Past Trainees

  • Alexandra Abu-Shmais

    Alexandra’s project will focus on gaining a better understanding of the fundamental rules of antibody-antigen interactions. Recently our laboratory developed a technology termed Linking B cell Receptor to Antigen Specificity through Sequencing (LIBRA-seq) that enables the rapid identification of antigen-specific B cells. Using this technology, we have successfully identified B cells capable of recognizing antigens encoded within human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza virus. LIBRA-seq turns BCR-antigen interactions into sequence-able events using DNA barcoding, antigen-specific B cell sorting and single-cell sequencing. As her primary project, Alexandra will leverage the LIBRA-seq technology to construct a human antibody-antigen atlas with specificity towards antigens from a number of common viral pathogens, such as influenza, respiratory syncytial virus, human metapneumovirus, and others. Due to the continuous exposure every person experiences to infection by or vaccination against these common pathogens, antigen-specific B cells can be identified in virtually anyone. Yet, there is still extremely limited information about the repertoires of B cells that different individuals use to recognize these common pathogens and vaccines. With the application of the LIBRA-seq technology, Alexandra will aim to create a high-resolution “atlas” of antibodies and their antigen specificity, resulting in unparalleled depth of information about antibody-antigen interactions. Identified B cells will be produced as recombinant monoclonal antibodies and tested in various assays to define their structural, functional, and other characteristics. Aligned with the CBID goals, this project will entail a variety of biochemical methods, such as protein purification and binding assays, oligonucleotideprotein conjugation, structural biology, and others, in order to gain novel insights into the fundamental rules of antibody-antigen interactions for a variety of pathogens. Furthermore, the outcomes of this proposal may lead to the discovery of novel antibodies of potential therapeutic or vaccine template interest against biomedically relevant agents of infectious disease.

    Cohort: 2019
    Principal Investigator: Ivelin Georgiev, Ph.D.
    Internship Company: AstraZeneca
    Internship Year: 2022
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  • Maria Agostini

    Coronaviruses (CoVs) are widely distributed amongst several species and exhibit great potential for crossing species barriers, as exemplified by the emergence of two novel CoVs, SARS-CoV and MERS-CoV, within the past 15 years. There are no antivirals or vaccines currently available against these infections, demonstrating the need for new therapeutic agents that are broadly effective against CoVs. With a genome of up to 34 kb in length, coronaviruses are the largest of the non-segmented, positive sense, single-stranded RNA viruses. They encode 16 non-structural proteins (nsps) involved in replication. The viral RNA-dependent RNA polymerase (RdRp) encoded within nsp12 is central to viral propagation, as it is required for replication and transcription of the viral genome. Thus, it is an attractive target for antiviral development. GS-5734 and EIDD-1931 are nucleoside analogs that show strong antiviral activity against several viruses, including CoVs. However, the mechanism of action of these antiviral nucleosides in CoVs remains unknown. The goals of this project have been to identify the viral target of the nucleosides as well as assess the ability of EIDD-1931 and GS-5734 to cause mutagenesis and chain termination in CoVs. Together, these studies have helped identify the viral target of the compounds and their effects on viral genome replication. The work contributes to the preclinical development of these promising agents in collaboration with Gilead Sciences and the Emory Institute for Drug Development, and will also aid and inform future antiviral drug design.

    Cohort: 2014
    Principal Investigator: Mark R. Denison, M.D.
    Internship Company: Gilead
    Internship Year: 2017
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  • Katherine Almasy

    Flaviviruses, such as Dengue virus, are known to co-opt several host factors within the host cell endoplasmic reticulum (ER) proteostasis network, which is composed of chaperones and other factors important for protein folding, assembly, and quality control. As the virus begins to translate, replicate, and assemble new virions around the ER membrane, the unfolded protein response (UPR) is activated to increase the folding capacity of the organelle. It is composed of three distinct signaling branches, each of which the virus modulates. The specific function of each UPR branch in the context of viral propagation is not well characterized, largely due to a dearth of tools to selectively modulate each branch. We hypothesize that some of the protein-protein interactions between host proteostasis factors and viral proteins are crucial for viral propagation. Using small molecule modulators of the UPR, the project’s aim is to develop a profile of how selective chemical modification of each branch affects specific protein-protein interactions which are critical for viral propagation. Various transcriptomic and proteomic techniques will also be used to determine which steps in the viral life cycle are affected by the modulation. This work may be extended to other flaviviruses such as Yellow Fever and Zika. 

