Browsing by Author "Schmidt, Nathan"

Now showing 1 - 4 of 4
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    Antibodies and Risk of Clinical Malaria in an Area of Low Malaria Transmission in Western Kenya
    (2024-12) Odhiambo, Eliud Isaac Onyango; John, Chandy; Dent, Alexander; Cook-Mills, Joan; Schmidt, Nathan; Jerde, Travis
    Children and adults are at risk for clinical malaria in areas of low malaria transmission. Antibody or antibody effector mechanism correlates of immunity in these areas, and their differences by age, are poorly characterized. To address this research gap, we evaluated the relationship of Plasmodium falciparum-specific antibody levels and merozoite opsonic phagocytosis to the risk of clinical malaria in a case-control study nested within a cohort of 5,753 individuals in a Kenyan highland area with low malaria transmission. Plasma samples were collected in 2007, and individuals evaluated over 10-year follow-up for risk of clinical malaria. Individuals who developed clinical malaria (cases) were matched by village and age to those who did not (controls). We evaluated total IgG, IgG1, IgG3, IgA, and IgM antibodies to Plasmodium falciparum antigens by cytometric bead assay, and opsonic phagocytosis (OP) by flow cytometry. Antibody and OP levels were compared to risk of clinical malaria in three age groups (< 5 years, 5-14 years and  15 years), adjusting for multiple markers of malaria exposure. Antibody and OP levels increased with age. In children < 5 years old, higher levels of total IgG and IgG1 to the P. falciparum antigen GLURP-R2 and total IgG and IgG3 to the P. falciparum antigen MSP-2 were associated with reduced risk of clinical malaria, but OP levels were not associated with risk of clinical malaria. Conversely, in children 5-14 years old and individuals ≥ 15 years old, higher antibody levels to multiple antigens as well as higher OP levels were associated with increased risk of clinical malaria. In this low transmission area, antibody and OP levels in individuals ≥ 5 years old may serve as markers of malaria risk that add to known risk markers in this area such as insecticide-treated net use, elevation and proximity to forest.
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    Investigation of the Knockout of LMF1 on the Transcriptome of Toxoplasma gondii
    (2024-01) Thibodeau, Katherine E.; Arrizabalaga, Gustavo; Absalon, Sabrina; Fehrenbacher, Jill; Flak, Jonathan; Schmidt, Nathan
    Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects one third of the global population. There are limited treatments for Toxoplasmosis, however a potential drug target for Toxoplasma is its mitochondrion. While much is known about the function of this organelle in Toxoplasma, little is known about the mechanisms that regulate mitochondrial structure and division. The shape of the mitochondrion changes throughout the life cycle of the parasite. When inside a host cell, the mitochondrion is in a lasso shape, stretching around the periphery of the parasite, while in extracellular parasites it is collapsed towards the apical end of the parasite. While in a lasso shape the mitochondrion shows areas of contact with the parasite pellicle. We have determined that the proteins LMF1 (associated with the outer mitochondrial membrane) and IMC10 (inner membrane complex) interact and form a reversible tether that maintains the lasso shape of the mitochondrion. When either of these proteins are knocked out, the mitochondrion collapses. To elucidate the biological relevance of the interaction between the mitochondrion and the pellicle we explored the consequence of disrupting the interaction on the transcriptome of the parasite. RNA sequencing of the LMF1 knockout strain showed a disruption in the expression of genes involved in nucleotide metabolism and Coenzyme A biosynthesis, which might be an adaptation mechanism to the disruption of mitochondrial morphology. Current work focuses on investigating the connection between mitochondrial tethering and these pathways as well as a potential role for the mitochondrion/pellicle connection in metabolite transport.
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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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    The Role of T Cells in Toxoplasma gondii-Induced Prostatic Hyperplasia
    (2024-08) Schmidt, Tara D.; Jerde, Travis; Arrizabalaga, Gustavo; Fehrenbacher, Jill; Relich, Ryan; Schmidt, Nathan
    Chronic inflammation is the most common histological feature in Benign Prostatic Hyperplasia (BPH), and T cells are a key component of immune infiltrate. Advanced BPH is commonly associated with the formation of nodules, but it remains unclear whether a link exists among T cell infiltration, nodular development, and BPH progression. Using a Toxoplasma gondii (T. gondii) model and human specimens, we characterize the subtypes of T cells present during prostatic hyperplasia and their association with nodular development of the prostate. Using flow cytometry, we found that infecting male mice with T. gondii resulted in an increase of both CD4+ and CD8+ T cells in the prostate that was most prominent at 14 days post-infection. Next, we established the presence of microglandular hyperplasia (MGH) and glandular nodule formation at this timepoint through hematoxylin and eosin (H&E) staining. Immunofluorescence revealed that CD8+ cells were found proximal to forming glandular nodules relative to non-nodular glands. We also found that more CD8+ cells localized to non-nodular glands in nodular BPH tissue versus non-nodular BPH tissue. Finally, we discovered a higher prevalence of CD8+ cells in T. gondii IgG+ patients than in IgG- patients. All T. gondii IgG+ patients exhibited nodular BPH, whereas all but one IgG- patient exhibited non-nodular BPH. This study is the first to identify the subsets of T cells in T. gondii-infected mouse prostates. Additionally, the locality of CD4+ and CD8+ T cells to nodular and non-nodular glands within our mouse model and human BPH prostate tissue has never been analyzed. Translationally, CD8+ T cells may enhance nodular BPH progression, and T. gondii infection may promote this CD8+ T cell-mediated response. Future work will focus on dissecting the molecular pathways induced by secreted factors from these CD8+ T cells that may contribute to epithelial cell proliferation and re-activation of glandular patterning in BPH.