About

Suzanne McDermott is an Assistant Professor in the Department of Pediatrics, Division of Infectious Diseases at the University of Washington School of Medicine, and a Principal Investigator at the Center for Global Infectious Disease Research at Seattle Children’s Research Institute. Her research focuses on understanding the biology of major protozoan pathogens with broad, global infectious disease impact, and human immune responses to their infection and vaccination. Specifically, she studies the molecular biology of trypanosomes, including Trypanosoma brucei that causes Human African Trypanosomiasis (Sleeping Sickness) and T. cruzi that causes Chagas disease, utilizing structural proteomics and genetics to identify potential therapeutic targets. Additionally, her work involves characterizing immune responses and identifying protective antigens and receptors following Plasmodium and Trypanosoma cruzi infection and vaccination, employing multiomic and systems approaches.

Research topics

• Genetics
• Biology
• Cell biology
• Computational biology

Selected publications

• KREPA6 functions in RNA editing catalytic complex structural organization and gRNA utilization in <i>Trypanosoma brucei</i>

  Nucleic Acids Research · 2026-03-19

  articleOpen access

  Functional mitochondrial mRNAs in Trypanosoma brucei are generated by the post-transcriptional guide RNA (gRNA) directed insertion and deletion of uridine residues, called RNA editing, that is catalyzed by three closely related multiprotein RNA Editing Catalytic Complexes (RECCs). These RECCs contain a common set of 12 proteins including KREPA6 which is largely comprised of an oligonucleotide binding (OB)-fold domain with a predicted intrinsically disordered region (IDR) at its C-terminus. Here we show that certain single amino acid substitutions throughout KREPA6 or deletion of the IDR inhibit the growth and viability of bloodstream form (BF) parasites. These mutations variously impact RECC structure, many alter but do not eliminate RNA editing, and some result in differential utilization of gRNAs. The results indicate that KREPA6 protein has multiple functions some of which stem from its interactions with multiple RECC proteins and perhaps with substrate RNA in each of the three different RECCs. These functions likely involve dynamic interactions of KREPA6 with key domains of other RECC proteins, other editing proteins, and with messenger RNA/gRNA substrates during the multiple catalytic and noncatalytic steps that occur during the complicated editing process.

  PublisherDOI

• Stunning Intricacies of <scp>RNA</scp> Editing Complexes <scp>RECC</scp> , <scp>RESC</scp> , and <scp>REH2C</scp> : Functional Organization, Developmental Regulation, and Evolutionary History in Kinetoplastid Protists

  Wiley Interdisciplinary Reviews - RNA · 2026-02-25

  articleOpen access1st authorCorresponding

  RNA metabolism in kinetoplastid protists (Kinetoplastea), including trypanosomes and Leishmania, involves unique post-transcriptional mitochondrial RNA editing that creates translatable mRNAs through uridine (U) insertions and deletions (U-indels) directed by antisense guide RNAs (gRNAs). Like other biological processes that require specific RNA targeting, this system faces several challenges beyond coordinating its many components: assembling mRNA-gRNA hybrids, recognizing hundreds of sites, and accurately distinguishing pre-edited, partially edited, and fully edited transcripts in the mitochondrial environment. In parasites such as Trypanosoma brucei, significant energetic adaptations to different host environments also involve critical editing changes during development. The editing holoenzyme includes three molecular complexes and isoforms that carry most proteins: RNA Editing Catalytic Complexes (RECCs), which catalyze U-indel cycles; RNA Editing Substrate Complexes (RESCs), which serve as scaffolds to coordinate the editing components; and the RNA Editing Helicase 2 Complex (REH2C), which contains key proteins involved in developmental editing regulation. However, more proteins and functions are being discovered. The editing system, best understood in T. brucei, shows considerable evolutionary conservation in its core machinery; however, it varies in the extent of RNA editing and the organization of mitochondrial mRNA and gRNA genes across different species. Here we explore recent progress in our understanding of RNA editing and the growing use of modern computational tools, including artificial intelligence (AI) and structural methods, to examine function, organization, developmental regulation, and evolutionary aspects of this amazing system. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Processing > RNA Editing and Modification.