    Cohort: 2017
    Principal Investigator: Lars Plate, Ph.D.
    Internship Company: Pfizer
    Internship Year: 2020
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  • Sarah Arcos

    The battle between viral RNA and host factors begins the instant the viral genome enters a cell. Prior to transcriptional upregulation of interferons, cytokines, and antiviral genes, a cell must rely on mRNAs and proteins that already exist in its cytoplasmic arsenal. In contrast, the virus benefits from any mechanism it can utilize to co-opt host processes before the onslaught of new defenses from transcription alters the internal cellular environment. As the molecular events that comprise these primary interactions between host protein and viral RNA are not well understood, we developed a novel method, VIR-CLASP for Viral Cross-Linking And Solid-phase Purification, to identify proteins that directly bind to pre-replicated, primary, viral RNA genomes. Our approach is applicable to essentially any RNA virus, and captures interactions that occur within minutes of viral entry. We used this approach to identify hundreds of host RBPs that interact with the primary Chikungunya virus (CHIKV) RNA genome, including the YTHDF family of N6-methyladenosine (m6A) binding proteins. We established that m6A modifications are abundant on CHIKV genomic RNA. Furthermore, m6A is involved in regulating many aspects of cellular RNA metabolism and can modulate the pathogenicity of several RNA viruses including Zika, HIV, and Influenza. However, the biological impact of interaction between m6A-binding proteins and primary viral genomes is not known. We discovered that the effect of m6A on CHIKV viral replication is subject to combinatorial regulation by YTHDFs: knockdown and over-expression studies revealed that YTHDF1 strongly restricts viral replication, while YTHDF2 and YTHDF3 have the opposite effect. Our data indicate that the YTHDF proteins have distinct regulatory effects on CHIKV replication and depending on their relative intrinsic cellular levels, can tip the balance of a successful infection. There are currently no direct therapeutic options available to those at risk for CHIKV infection and the debilitating, long-lasting joint pain that follows. VIR-CLASP aims to increase the known repertoire of drug targets for CHIKV, and other RNA viruses, in order to advance current efforts to design vaccines and anti-viral compounds. 

    Cohort: 2015
    Principal Investigator: Manuel Ascano, Ph.D.
    Internship Company: AstraZeneca
    Internship Year: 2018
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  • Monique Bennett

    Nutrient acquisition is necessary for the survival of microorganisms. Nutrient metals, including iron, play key roles in cellular metabolism, respiration, and redox catalysis. One particularly important nutrient acquisition system is the iron-regulated surface determinant (Isd) system that scavenges heme iron from the human host and enables the acquisition of iron in iron-deplete conditions. Staphylococcus aureus uses the cell surface receptors IsdB and IsdH to bind hemoproteins and transfer heme to IsdA, ultimately leading to the transfer of heme across the cell surface for use as an iron source. IsdA is the final surface protein before heme-iron is transported through the peptidoglycan, which presents a unique bottleneck for disruption of heme uptake and establishes IsdA as a promising and unexplored therapeutic target. To define the human B cell response to IsdA, panels of cross-reactive human monoclonal antibodies (mAbs) specific to the surface proteins of the staphylococcal Isd system were isolated and investigated to determine if their function was solely the blocking of heme iron uptake. Two of the identified IsdA-specific mAbs worked cooperatively in a murine septic model of infection to reduce bacterial burden during staphylococcal infection. The protection depended largely on Fc-mediated antibody effector functions, with additional protection imparted from partial heme blocking. This study suggests that IsdA is a potential target for therapeutic human monoclonal antibodies that mediate anti-staphylococcal effects using diverse functions. 

    Cohort: 2014
    Principal Investigator: James E. Crowe, Jr., M.D.
    Internship Company: Merck
    Internship Year: 2017
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  • Mike Doyle

    Cohort: 2016
    Principal Investigator: James E. Crowe, Jr., M.D.
    Internship Company: MedImmune
    Internship Year: 2019
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  • Christopher Good

    Uncovering the complex biological processes which drive pathogenesis requires multimodal technologies that consolidate multi-omics data with spatial and temporal analysis in tissue. Matrix assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is one such technology that offers spatially correlated molecular detection with high sensitivity and label-free chemical specificity. In our laboratory, MALDI IMS has been successfully applied to infectious disease models in order to understand the dynamic molecular interactions at the host-pathogen interface.

    We are interested in exploring Staphylococcus aureus infection in situ to discover bacterial and host factors fundamental to abscess pathology. Currently, I have piloted MALDI IMS lipidomic studies of undecalcified cortical bone, marrow, and surrounding tissue. Using a murine osteomyelitis model, lipid alterations localized to inflammatory lesions will be identified after proper registration of complementary histological techniques. Proteins involved at the foci of infection will be defined and correlated to lipid signatures by using additional spatial proteomic methods. Molecular heterogeneity between abscesses and differences attributed to a host comorbidity like hyperglycemia are unique research directions obtainable by MALDI IMS.

