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Schmidt Lab

Plasmodium infections are responsible the infectious disease malaria, which continues to ravage tropical regions around the world. The laboratory of Nathan W. Schmidt, PhD, investigates the host immune response to Plasmodium and how gut microbiota impact the severity of malaria. The goal of this research is to develop approaches to prevent severe malaria-related fatalities.

Dr. Schmidt conducts his research within the Herman B Wells Center for Pediatric Research and the Ryan White Center for Pediatric Infectious Diseases and Global Health.

Herman B Wells Center for Pediatric Research

Ryan White Center for Pediatric Infectious Diseases and Global Health

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Malaria is an infectious disease caused by the parasite Plasmodium, which is 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. The majority of cases and deaths occur in Africa, primarily in children less than 5 years old. The majority of Plasmodium infections are asymptomatic. While some infections progress to clinical uncomplicated malaria, which is debilitating in its own right, a small percentage of infections progress to clinical forms of severe malaria, which are responsible for Plasmodium related deaths. To date, it is not fully understood what factors contribute towards the susceptibility of Plasmodium infection progressing to severe malaria. This knowledge gap hinders discovery of new strategies to prevent this evolution.

Research in the Schmidt Laboratory is focused on understanding the factors that contribute to the severity of malaria, with a particular focus 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 both the murine model of malaria and human samples collected from field studies conducted 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 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 the use of 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 the development of gut microbiome-based therapeutics, we have developed collaborations with investigators conducting studies in several African countries. These studies provide us an opportunity 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, and 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 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.

 

Current Funding

Publications

For a full list of publications from Dr. Schmidt, view his bibliography on PubMed.

  • 2016
    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.
  • 2019
    Chakravarty S, Mandal RK, Duff ML, and Schmidt NW. Intestinal short-chain fatty acid composition does not explain gut microbiota mediated effects on malaria severity. PLoS ONE, 2019, 14 (3): e0214449.

    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.

    Denny JE and Schmidt NW. Oral administration of clinically relevant antimalarial drugs does not modify the murine gut microbiota. Scientific Reports, 2019, 9:11952.
  • 2020
    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.

    Ippolito MM, Denny JE, Nenortas E, Shapiro TA, and Schmidt NW. Evidence of Microbiome–Drug Interaction between the Antimalarial Lumefantrine and Gut Microbiota in Mice. American Journal of Tropical Medicine & Hygiene, 2020, 103:1553-1555.

    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.

    Waide ML and Schmidt NW. The host gut microbiome, immunity and Plasmodium severity. Current Opinion in Microbiology, 2020, 58:56-61.
  • 2021
    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.

Research Team

12491-Schmidt, Nathan

Nathan W. Schmidt, PhD

Associate Professor of Pediatrics

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Kristin M. Van Den Ham, PhD

Postdoctoral Fellow in Pediatrics

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Morgan Little

Lab Manager, Schmidt Lab

Olivia Bednarski

Graduate Student

44179-Mandal, Rabindra

Rabindra Mandal, PhD, BVSCAH

Assistant Research Professor of Pediatrics

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Rafael Polidoro, PhD, MSC

Postdoctoral Fellow in Pediatrics

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Elizabeth Fusco

Graduate Student