  PublisherDOI

• KREH2 helicase represses ND7 mRNA editing in procyclic-stage <i>Trypanosoma brucei</i> by opposite modulation of canonical and “moonlighting” gRNA utilization creating a proposed mRNA structure

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-07

  preprintOpen access

  ABSTRACT Unknown factors regulate mitochondrial U-insertion/deletion (U-indel) RNA editing in procyclic-form (PCF) and bloodstream-form (BSF) T. brucei . This editing, directed by anti-sense gRNAs, creates canonical protein-encoding mRNAs and may developmentally control respiration. Canonical editing by gRNAs that specify protein-encoding mRNA sequences occurs amid massive non-canonical editing of unclear sources and biological significance. We found PCF-specific repression at a major early checkpoint in mRNA ND7, involving helicase KREH2-dependent opposite modulation of canonical and non-canonical “terminator” gRNA utilization. Terminator-programmed editing derails canonical editing and installs proposed repressive structure in 30% of the ND7 transcriptome. BSF-to-PCF differentiation in vitro recreated this negative control. Remarkably, KREH2-RNAi knockdown relieved repression and increased editing progression by reverting canonical/terminator gRNA utilization. ND7 transcripts lacking early terminator-directed editing in PCF exhibited similar negative editing control along the mRNA sequence, suggesting global modulation of gRNA utilization fidelity. The terminator is a “moonlighting” gRNA also associated with mRNA COX3 canonical editing, so the gRNA transcriptome seems multifunctional. Thus, KREH2 is the first identified repressor in developmental editing control. This and our prior work support a model whereby KREH2 activates or represses editing in a stage and substrate-specific manner. KREH2’s novel dual role tunes mitochondrial gene expression in either direction during development.

  PublisherOA PDFDOI

• KREH2 helicase represses ND7 mRNA editing in procyclic-stage <i>Trypanosoma brucei</i> by opposite modulation of canonical and ‘moonlighting’ gRNA utilization creating a proposed mRNA structure

  Nucleic Acids Research · 2024-08-16 · 3 citations

  articleOpen access

  Unknown factors regulate mitochondrial U-insertion/deletion (U-indel) RNA editing in procyclic-form (PCF) and bloodstream-form (BSF) T. brucei. This editing, directed by anti-sense gRNAs, creates canonical protein-encoding mRNAs and may developmentally control respiration. Canonical editing by gRNAs that specify protein-encoding mRNA sequences occurs amid massive non-canonical editing of unclear sources and biological significance. We found PCF-specific repression at a major early checkpoint in mRNA ND7, involving helicase KREH2-dependent opposite modulation of canonical and non-canonical 'terminator' gRNA utilization. Terminator-programmed editing derails canonical editing and installs proposed repressive structure in 30% of the ND7 transcriptome. BSF-to-PCF differentiation in vitro recreated this negative control. Remarkably, KREH2-RNAi knockdown relieved repression and increased editing progression by reverting canonical/terminator gRNA utilization. ND7 transcripts lacking early terminator-directed editing in PCF exhibited similar negative editing control along the mRNA sequence, suggesting global modulation of gRNA utilization fidelity. The terminator is a 'moonlighting' gRNA also associated with mRNA COX3 canonical editing, so the gRNA transcriptome seems multifunctional. Thus, KREH2 is the first identified repressor in developmental editing control. This and our prior work support a model whereby KREH2 activates or represses editing in a stage and substrate-specific manner. KREH2's novel dual role tunes mitochondrial gene expression in either direction during development.