    Regarding the mission of the CBID Training Program, elucidating the factors involved in pathogenesis with MALDI IMS is a valid approach to combating the growing threat of infectious diseases. Classic industrial approaches to antibiotic and drug discovery are insufficient; a more advanced technical investigation of the processes involved is necessary to further drug development and improve human health.

    Cohort: 2019
    Principal Investigator: Richard M. Caprioli, Ph.D.
    Internship Company: GSK
    Internship Year: 2022

  • Samantha Grimes

    Samantha’s research project will focus on the biochemical and genetic determinants of small molecule inhibitors of coronavirus replication. The pandemic SARS-CoV-1 (COVID-19) pandemic has with incredible force demonstrated the capacity of CoVs to emerge to cause profound health consequences and societal disruption, perhaps unprecedented in human history. The need for effective countermeasures (antivirals, monoclonal antibodies, vaccines) is both immediate and long-term. The Denison lab has been a world leader over the past 10 years in preparing for this eventuality, preforming pre-clinical development on two drugs already in human testing in COVID- 19 patients: Remdesivir and EIDD-1931. Both are nucleoside analogs that target the viral RNA dependent RNA polymerase to interfere with viral RNA synthesis by chain termination (remdesivir) and lethal mutagenesis (EIDD-1931). An important feature of both compounds is their ability to evade the unique CoV proofreading exonuclease to inhibit the viral polymerase. Samantha’s project will focus on the use of remdesivir and EIDD-1931 in combination to test their impact on efficacy, prevention of resistance, mechanism of action against the proofreading exonuclease, and testing additional nucleoside analog inhibitors as well as potential direct inhibitors of the exonuclease. She will initiate work with the model CoV, murine hepatitis virus, which has been directly applicable in the results to MERS and SARS-CoV. This will allow rapid progress and testing at BSL2. Concurrently she will initiate training for work at BSL3 with SARSCoV- 2 and will be able to apply her results on inhibitor efficacy, combination Rx, exonuclease mutations and other findings directly to SARS-CoV-2. Based on our previous studies, student outcomes and her project, I believe this work will be of high impact from both research productivity and training perspectives.

    Relevance to CBID: The project has high relevance to the CBID in that the project will use small molecule inhibitors to directly attack CoV replication and determine the virological response to identify new targets. Additionally, this project will work to directly support global efforts to control the COVID-19 pandemic and address future zoonotic CoVs. Further, the project is integrated across multiple disciplines – genetics, biochemistry, pathogenesis, drug development - and is based on established collaborations with a pharmaceutical company and UNC for animal model development. Samantha is very interested in this interface of fundamental biology, biochemistry, and throughput to translational potential. Samantha’s background and training are in microbiology and immunology with demonstrated success in these areas. Now with training and direct application to viral inhibition the project is likely to lead to important discoveries and prepare her for a career at the interface of Chemistry and Biology.

    Cohort: 2019
    Principal Investigator: Mark R. Denison, M.D.
    Internship Company: AstraZeneca
    Internship Year: 2023
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  • Parker Jamieson

    The HIV-1 vaccine field has gone through several significant paradigm shifts, with recent years seeing an overwhelming push toward “rational” immunogen design that incorporates information about known broadly neutralizing antibodies (bNAbs), their epitopes on HIV-1 Env, and the bNAb-epitope interactions. A significant challenge that has hindered the development of an effective HIV-1 vaccine is the limited ability to study antibody responses to vaccination. In particular, current approaches for characterizing antibody responses to vaccination are limited in their ability to generate high-resolution antigen specificity information linked to antibody sequence, thus providing an incomplete understanding of the types and specificities of vaccine-elicited antibody repertoires. This issue is particularly pronounced in the context of multivalent vaccines, since it prevents a detailed understanding of cross-specific vs. strain-specific antibody responses to the different components of the candidate vaccine. To address this issue, we recently developed LIBRA-seq, a technology that enables high-throughput mapping of antibody sequence to antigen specificity for a theoretically unlimited number of antigens, from a single next-generation sequencing experiment. Parker’s project will focus on applying the LIBRA-seq technology to the characterization of antibody responses to vaccination with multivalent immunogens. These efforts will lead to new insights into how the human immune system responds to multivalent vaccines that incorporate a cocktail of multiple different HIV-1 strains.

