The Viral Pathogenesis and Evolution Training Program links students from various graduate programs who are currently training in virology laboratories in Seattle. The program brings together laboratories at Fred Hutch and the University of Washington with the goal of drawing on the rich history of viral research at these institutions to form a unique training opportunity for Seattle-area graduate students.
Funds are available for pre-doctoral trainees interested in viral pathogenesis and evolution research. One or two years of funding is available. The training program will also cover a portion of tuition. The scope of the submitted proposal should include a two-year research plan unless the applicant specifically requests only one year of funding.
Preference will be given to trainees who have not yet received a training grant appointment from another T32 grant.
Please note, this training grant is managed by the UW and thus pay and benefits will be through the UW.
In addition to the curriculum required by the student’s graduate program, students who are funded by the VPETG will be required to take courses that will enhance their training in viral pathogenesis and evolution research, including one course in viral pathogenesis/virology (MCB532 or MICRO 540) and one elective course in either computation biology and immunology (MCB 517 or IMMUN 532). Finally, because writing is an important component of academic scientists' training, VPETP trainees will receive opportunities for additional training in this area.
First, the applicant should send items 1-4 in a single PDF format to the Training Grant Administrator, Jasmine Gonzalez.
File title: "ApplicantLastName_VPETP2022.pdf"
2. Biosketch providing details of your academic training to-date, any relevant research/work experience
3. A copy of your current academic transcript (unofficial OK)
4. Research Proposal. The proposal must be applicable to viral pathogenesis, viral evolution, or computational studies of viruses and you must explain the relevance in the proposal. Please include an explanation of how your research reflects the training grant's goals. This may be included in the Abstract, Background and Significance, or a paragraph at the end of the proposal. The scope of the submitted proposal should include a two-year research plan unless the applicant specifically requests only one year of funding. Proposal guidelines: The proposal should not exceed 2 pages (single spaced, Arial font, 11 pt., including figures). References may be on additional pages. Follow the general NIH format to include Specific Aims, Significance, Innnovation, and Approach.
Second, the applicant’s mentor and the two individuals (non-mentors) writing the applicant’s letters of recommendations should send items 5-6 directly to the Training Grant Administrator, Jasmine Gonzalez.
5. Mentor Summary Form. This form should be filled out by your mentor. In past years we have asked for more traditional letters. However, all the mentor letters said their student was one of the best they have ever seen and they should be funded, which was not helpful to the review committee. It is our hope, that the mentor summary form will be a more informative evaluation of each trainee. Since the success and future funding of the training grant depends on the quality of the students it supports, the review committee would appreciate an honest and realistic summary of the student. Please have your mentor send their summary directly to the Training Grant Administrator, Jasmine Gonzalez.
File Title: : ApplicantLastName_MentorForm_VPETP2022.pdf
6. Letters of Recommendation. Request letters from 2 individuals who are not your mentor. Please have your recommenders send their letters directly to the Training Grant Administrator, Jasmine Gonzalez.
The Avgousti lab is focused on the mechanisms by which viruses hijack chromatin. Studies in her group focus on DNA viruses, which are packaged with small basic proteins that can resemble histones and incorporate histones onto their genomes during infection. The lab uses a multidisciplinary approach including biochemical, molecular biology, cell biology and biophysics to decipher virus-host interactions at the epigenetic level. Trainees in her lab engage in studies of virus-host interactions, proteomics, genome-wide analyses, and viral pathogenesis.
Collaborators on the TG: Adam Geballe, Michael Lagunoff, Jason Smith
The Bedford lab focuses on phylodynamic analysis of pathogen sequence data with an intent of making inferences that are actionable to public health. His primary research goal is to develop mathematical and statistical methods to integrate infectious disease sequence data into evolutionary and epidemiological models. His work integrates population genetics, phylogenetics and epidemiological modeling to understand virus evolution and transmission patterns. This work has a strong statistical and computational basis, using sequence data to arrive at an understanding of underlying processes. By analyzing genetic relationships among viral samples, phylogenetic trees can be constructed that describe the evolutionary history of the viral population and from these trees, patterns of infection can be inferred. Such analyses may offer substantial public health benefit through improvements to vaccine strain selection and outbreak response. Trainee’s in the Bedford lab learn computational and are exposed to public health strategies and they often collaborate closely with other groups on the training grant.
