiome composition compared to infants with a pro-inflammatory profile of tocopherol isoforms. These data may inform design of future studies for approaches in the prevention or intervention in asthma and allergic disease early in life.Item Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria(Springer, 2023-10-13) Mandal, Rabindra K.; Mandal, Anita; Denny, Joshua E.; Namazii, Ruth; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of MedicineMalaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.Item Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria(Springer Nature, 2023-10-13) Mandal, Rabindra K.; Mandal, Anita; Denny, Joshua E.; Namazii, Ruth; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of MedicineMalaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.Item Gut Microbial Changes Associated With Obesity in Youth With Type 1 Diabetes(Oxford University Press, 2025) Ismail, Heba M.; Perera, Dimuthu; Mandal, Rabindra; DiMeglio, Linda A.; Evans-Molina, Carmella; Hannon, Tamara; Petrosino, Joseph; Javornik Cregeen, Sara; Schmidt, Nathan W.; Pediatrics, School of MedicineContext: Obesity is prevalent in type 1 diabetes (T1D) and is problematic with higher risk for diabetes complications. It is unknown to what extent gut microbiome changes are associated with obesity and T1D. Objective: This work aimed to describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized statistically significant gut microbial and metabolite differences in lean T1D youth (body mass index [BMI]: 5%-<85%) vs those with obesity (BMI: ≥95%). Methods: We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) differences in lean (n = 27) and obese (n = 21) T1D youth in a pilot study. The mean ± SD age was 15.3 ± 2.2 years, glycated hemoglobin A1c 7.8 ± 1.3%, diabetes duration 5.1 ± 4.4 years, 42.0% female, and 94.0% were White. Results: Bacterial community composition showed between sample diversity differences (β-diversity) by BMI group (P = .013). There was a higher ratio of Prevotella to Bacteroides in the obese group (P = .0058). There was a differential distribution of significantly abundant taxa in either the lean or obese groups, including increased relative abundance of Prevotella copri, among other taxa in the obese group. Functional profiling showed an upregulation of branched-chain amino acid (BCAA) biosynthesis in the obese group and upregulation of BCAA degradation, tyrosine metabolism, and secondary bile acid biosynthesis in the lean group. Stool SCFAs were higher in the obese vs the lean group (P < .05 for all). Conclusion: Our findings identify a gut microbiome and microbial metabolite signature associated with obesity in T1D. These findings could help identify gut microbiome-targeted therapies to manage obesity in T1D.Item Gut Microbiome Dysbiosis Exacerbates Malaria Severity in Ugandan Children(2025-03) Bednarski, Olivia Joanna; Schmidt, Nathan W.; John, Chandy C.; Kaplan, Mark H.; Sankar, Uma; Tran, Tuan M.Malaria is a life-threatening infectious disease caused by the parasite Plasmodium. Sub-Saharan Africa faces the greatest disease burden and most deaths from severe malaria (SM) occur in children <5 years old. The pathogenesis of SM is not fully known, but murine studies implicate the gut microbiome. It remains unknown if gut microbiota contributes to SM pathogenesis in children. To address this knowledge gap, we sequenced the gut bacteria populations in stool samples from Ugandan children <5 years-old with SM and community children. Our analysis revealed that children with SM have gut bacteria dysbiosis, defined by an increased relative abundance of potentially pathogenic Enterobacteriaceae. Enterobacteriaceae thrive in the presence of inflammation and use diverse nutrients to support growth, and several features of SM associated with gut bacterial dysbiosis, including excess uric acid. Elevated blood uric acid levels during SM from hemolysis and impaired renal clearance likely increases levels of intestinal uric acid, which supports the growth of uricase producing bacteria such as Enterobacteriaceae. Furthermore, Enterobacteriaceae associated with multiple complications of SM such as coma, severe anemia, acidosis, acute kidney injury (AKI), and intestinal damage. Most positive blood cultures from children with SM grew Enterobacteriaceae. Moreover, increased Enterobacteriaceae abundance independently predicted post-discharge mortality in children with SM. The SM complication of excess intravascular hemolysis known as blackwater fever (BWF) also associates with post-discharge mortality, and its incidence has sharply increased in Eastern Uganda. In our cohort, 24% of children with SM reported BWF. This coincided with a significantly greater relative abundance of Enterobacteriaceae bacteria that can cause hemolysis. Our analysis identified 8% of stool samples from children with SM were positive for bacterial Shiga toxin genes, which may contribute to intravascular hemolysis through hemolytic uremic syndrome. This study identified gut dysbiosis during SM that associates with worse clinical complications and post-discharge mortality in a cohort of Ugandan children, suggesting that the gut microbiome may contribute to SM pathogenesis in humans.Item The gut microbiome, immunity, and Plasmodium severity(Elsevier, 2020-12) Waide, Morgan L.; Schmidt, Nathan W.; Pediatrics, School of MedicineMalaria continues to pose a severe threat to over half of the world's population each year. With no long-term, effective vaccine available and a growing resistance to antimalarials, there is a need for innovative methods of Plasmodium treatment. Recent evidence has pointed to a role of the composition of the gut microbiota in the severity of Plasmodium infection in both animal models and human studies. Further evidence has shown that the gut microbiota influences the adaptive immune response of the host, the arm of the immune system necessary for Plasmodium clearance, sustained Plasmodium immunity, and vaccine efficacy. Together, this illustrates the future potential of gut microbiota modulation as a novel method of preventing severe malaria.