  PublisherDOI

• Deep mutational scanning of the RNase III-like domain in Trypanosoma brucei RNA editing protein KREPB4

  Frontiers in Cellular and Infection Microbiology · 2024-04-08 · 3 citations

  articleOpen access1st authorCorresponding

  Kinetoplastid pathogens including Trypanosoma brucei , T. cruzi , and Leishmania species, are early diverged, eukaryotic, unicellular parasites. Functional understanding of many proteins from these pathogens has been hampered by limited sequence homology to proteins from other model organisms. Here we describe the development of a high-throughput deep mutational scanning approach in T. brucei that facilitates rapid and unbiased assessment of the impacts of many possible amino acid substitutions within a protein on cell fitness, as measured by relative cell growth. The approach leverages several molecular technologies: cells with conditional expression of a wild-type gene of interest and constitutive expression of a library of mutant variants, degron-controlled stabilization of I-SceI meganuclease to mediate highly efficient transfection of a mutant allele library, and a high-throughput sequencing readout for cell growth upon conditional knockdown of wild-type gene expression and exclusive expression of mutant variants. Using this method, we queried the effects of amino acid substitutions in the apparently non-catalytic RNase III-like domain of KREPB4 (B4), which is an essential component of the RNA Editing Catalytic Complexes (RECCs) that carry out mitochondrial RNA editing in T. brucei . We measured the impacts of thousands of B4 variants on bloodstream form cell growth and validated the most deleterious variants containing single amino acid substitutions. Crucially, there was no correlation between phenotypes and amino acid conservation, demonstrating the greater power of this method over traditional sequence homology searching to identify functional residues. The bloodstream form cell growth phenotypes were combined with structural modeling, RECC protein proximity data, and analysis of selected substitutions in procyclic form T. brucei . These analyses revealed that the B4 RNaseIII-like domain is essential for maintenance of RECC integrity and RECC protein abundances and is also involved in changes in RECCs that occur between bloodstream and procyclic form life cycle stages.

  PublisherOA PDFDOI

• mt-LAF3 is a pseudouridine synthase ortholog required for mitochondrial rRNA and mRNA gene expression in Trypanosoma brucei

  International Journal for Parasitology · 2023-06-01 · 4 citations

  articleOpen access1st authorCorresponding

  Trypanosoma brucei and related kinetoplastid parasites possess unique RNA processing pathways, including in their mitochondria, that regulate metabolism and development. Altering RNA composition or conformation through nucleotide modifications is one such pathway, and modifications including pseudouridine regulate RNA fate and function in many organisms. We surveyed pseudouridine synthase (PUS) orthologs in trypanosomatids, with a particular interest in mitochondrial enzymes due to their potential importance for mitochondrial function and metabolism. Trypanosoma brucei mitochondrial (mt)-LAF3 is an ortholog of human and yeast mitochondrial PUS enzymes, and a mitoribosome assembly factor, but structural studies differ in their conclusion as to whether it has PUS catalytic activity. Here, we generated T. brucei cells that are conditionally null (CN) for mt-LAF3 expression and showed that mt-LAF3 loss is lethal and disrupts mitochondrial membrane potential (ΔΨm). Addition of a mutant gamma ATP synthase allele to the CN cells permitted ΔΨm maintenance and cell survival, allowing us to assess primary effects on mitochondrial RNAs. As expected, these studies showed that loss of mt-LAF3 dramatically decreases levels of mitochondrial 12S and 9S rRNAs. Notably, we also observed decreases in mitochondrial mRNA levels, including differential effects on edited vs. pre-edited mRNAs, indicating that mt-LAF3 is required for mitochondrial rRNA and mRNA processing, including of edited transcripts. To assess the importance of PUS catalytic activity in mt-LAF3 we mutated a conserved aspartate that is necessary for catalysis in other PUS enzymes and showed it is not essential for cell growth, or maintenance of ΔΨm and mitochondrial RNA levels. Together, these results indicate that mt-LAF3 is required for normal expression of mitochondrial mRNAs in addition to rRNAs, but that PUS catalytic activity is not required for these functions. Instead, our work, combined with previous structural studies, suggests that T. brucei mt-LAF3 acts as a mitochondrial RNA-stabilizing scaffold.

