Marilynn Larson, PhD

Assistant Professor

BS, University of Indiana - Bloomington
PhD, University of Louisville Medical School
Postdoctoral training, Washington State University



Our research focuses on the metabolic mechanisms that allow the facultative intracellular pathogen F. tularensis to evade immune killing, tolerate host stress factors, and then rapidly replicate intracellularly in infected macrophages.  Similar to other highly virulent intracellular pathogens, F. tularensis is auxotrophic for a number of amino acids.  Although excellent progress has been made in the study of this pathogen, particularly for attenuated F. tularensis live vaccine strain (LVS), the factors that allow hypervirulent F. tularensis A.I strains to subvert immune killing and acquire nutrients for rapid replication in the cytosol are predominately unknown.  Accordingly, our goal is to better understand the mechanisms utilized by this select agent to acquire these essential metabolites from the infected immune cell, and to determine the resulting effect on host immune modulation.  Our transcriptome analyses have revealed critical factors that are expressed at considerably higher levels in the hypervirulent F. tularensis A.I strains compared to other less pathogenic clades in this species.  Confirmation of these results were obtained by reverse transcription quantitative PCR (RT-qPCR), as well as by proteomic and metabolomic assessments.  Ongoing study is underway to delineate the functional role of these gene products and the associated metabolites during an infection.

Another area of our research focuses on iron metabolism, since this element is essential to both the host cell and pathogen for numerous redox reactions, including electron transport and the generation of a protein gradient for ATP synthesis.  However, iron levels need to be tightly regulated since high concentrations of this metabolite can be toxic.  During an infection, the immune system initiates an important defense process to withhold iron from the pathogen.  This nutritional immunity requires the pathogen to expend more energy for acquiring iron in order to reproduce and persist.  Conversely, to eliminate an infection, immune cells produce free radicals, which is catalyzed by iron via the Fenton reaction.  These reactive molecules cause a chain of reactions that result in damage to cellular components, potentially causing cell death.  We are investigating the mechanisms utilized by F. tularensis to reduce free radical damage and withstand other host-derived stress factors.