Collaborators on the TG: Jesse Bloom, Erick Matsen, Julie Overbaugh
Dr. Bedford will be mentored until the student(s) who are currently being trained in the lab obtain their PhD.
The Bloom lab uses a mix of experimental and computational approaches to study the evolution of viruses. Much of their work focuses on influenza virus, although they also have projects on HIV, Zika virus, and RSV. One major focus of the group is to use high-throughput experiments to map the effects of large numbers of mutations on the function and antigenicity of viral proteins, and then relate these maps to viral evolution in nature. Another major focus of the group is to use deep-sequencing to characterize the diversity of viral infections of humans. Finally, the group is developing new single-cell sequencing approaches to study viral infection. Trainee’s in the Bloom lab learn a mix of computational and experimental biology, and often collaborate closely with other groups on the training grant.
Collaborators on the training grant: Trevor Bedford, Kelly Lee, Harmit Malik, Erick Matsen, Julie Overbaugh, Rasi Subramaniam
The Bradley lab studies the regulation of RNA processing and metabolism in healthy and diseased cells. His group uses both computational and experimental technologies to identify new regulatory mechanisms governing RNA splicing, surveillance, and decay. His lab seeks to find new disease biology as well as discover ways that basic mechanistic insights can be used to identify new therapeutic opportunities. Areas of current focus in his lab relevant to the VPETP include branchpoint recognition and RNA lariat metabolism in viral encephalitis. Trainees gain a mix of wet-lab and computational skills relevant to RNA biology.
Collaborators on the TG: Rasi Subramaniam
The Emerman lab studies host-cell interactions of the human immunodeficiency virus (HIV) and related viruses in order to understand the molecular and evolutionary basis of virus replication and pathogenesis. They do this by studying the evolution and function of host antiviral genes. Their goal is to determine how HIV adapted to humans, and how ancient viral infections influenced the susceptibility or resistance of humans to modern lentiviruses. Trainees in his lab engage in studies of gene and virus evolution, virus-host cell interactions, high-throughput genetic screens, and functional studies of viral and host proteins.
Collaborators on the TG: Adam Geballe, Harmit Malik, Erick Matsen, Julie Overbaugh
The Galloway laboratory focuses on small DNA tumor viruses, namely human papillomaviruses (HPVs) and human polyomaviruses (HPyVs), in order to better prevent, diagnose and treat the diseases they cause. They have taken a broad-based approach to studying these viruses employing state of the art molecular and immunologic tools, and collaborating with clinicians, epidemiologists and biostatisticians to answer questions of relevance to viral pathogenesis. Trainees learn aspects of virus/host interaction and the epidemiology of viral pathogens.
Collaborators on the TG: Harmit Malik, Paul Nghiem, Roland Strong
Research in the Geballe lab focuses on identifying the factors, dissecting the mechanisms, and understanding the evolutionary pathways used by large DNA viruses, such as cytomegaloviruses and poxviruses, to enable them to replicate efficiently despite host defenses. The lab is interested in the evolutionary “arms race,” between the virus and host cell in which the structure and specificities of the participating genes change with surprising rapidity. Trainees in the lab engage in research aiming to clarify how genes such as TRS1 and IRS1 of human cytomegalovirus genes block the protein kinase R pathway, and how homologous genes in different primate viruses have and can adapt to changes in this and other host defenses.
Collaborators on the TG: Daphne Avgousti, Michael Emerman, Michael Lagunoff, Harmit Malik
The Goo Lab at Fred Hutch studies the immune response to mosquito-borne flaviviruses such as dengue virus, West Nile virus, and Zika virus. We are particularly interested in how antibodies contribute to flavivirus immunity and pathogenesis. By combining tools in virology, molecular biology, immunology, genomics, and epidemiology, we hope our studies will inform the design of vaccines and antiviral drugs.
The Jerome lab focuses on the chronic and latent phases of virus infections, virus immune evasion mechanisms, and potential curative therapeutic approaches to these infections. His most recent work involves the use of enzymes we classify as rare-cutting endonucleases that can specifically target latent viral DNA for cleavage. Upon cleavage of viral DNA mutations are introduced in viral coding sequences and this results in virus inactivation. This approach may allow precise inactivation of functional viral DNA within infected cell reservoirs and offers the prospect of a cure for HIV, HBV and HSV. Trainees in the lab learn methods relevant to gene therapy approaches for viral infections including current approaches aimed at cure.