  PublisherDOI

• Proteome Analysis for Inflammation Related to Acute and Convalescent Infection

  Inflammation · 2023-10-13 · 5 citations

  articleOpen access

  Infectious diseases are a significant burden in global healthcare. Pathogens engage with different host defense mechanisms. However, it is currently unknown if there are disease-specific immune signatures and/or if different pathogens elicit common immune-associated molecular entities to common therapeutic interventions. We studied patients enrolled through the Human Immunology Project Consortium (HIPC), which focuses on immune responses to various infections. Blood samples were collected and analyzed from patients during infection and follow-up time points at the convalescent stage. The study included samples from patients with Lyme disease (LD), tuberculosis (TB), malaria (MLA), dengue virus (DENV), and West Nile virus (WNV), as well as kidney transplant patients with cytomegalovirus (CMV) and polyomavirus (BKV) infections. Using an antibody-based assay, we quantified ~ 350 cell surface markers, cytokines, and chemokines involved in inflammation and immunity. Unique protein signatures were identified specific to the acute phase of infection irrespective of the pathogen type, with significant changes during convalescence. In addition, tumor necrosis factor receptor superfamily member 6 (TNR6), C-C Motif Chemokine Receptor 7 (CCR7), and C-C motif chemokine ligand-1 (CCL1) were increased in the acute and convalescent phases across all viral, bacterial, and protozoan compared to blood from healthy donors. Furthermore, despite the differences between pathogens, proteins were enriched in common biological pathways such as cell surface receptor signaling pathway and response to external stimulus. In conclusion, we demonstrated that irrespective of the pathogen type, there are common immunoregulatory and proinflammatory signals.

  PublisherOA PDFDOI

• RNA editing catalytic complexes edit multiple mRNA sites non-processively in Trypanosoma brucei

  Molecular and Biochemical Parasitology · 2023-09-22 · 3 citations

  articleOpen access

  RNA editing generates mature mitochondrial mRNAs in T. brucei by extensive uridine insertion and deletion at numerous editing sites (ESs) as specified by guide RNAs (gRNAs). The editing is performed by three RNA Editing Catalytic Complexes (RECCs) which each have a different endonuclease in addition to 12 proteins in common resulting in RECC1 that is specific for deletion ESs and RECC2 and RECC3 that are specific for insertion ESs. Thus, different RECCs are required for editing of mRNA sequence regions where single gRNAs specify a combination of insertion and deletion ESs. We investigated how the three different RECCs might edit combinations of insertion and deletion ESs that are specified by single gRNAs by testing whether their endonuclease compositions are stable or dynamic during editing. We analyzed in vivo BirA* proximity labeling and found that the endonucleases remain associated with their set of common RECC proteins during editing when expressed at normal physiological levels. We also found that overexpression of endonuclease components resulted in minor effects on RECCs but did not affect growth. Thus, the protein stoichiometries that exist within each RECC can be altered by perturbations of RECC expression levels. These results indicate that editing of consecutive insertion and deletion ESs occurs by successive engagement and disengagement of RECCs, i.e., is non-processive, which is likely the case for consecutive pairs of insertion or deletion ESs. This clarifies the nature of the complex patterns of partially edited mRNAs that occur in vivo.

