The Schmidt laboratory investigates the host immune response to Plasmodium and how gut microbiota impacts the severity of malaria. This research aims to develop approaches to prevent severe malaria-related fatalities.
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Malaria is an infectious disease caused by the parasite Plasmodium, transmitted between humans by infected mosquitoes. Plasmodium infections remain endemic throughout the tropical regions of the world, where they cause >200 million cases of malaria and >400,000 deaths annually. Most malaria cases and deaths occur in Africa, primarily in children under 5 years old. While some Plasmodium infections progress to uncomplicated clinical malaria, which is debilitating in its own right, a small percentage of infections progress to clinical forms of severe malaria that are responsible for Plasmodium-related deaths. The factors contributing to the susceptibility of Plasmodium infection progressing to severe malaria remain undefined. This knowledge gap hinders the discovery of new strategies to prevent this evolution.
The Schmidt Laboratory focuses on understanding the factors contributing to the severity of malaria, particularly focusing on the gut microbiota-host-Plasmodium triad. The long-term goal is the development of therapeutics that target this triad to prevent children from dying of severe malaria. To accomplish this goal, the Schmidt Laboratory conducts studies using the murine model of malaria and human samples collected from field studies across sub-Saharan Africa.
Murine models of malaria provide an opportunity to gain fundamental insight into how gut microbiota, in particular gut bacteria, interact with the intestinal and gut-distal immune system to shape the quality and magnitude of the host immune response to Plasmodium. These models also provide an opportunity to explore the direct effects of gut bacteria-derived metabolites on Plasmodium biology. In addition to diverse approaches that interrogate the host immune system, these experiments also incorporate germ-free mice and multi-omics to investigate the gut microbiome.
As the long-term goal is to prevent children from dying of severe malaria through developing gut microbiome-based therapeutics, we have developed collaborations with investigators conducting studies in several African countries. These studies allow us to collect stool and blood samples from children with malaria ranging from asymptomatic infections to severe malaria. We use multi-omics approaches to interrogate the gut microbiome. The host immune response is investigated through analysis of serum biomarkers and phenotypic and functional analysis of immune cell subsets. These approaches allow us to correlate compositional and functional attributes of the gut microbiome with the host immune response and severity of malaria. Finally, through the colonization of germ-free mice with stool samples collected from these African children, we can assess the potential role of the gut microbiota in causing the differential severity of malaria.
NIH R01 AI148525 (Schmidt and John, MPI)
Gut Microbiota and Human Malaria
NIH R01 AI158719 (PI: Tran; Schmidt – Co-I)
Evaluating the Roles of p53 Pathways in Malaria
Villarino NF, LeCleir GR, Denny JE, Dearth SP, Harding CL, Sloan SS, Gribble JL, Campagna SR, Wilhelm SW and Schmidt NW. Composition of the gut microbiota modulates the severity of malaria. Proceedings of the National Academy of Sciences, 2016, 113:2235-2240.
Mandal RK, Crane RJ, Berkley JA, Gumbi W, Wambua J, Ngoi JM, Ndungu FM, and Schmidt NW. Longitudinal analysis of infant stool bacteria communities before and after acute febrile malaria and artemether/lumefantrine treatment. The Journal of Infectious Diseases, 2019, 220:687-698.
Mandal RK, Denny JE, Waide ML, Li Q, Bhutiani N, Anderson CD, Baby BV, Jala VR, Egilmez NK, and Schmidt NW. Temporospatial shifts within commercial laboratory mouse gut microbiota impact experimental reproducibility. BMC Biology, 2020, 18:83.
Waide ML, Polidoro R, Powell WL, Denny JE, Kos J, Tieri DA, Watson CT, and Schmidt NW. Gut microbiota composition modulates the magnitude and quality of germinal center during Plasmodium infections. Cell Reports, 2020, 33:108503.
Mandal RK, Denny JE, Namazzi R, Opoka RO, Datta D, John CC, and Schmidt NW. Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium. Cell Reports, 2021, 35:109094.
Lab Manager, Schmidt Lab
Kristin M. Van Den Ham, PhD
Postdoctoral Fellow in Pediatrics
PhD Graduate Student
MD/PhD Graduate Student