Collaborators on the TG: Nicole Frahm, Deobrah Fuller
The Lehman lab studies viral dynamics, viral reservoirs and viral transmission. They conduct molecular virology studies in Kenyan cohorts in collaboration with epidemiologists, biostatisticians and clinician scientists at both the University of Washington and the University of Nairobi. Current studies include modeling long term dynamics of the latent HIV reservoir in Kenyan infants and determining the influence of immune activation and function on HIV reservoir size and decay. In addition, Lehman leads a study to define novel components of the human virome (population of all viruses) that impact infant health and to explore mechanisms by which maternal HIV and ART alters the transmission of the virome from mother to infant. Trainees acquire skills in molecular biology, epidemiology, and statistics and are exposed to interdisciplinary research.
Collaborators on the TG: Julie Overbaugh, Erick Matsen
Dr. Lehman will be mentored until the student(s) who are currently being trained in the lab obtain their PhD.
The Lund lab focuses on elucidating the basic mechanisms of anti-viral immunity and mucosal immunity using both mouse models as well as human tissues. Current projects include defining the roles and modes of action of tissue-resident memory T cells and regulatory T cells during mucosal virus infection, identifying novel mucosal immune correlates of protection from HIV-1 infection, and discovering new genes involved in immune responses to flavivirus infection, including both Zika and West Nile viruses. The goal of these studies is to improve clinical interventions for virus infections of public health importance. Trainees in the lab engage in studies of viral immunity and mucosal immunity.
Collaborators on the TG: Nicole Frahm, Michael Gale, Martin Prlic
The Malik lab is interested in the evolutionary rules that shape host-virus interactions. His lab has dissected the evolutionary history of host-virus interactions between primate genomes and retroviruses (with Emerman lab), poxviruses (with Geballe lab), hepaciviruses (with Gale lab) and orthomyxoviruses (with Emerman lab). These case studies of antiviral genes have revealed many common 'evolutionary rules' about when (how old), where (which protein domains) and how (functional consequences of adaptive changes) host-virus 'arms races' have altered the host and viral proteins involved. His work with the Emerman lab has shown that evolutionary analyses can derive evidence of past viral infections, even those that may not have left imprints in host genomes – a term he coins indirect 'paleovirology'. His lab has discovered that one previously unappreciated form of viral adaptation is via 'gene-accordions' that facilitate acquisition of adaptive alleles. Recent focus in the lab has been on the Mx antiviral proteins, and whether their broad specificity against multiple DNA and RNA viruses incurs fitness tradeoffs. Trainees learn both evolutionary and combinatorial mutagenesis strategies to dissect what constraints act on host immunity.
Collaborators on the TG: Jesse Bloom, Michael Emerman, Adam Geballe, Michael Gale, Denise Galloway, Erick Matsen
The Matsen group develops and apply evolutionary methods for molecular sequence data (i.e. DNA and RNA). They enjoy all facets of computational biology research, from diving deeply into biological questions, to mathematical and statistical analysis, algorithm development, and efficient algorithm implementation. Their recent work has developed new methods to analyze metagenomic, viral, and immune cell sequence data, as well as pursued more abstract methodological questions in evolutionary tree reconstruction. They also work to improve the software environment for computational biologists, both by developing our own open-source tools and contributing to work on larger projects. Trainees learn advanced computational skills relevant to the study of viral and immune system evolution.
Collaborators on the TG: Trevor Bedford, Jesse Bloom, Michael Emerman, Dara Lehman, Harmit Malik, Julie Overbaugh
Dr. Matsen will be mentored until the student(s) who are currently being trained in the lab obtain their PhD.