  PublisherDOI

• Distinct immune responses associated with vaccination status and protection outcomes after malaria challenge

  PLoS Pathogens · 2023-05-17 · 11 citations

  articleOpen accessCorresponding

  Understanding immune mechanisms that mediate malaria protection is critical for improving vaccine development. Vaccination with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) induces high level of sterilizing immunity against malaria and serves as a valuable tool for the study of protective mechanisms. To identify vaccine-induced and protection-associated responses during malarial infection, we performed transcriptome profiling of whole blood and in-depth cellular profiling of PBMCs from volunteers who received either PfRAS or noninfectious mosquito bites, followed by controlled human malaria infection (CHMI) challenge. In-depth single-cell profiling of cell subsets that respond to CHMI in mock-vaccinated individuals showed a predominantly inflammatory transcriptome response. Whole blood transcriptome analysis revealed that gene sets associated with type I and II interferon and NK cell responses were increased in prior to CHMI while T and B cell signatures were decreased as early as one day following CHMI in protected vaccinees. In contrast, non-protected vaccinees and mock-vaccinated individuals exhibited shared transcriptome changes after CHMI characterized by decreased innate cell signatures and inflammatory responses. Additionally, immunophenotyping data showed different induction profiles of vδ2+ γδ T cells, CD56+ CD8+ T effector memory (Tem) cells, and non-classical monocytes between protected vaccinees and individuals developing blood-stage parasitemia, following treatment and resolution of infection. Our data provide key insights in understanding immune mechanistic pathways of PfRAS-induced protection and infective CHMI. We demonstrate that vaccine-induced immune response is heterogenous between protected and non-protected vaccinees and that inducted-malaria protection by PfRAS is associated with early and rapid changes in interferon, NK cell and adaptive immune responses. Trial Registration: ClinicalTrials.gov NCT01994525.

  PublisherOA PDFDOI

• Multiple domains of the integral KREPA3 protein are critical for the structure and precise functions of RNA editing catalytic complexes in <i>Trypanosoma brucei</i>

  RNA · 2023-07-20 · 4 citations

  articleOpen access

  The gRNA directed U-insertion and deletion editing of mitochondrial mRNAs that is essential in different life-cycle stages for the protozoan parasite Trypanosoma brucei is performed by three similar multiprotein catalytic complexes (CCs) that contain the requisite enzymes. These CCs also contain a common set of eight proteins that have no apparent direct catalytic function, including six that have an OB-fold domain. We show here that one of these OB-fold proteins, KREPA3 (A3), has structural homology to other editing proteins, is essential for editing, and is multifunctional. We investigated A3 function by analyzing the effects of single amino acid loss of function mutations, most of which were identified by screening bloodstream form (BF) parasites for loss of growth following random mutagenesis. Mutations in the zinc fingers (ZFs), an intrinsically disordered region (IDR), and several within or near the carboxy-terminal OB-fold domain variably impacted CC structural integrity and editing. Some mutations resulted in almost complete loss of CCs and its proteins and editing, whereas others retained CCs but had aberrant editing. All but a mutation which is near the OB-fold affected growth and editing in BF but not procyclic form (PF) parasites. These data indicate that multiple positions within A3 have essential functions that contribute to the structural integrity of CCs, the precision of editing and the developmental differences in editing between BF and PF stages.

  PublisherOA PDFDOI

Recent grants

• Collaborative Research: RNA Processing in Trypanosome Mitochondria

  NSF · $523k · 2022–2026

Frequent coauthors

• Kenneth Stuart

  Infectious Disease Research Institute

  48 shared

• Jason Carnes

  Infectious Disease Research Institute

  35 shared

• Julius Lukeš

  University of South Bohemia in České Budějovice

  12 shared

• Achim Schnaufer

  University of Edinburgh

  11 shared

• Ken Stuart

  9 shared

• Alasdair Ivens

  University of Edinburgh

  9 shared

• Igor Cestari

  McGill University

  8 shared

• De‐Hua Lai

  Biocon (Switzerland)

  8 shared

Education

• PhD Developmental Cell Biology, Ilan Davis lab

  University of Edinburgh

  2009

• MRes Life Sciences

  University of Edinburgh

  2005

• BA/MSci Natural Sciences (Biochemistry), Robinson College

  University of Cambridge

  2004