    Cohort: 2020
    Principal Investigator: Ivelin Georgiev, Ph.D.
    Internship Company: AstraZeneca
    Internship Year: 2023
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  • Grace Morales

    Clostridium difficile is a gram-positive, spore-forming anaerobe, and a leading cause of nosocomial infection in the United States. The infection is dependent on the secretion of one or more AB-type toxins: toxin A (TcdA), toxin B (TcdB), and the C. difficile transferase toxin (CDT, or binary toxin). While TcdA and TcdB are considered the primary virulence factors, multiple studies suggest that CDT increases the severity of CDI. While the mechanism of how CDT contributes to disease is unclear, there are reports that suggest roles for CDT in epithelial cell remodeling and inflammasome activation. This work will define the cell types targeted by CDT and the consequences of CDT intoxication in the context of infection. Training in chemical biology will drive the generation of innovative reagents (ex. toxins with site-specific crosslinkers, fluorescent reporter constructs, cellular probes, and nanobodies) for addressing fundamental questions about CDT function. A better understanding of how CDT contributes to disease is expected to guide vaccine development and therapeutic strategies.

    Cohort: 2018
    Principal Investigator: Maria Hadjifrangiskou, Ph.D.
    Internship Company: Pfizer
    Internship Year: 2018
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  • Aimee (Wilde) Potter

    Staphylococcus aureus is a widespread human pathogen, capable of infecting nearly every organ in the human body. S. aureus is particularly adept at colonizing bone to cause osteomyelitis. In order to discover the genetic programs that accommodate bacterial survival in the skeletal environment, we used an unbiased, genome-wide approach known as transposon sequencing (TnSeq), which identified the S. aureus two-component system SrrAB as essential for sustaining invasive osteomyelitis. SrrAB is known to regulate the aerobic/anaerobic shift and modulate toxin production. These characteristics are especially important in bone, which is an intrinsically hypoxic tissue and is sensitive to pathogen-induced bone destruction. Intriguingly, preliminary data indicate that SrrAB also regulates nutrient utilization programs. The ability of SrrAB to modulate nutrient utilization may be particularly important during osteomyelitis, as resident bone-forming osteoblasts and bone-resorbing osteoclasts exhibit a specialized metabolism requiring elevated glucose uptake, thereby limiting carbon availability to S. aureus during osteomyelitis.  Accordingly, this research investigates SrrAB-dependent virulence responses and metabolic adaptations to the hypoxic skeletal environment.

    Cohort: 2014
    Principal Investigator: James E. Cassat, M.D., Ph.D.
    Internship Company: MedImmune
    Internship Year: 2017
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  • Sydni Caet Smith

    Extracellular vesicles, including exosomes and ectosomes, are used for intercellular communication and cargo transfer, including modulation of inflammation and immunity. Apoptotic bodies are used to systematically clear dead cell debris. A small but growing body of research suggests several viruses are transmitted in extracellular vesicles, which may enable immune evasion and multi-particle transmission. In the Ogden lab, we study mechanisms by which viruses of the Reoviridae family acquire genetic diversity and interact with the host to mediate infection. We have previously observed reovirus release in extracellular vesicles similar in size to ectosomes or apoptotic bodies. We hypothesize that reovirus transmission in extracellular vesicles promotes genetic complementation by enabling simultaneous multi-particle infection of target cells. For my thesis project, I will determine (1) the origin of reovirus-containing vesicles released from infected cells and (2) effects of vesicle-contained virus release on genetic complementation in vitro.

    Cohort: 2018
    Principal Investigator: Kristen M. Ogden, Ph.D.
    Internship Company: Pfizer
    Internship Year: 2021
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  • Ty Sornberger

    Ty Sornberger is a graduate student in the Department of Pathology, Microbiology, and Immunology at Vanderbilt University, mentored by Dr. James E. Crowe, Jr. He graduated from Pennsylvania State University in 2020 with a B.S. in Immunology & Infectious Disease and a B.S. in Pharmacology & Toxicology. Afterward, Ty worked in the Pennsylvania State University COVID-19 Testing and Surveillance Center (TASC), running clinical diagnostic tests for SARS-CoV-2 and assisting with research projects involving SARS-CoV-2 and High-Pathogenicity Avian Influenza (HPAI). Ty entered Vanderbilt University through the Interdisciplinary Graduate Program (IGP) in Fall 2021 and joined the Crowe Lab in Spring 2022. His current research focuses on isolating and characterizing human antibodies against influenza viruses.