The Overbaugh lab studies mechanisms of HIV transmission and pathogenesis. Studies of her group focus on how the dynamics between the virus and the host influence virus spread and disease outcome. These studies include a detailed analysis of the characteristics of viruses that spread from host to host with a particular emphasis on mother-infant transmission and transmission to high-risk women. The role of HIV-specific immunity in HIV acquisition and pathogenesis, particularly the function of antibodies in providing protection from HIV are current areas of emphasis in the lab. The infant response to infection is also being studied. These studies are done as part of a larger collaborative effort that includes her lab and clinician scientists, epidemiologists and statisticians in both Seattle and Kenya. Trainees engage in studies of viral evolution, virus-host cell interactions, and viral immunology.
Collaborators on the TG: Trevor Bedford, Jesse Bloom, Michael Emerman, Kelly Lee, Dara Lehman, Erick Matsen
The Prlic lab studies how T cell receptor and cytokine signals dictate T cell function and survival in the context of infection. These studies dissect mechanisms of T cell fate decisions using the mouse model system as well as primary human mucosal tissues. The Prlic lab also studies the consequences of innate-like T response in human mucosal tissues, including mucosal-associated invariant T (MAIT) cells. The overall goal is to understand the plasticity of T cell function to ultimately manipulate the T cell response to improve human health, including response to viral infections. Trainees engage in studies of cellular immunology using various single-cell analysis approaches to define cell function relevant to response to infections.
Collaborators on the Training Grant: Jennifer Lund, Ram Savan
The overarching scientific interest of the Strong lab is understanding the molecular mechanisms that functionally differentiate specific versus degenerate or polyspecific protein recognition events. His research focus has been on molecular immunology and vaccinology. They use the tools of structural molecular biology, particularly x-ray crystallography and surface plasmon resonance biomolecular interaction analysis, to study and exploit antibody/antigen interactions including the highly variable HIV Env antigen. Trainees learn basic biochemical and structural methods and are exposed to virology and immunology because the projects are often inherently multi-disciplinary and highly collaborative.
Collaborators on the TG: Denise Galloway
The Subramaniam lab studies mechanisms of mRNA translation in microbial and mammalian cells. Studies in his group focus on identifying kinetic and biophysical constraints on factors mediating translational regulation. These studies utilize genome-wide and computational approaches for identifying how translation is regulated at the initiation, elongation, and termination phases, and are followed by biochemical dissection of the factors involved. Recent work from the group has identified novel sites of translation initiation during influenza infection of human cells. One of these sites were shown to produce functional protein that retains activity. Current efforts are directed towards applying unbiased sequencing-based approaches for uncovering translational regulatory mechanisms during influenza and HIV infection. Trainees in his lab engage in mechanistic studies of viral and host mRNA translation during infection.
Collaborators on the TG: Jesse Bloom, Robert Bradley
The Fuller lab is investigating new vaccine and antiviral concepts aimed at achieving broader, more universal protection against a wider range of highly variable viruses. Using DNA vaccines and antivirals designed to precisely target highly conserved regions in influenza, they have shown significant protection against a wide range of influenza strains in mice, ferrets and nonhuman primates. These studies demonstrate the feasibility of these new platforms for achieving broad protection against HIV and influenza and other highly variable pathogens. These projects involve highly interdisciplinary collaborative efforts with investigators in academia and industry. Trainees in the Fuller lab engage in studies to elucidate mechanisms of protection mediated by these strategies and investigate various approach including novel adjuvants, DNA vaccine delivery approaches and combinatorial regimens to further improve these outcomes.
Collaborators on the TG: Nicole Frahm, Keith Jerome, James Mullins, Shiu-lok Hu, Michael Gale, Don Sodora
Research in the Gale laboratory is focused on:
· Understanding the basis of non-self discrimination and immune response triggering by emerging RNA viruses
· Defining the virus and host interactions that trigger and control innate antiviral immune defenses
· Identifying therapeutic targets for induction and enhancement of innate immunity against RNA virus infection
· Discovery and development of small molecule therapeutics as vaccine adjuvants and for the treatment of viral infection
· Development of vaccines for protection against emerging RNA viruses. Trainees are exposed to both virology and immunology and learn a range of techniques, ranging from classic methods in the study of viruses to high-throughput screening methods for studying innate immune responses.
Collaborators on the TG: Deborah Fuller, Junnifer Lund, Harmit Malik, Ram Savan, Don Sodora
The Hu lab focuses on understanding the pathogenic mechanisms of HIV-1 infection and developing approaches to prevent or control such infections. Current projects include: studies of the role of CS-1 fibronectin in HIV-1 infection of gut-homing T lymphocytes; the role of specific glycans in modulating the structure/function, antigenicity and immunogenicity of HIV-1 envelope proteins; and the use of non-human primate models to study therapeutic approaches against HIV/AIDS, including gene therapy and targeted long-acting combination antiretroviral drugs. Trainees in the lab learn about the preclinical development of vaccines and also how viruses interact with the host immune system.
Collaborators on the TG: Deborah Fuller, Kelly Lee
The Hyde lab studies how virus-host interactions contribute to the pathogenesis of alphaviruses. Studies in her group focus on identifying and characterizing interactions between viruses and host immune molecules (ISGs) that contribute to the development of pathogenesis, and how viral RNA functions to modulate these interactions. These studies include analysis of the molecular mechanism of action of host ISGs, as well as the mechanisms that alphaviruses have evolved to evade these restriction factors. Current areas of focus in the lab are the identification of novel viral RNA structures that modulate interferon sensitivity, and identification of novel host RNA-binding proteins that play a role in restriction or promotion of viral replication. Trainees in the lab learn hos viruses interact with the host to sustain infection.
Collaborators on the TG: Ram Savan
Dr. Hyde will be mentored until the student(s) who are currently being trained in the lab obtain their PhD.
The Lagunoff lab is studying how Kaposi’s Sarcoma herpesvirus alters host endothelial cells to cause Kaposi’s Sarcoma, an endothelial cell-based hyperplasia. The lab studies two main areas of KSHV pathogenesis, KSHV alteration of cellular metabolism and KSHV induction of oncogenic signal transduction pathways to activated latently infected endothelial cells. The lab has shown that KSHV latent infection dramatically alters host cell metabolism and that the alterations in host cell metabolism are required for the survival of latently infected cells, providing a novel therapeutic opportunity. Their studies of KSHV activation of endothelial cells have shown that KSHV induces angiogenic phenotypes and endothelial cell differentiation and that latent KSHV infection can lead to proliferation past senescence in specific types of endothelial cells. Trainees in the lab learn virology and cell biology.
Collaborators in the TG: Daphne Avgousti, Adam Geballe, Jason Smith, Joshua Woodward
The Lee lab studies virus structure and function using cryo-EM, structural mass spectrometry and a range of biophysical approaches. The lab is particularly focused on studies of enveloped viruses including influenza, HIV, and chikungunya virus. Using the complementary approaches, the function of enveloped virus fusion machinery is being characterized. In addition, mechanisms of activation of fusion proteins by receptor binding or inhibition by neutralizing antibodies and anti-viral inhibitors are being investigated. The group collaborates with a number of virus-focused labs including the Overbaugh, Bloom, and Hu groups to study a range of topics including development of neutralizing responses to HIV, influenza virus evolution, and HIV vaccine development. Trainees learn the latest biophysical approaches to understanding viral proteins and how they interact with host proteins and the immune system.
Collaborators in the TG: Jesse Bloom, Shiu-lok Hu, Julie Overbaugh
The Nghiem lab and its multi-disciplinary clinical team focuses on Merkel cell carcinoma (MCC), a UV- and polyomavirus-associated skin cancer that has quadrupled in the past 2 decades. The lab has characterized Merkel polyomavirus-specific T lymphocytes and shown evidence of antigen-specific dysfunction that led them to suggest that PD1 pathway blockade could be beneficial for patients with advanced MCC. Clinical trials of their team have now resulted in PD1 pathway blockade as the new standard of care for MCC, with durable responses for about half of patients with advanced MCC. Trainees learn virology and immunology and also have the opportunity to participate in bench to bedside research.
Collaborators on the TG: Denise Galloway
The Savan lab studies gene regulatory mechanisms that modulate innate immune responses, with a specific focus on exploring the effect of genetic variations in immune genes that affect viral infection. The lab has identified non-coding polymorphisms that strongly associate with susceptibility to HCV and human HIV infections. The lab has also identified new molecular pathways that lead to distinct antiviral responses to type I and III interferons. Savan lab integrates studies on genetic variation and gene-regulatory controls in innate immunity to reveal novel host-pathogen interface. Trainees learn fundamental aspects of the innate immune response to viral infections.