    Cohort: 2021
    Principal Investigator: James E. Crowe, Jr., M.D.
    Internship Company: AstraZeneca
    Internship Year: 2024
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  • Sirena Tran

    One of the most pressing clinical challenges that we are currently facing today is the antimicrobial resistance (AMR) problem. Historically we have been trying to battle this problem by creating more potent antibiotics. However, it has become evident that this approach is failing. Part of the efforts in the Cover lab are focused on the development of an alternate strategy to resolve this problem: inhibiting evolution. As the first step towards this goal, the lab is identifying and characterizing proteins that accelerate evolution (“evolvability factors”). One of these proteins is the DNA translocase and RNA polymerase interacting protein, Mfd. The lab has recently found that Mfd is required for the rapid development of AMR, to multiple classes of antibiotics in highly divergent bacteria. However, it is unclear 1) how Mfd increases mutagenesis and 2) whether the microbiome impacts Mfd-dependent AMR development (or AMR development in general). To investigate these questions, Salmonella typhimurium will be used as the model system with various biochemical, molecular biology, and genetic techniques. Additionally, a mouse model of evolution will be developed where we can both monitor the kinetics and degree of AMR development in bacterial pathogens in “regular” versus germ-free mice with and without Mfd.

    Cohort: 2018
    Principal Investigator: Timothy L. Cover, M.D.
    Internship Company: Pfizer
    Internship Year: 2018
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  • Michelle Wiebe

    Two-component signaling (TCS) systems are an important way bacteria sense and respond to changes in their environment. TCSs are typically composed of a sensor histidine kinase and its cognate response regulator. Recent work has revealed that noncognate components of different TCSs can cross interact with each other, complicating the relatively simple signal transduction of these systems. One example of this cross interaction in Uropathogenic E. coli (UPEC) is BtsSR and YpdAB. Serine-pyruvate homeostasis in UPEC appears to be controlled by two two-component systems, BtsSR and YpdAB, with BtsS and YpdA being the receptors and BtsR and YpdB being the corresponding cognate response regulators. Previous studies by our lab demonstrated that YpdAB and BtsSR are active during acute urinary tract infection, where serine is one of the key amino acids utilized by UPEC. Serine is imported into the cell via the action of the SdaC transporter and is then broken down into pyruvate and ammonia by the actions of the SdaA and SdaB enzymes. My project will investigate how the BtsSR and YpdAB systems interact to regulate serine and pyruvate metabolism.

    Cohort: 2018
    Principal Investigator: Maria Hadjifrangiskou, Ph.D.
    Internship Company: AstraZeneca
    Internship Year: 2018
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  • Jade Williams

    The primary project focuses on the development of efficient and concise syntheses of naturally occurring microbial metabolites in order to enable their biological study. There is a growing need for novel therapeutic agents and identification of bacterial targets in the treatment of infectious disease. Thus far, successful completion of the synthesis of the siderophore coelichelin has enabled a collaboration with the Skaar Lab. To date, it has been demonstrated that synthetic coelichelin as well as an N-acylated analog can be utilized to promote bacterial growth in gram-negative, P. aeruginosa. Preliminary results indicate that coelichelin and its analogs could be used in the development of siderophore-antibiotic conjugates and enable advanced study of metal acquisition pathways. A second project focuses on the development of a synthetic route allowing access to the alkylpiperidine arenosclerin, which has not previously been synthesized. Arenosclerin has demonstrated antibacterial activity against several antibiotic-resistant clinical isolates in both gram-negative and gram-positive bacteria. However, further evaluation of arenosclerin has been limited by its availability. An efficient synthetic strategy to provide sufficient material for biological study has now been developed. Following total synthesis of arenosclerin, preliminary studies will commence to further characterize its antibacterial activity and identify its cellular target. 

    Cohort: 2016
    Principal Investigator: Gary A. Sulikowski, Ph.D.
    Internship Company: AbbVie
    Internship Year: 2019
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  • Rachael Wolters, DVM

    Rachael Wolters is a graduate student in the Department of Pathology, Microbiology, and Immunology at Vanderbilt, mentored by Dr. James E. Crowe, Jr. She obtained her B.S. in Animal Science from The University of Tennessee at Martin and went on to earn her Doctor of Veterinary Medicine from The University of Tennessee College of Veterinary Medicine, in Knoxville Tennessee. She is interested in the interface of computation and antibody discovery to infectious diseases. She is currently focused on Influenza B antibody discovery.

    Cohort: 2020
    Principal Investigator: James E. Crowe, Jr., M.D.
    Internship Company: AstraZeneca
    Internship Year: 2023
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