Collaborators on the Training Grant: Michael Gale, Jennifer Hyde, Martin Prlic, Joshua Woodward
The Smith lab studies mucosal immunity to viral infection, with a particular emphasis on the role of enteric alphadefensin antimicrobial peptides in the pathogenesis of gastrointestinal infections. These studies are part of a larger effort to understand the role of epithelial cells in the innate immune response to microbes. Major viruses of interest include adenoviruses and rotaviruses. The lab utilizes molecular virology, traditional cell culture, mouse pathogenesis models, and cutting-edge three-dimensional intestinal epithelial (enteroid) culture models to inform an integrated model of host-pathogen interactions at multiple scales of biology. Projects involve extensive collaboration with scientists both in Seattle and at other major research institutions. Trainees become versed in a wide range of molecular biology, biochemistry, virology, cell biology, and immunology approaches.
Collaborators on the TG: Daphne Avgousti, Michael Lagunoff
The Sodora lab focuses on three general areas that include factors that influence HIV transmission, preclinical vaccine development to prevent HIV transmission, and factors that contribute to HIV-associated co-morbidities, such as liver disease. The lab recently examined the impact of BCG vaccination in infants and how immune activation elicited by vaccination may affect HIV transmission and disease progression. The Sodora Lab also has an ongoing study to evaluate how oral administration of a pre-clinical HIV vaccine drives key innate immune responses required to drive protective adaptive immunity. In addition, there is also a focus on the mechanisms that drive disease pathogenesis after infection, particularly liver disease. Trainees study the dynamics of bacterial communities as they relate to viral infections.
Collaborators on the TG: Michael Gale, Deborah Fuller
The Veesler lab studies the structure and function of macromolecular complexes involved in viral pathogenesis to provide avenues for creating next-generation subunit vaccines and novel therapeutics. They are using a multidisciplinary approach integrating cryo-EM and X-ray crystallography with biophysics, virology and immunology to obtain multi-scale data ranging from atom to whole-cell. They are especially interested in emerging zoonotic viruses with high-pandemic potential, such as coronaviruses and henipaviruses, since cross-species transmission events pose great challenges for public health. Their work places a special emphasis on the glycoproteins decorating the surface of these human pathogens and that promote entry into host cells. Trainees learn skills in structural biology that inform the biology of viral proteins.
Dr. Veesler will be mentored until the student(s) who are currently being trained in the lab obtain their PhD.
The Woodward laboratory aims to define the molecular mechanisms that affect host pathogen interactions. They are interested in small molecules that shape the physiology and pathogenesis of infectious agents, as well as host derived metabolites that contribute to innate and cell intrinsic immunity. A central focus of the lab is the class of second messengers deemed cyclic dinucleotides. CdNs have emerged as key mediators of infectious responses to both bacterial and viral pathogens, eliciting both inflammatory immune responses and global cellular changes aimed at microbe restriction. Recent characterization of the cGAS signaling pathway is underway to define the cell intrinsic restriction of viral replication elicited by the second messenger cGAMP. Trainees utilize genetic, structure-function and biochemical studies to interrogate the molecular interactions between cdNs and their protein targets, together with tissue culture and murine models of infection and disease to define the biological impact of these interactions.
Collaborators on the TG: Michael Lagunoff, Ram Savan
Mentor: Jesse Bloom (Basic Sciences, Fred Hutch)
Project Title: Deep mutational scanning to map human immune selection on influenza neuraminidase
Mentor: Jennifer Hyde (Microbiology, University of Washington)
Project Title: The role of RNA structure in alphavirus pathogenicity
Mentor: Michael Emerman (Human Biology, Fred Hutch)
Project Title: Characterization of novel factors that promote a HIV-1 latency state
Mentor: Jason Smith (Microbiology, University of Washington)
Project Title: Characterizing Rhesus Rotavirus Neutralization by Alpha-Defensins
Mentor: Daphne Avgousti (Human Biology, Fred Hutch)
Project Title: Investigating the function of histone variant macroH2A1 during lytic HSV-1 infection
Mentor: Julie Overbaugh (Human Biology, Fred Hutch)
Project Title: Defining the Role of gp41-Specific Antibodies in Mother to Child Transmission of HIV-1