Biodefense Training Grant
The predoctoral BIODEFENSE TRAINING PROGRAM at UTMB capitalizes on our outstanding high containment facilities, including the only BSL-4 laboratory at a U.S. university, extensive, and our externally funded research opportunities to study the majority of NIAID Category A-C Priority Pathogens with high experienced faculty scientists. Research opportunities include several major NIH-funded programs such as the Emerging Viral Diseases Unit, the World Reference Center for Emerging Viruses and Arboviruses, the Biodefense Proteomics Collaboratory, and many regional, multidisciplinary biodefense projects through the UTMB-led Region VI Center of Excellence in Biodefense and Emerging Infectious Diseases. The program fosters the interdisciplinary training of young biodefense scientists through: 1) role-modeling by experienced faculty mentors; 2) flexible but rigorous didactic preparation in a wide variety of biomedical disciplines, through one of five different UTMB graduate programs, but united by a required, specialized biodefense curriculum and seminar series; 3) high containment laboratory training, including opportunities for animal and vector research training at BSL-3 and BSL-4; 4) pursuit of a specific biodefense-related dissertation research project under the supervision of experienced, externally funded, highly accomplished faculty members, and; 5) development of professional and ethical behavior that will promote high quality research and effective interdisciplinary interactions. Trainees are selected from a highly competitive applicant pool of students who have completed their required, first year core courses. The recruitment of underrepresented minority students is enhanced by an NIH-funded partnering program involving 7 undergraduate institutions with large minority enrollments, and through UTMB's Summer Undergraduate Research Program and Undergraduate Research Symposium, both of which specifically and successfully target minority students. An external advisory committee composed of outstanding, internationally recognized biodefense scientists and experienced research mentors periodically reviews and guide the program through site visits.
NIAID Priority Pathogens Available for Study in the Traning Program:
Bacillus anthracis (anthrax): Drs. Johnny Peterson
Yersinia pestis: Drs. Alfredo Torres, Ashok Chopra, Vladimir Motin
Francisella tularensis (tularemia): Dr. Gary Klimpel
Viral hemorrhagic fevers:
Arenaviruses: (Lassa Fever, Junin, Machupo, Guanarito viruses): Drs. Judith Aronson, Robert Tesh, Charles Fulhorst, C. J. Peters
Hantaviruses: Drs. Charles Fulhorst, Ramon Flick
Rift Valley Fever: Drs. C. J. Peters, Shinji Makino
Dengue: Drs. Robert Tesh, Scott Weaver, Stephen Higgs, Peter Mason, Alan Barrett
Typhus fever (Rickettsia prowazekii): Drs. David Walker, Juan Olano, Donald Bouyer
Diarrheagenic E. coli: Dr. Alfredo Torres
Pathogenic Vibrios: Dr. Johnny Peterson
Shigella species: Dr. David Niesel
Salmonella: Dr. Ashok Chopra
Viruses (Caliciviruses, Hepatitis A): Dr. Stanley Lemon
Additional viral encephalitides
West Nile Virus: Drs. Robert Tesh, Alan Barrett, Shu-Yuan Xiao, Stephen Higgs, Peter Mason
VEE virus: Drs. Scott Weaver, Robert Davey, Stanley Watowich
EEE virus: Drs. Scott Weaver,
WEE virus: Drs. Scott Weaver,
Japanese Encephalitis Virus: Drs. Alan Barrett, Peter Mason
Kyasanur Forest Virus: Dr. Alan Barrett
Tickborne hemorrhagic fever viruses
Crimean-Congo Hemorrhagic fever virus: Dr. Ramon Flick
Tickborne encephalitis viruses: Dr. Alan Barrett
Yellow fever: Drs. Robert Tesh, Stephen Higgs, Shu-Yuan Xiao, Alan Barrett, Peter Mason
Influenza: Dr. Norbert Roberts
Other Rickettsias: Drs. David Walker, Juan Olano, Donald Bouyer
Description of primary program faculty research programs:
Dr. Scott C. Weaver, Director. Dr. Weaver's research focuses on the pathogenesis, ecology, and genetics of arthropod-borne viruses, especially alphaviruses, and on biodefense including vaccine and antiviral development. His work focuses primarily on the encephalitic alphaviruses, including Venezuelan (VEEV), eastern (EEEV) and western equine encephalitis viruses (WEEV), which are important, naturally emerging pathogens as well as highly developed biological weapons. In collaboration with Dr. Ilya Frolov, chimeric Sindbis virus-based vaccine candidates are being developed against VEEV, EEEV and WEEV, and their safety and efficacy are being tested in mouse and hamster models. Transmission potential is also being evaluated with experimental infection of mosquito vectors. In collaboration with Drs. Stan Watowich and Robert Davey (Program Faculty), antiviral targets are being identified in mutagenized cells that resist cytolysis upon infection, and alphavirus structure and assembly is being studied using cryo-electron microscopy [in collaboration with Drs. Stan Watowich (Program Faculty) and Wah Chiu (Baylor College of Medicine)] and biochemical approaches (with Dr. Watowich). Dr. Weaver's other funded research projects include ecological studies of VEEV emergence in Venezuela, Colombia and Mexico, as well as ecological studies of arboviruses in the Amazon Basin of Peru. The genetic determinants of VEEV emergence are also being studied using small animal models and equine pathogenesis studies, and reverse genetic approaches using infectious cDNA clones.
Dr. Alan Barrett's laboratory investigates the molecular basis of attenuation and virulence of flaviviruses with the aim of generating fundamental information that can used towards the design of flavivirus vaccines. The lab works on yellow fever, tick-borne encephalitis, yellow fever, West Nile and dengue. Projects include structure-function of the envelope protein, investigation of the molecular basis of neurotropism of encephalitic flaviviruses and molecular basis of viscerotropism of yellow fever virus using reverse genetics/infectious clone technology. These studies involve utilizing the mouse and hamster models to study the pathogenesis of these viruses and utility of these animal models to study efficacy of vaccine candidates. Nucleotide sequence analyses are also being used to study the evolution of West Nile and yellow fever viruses.
Dr. Ashok Chopra's research focuses on identifying virulence factors from gram-negative bacterial pathogens and demonstrating their role in causing human diseases by employing biochemical, molecular, and cell biology approaches. Some of the microbial toxins are being tested as mucosal adjuvants. His laboratory has developed attenuated strains of various bacteria that may be new vaccine candidates. His proposal was approved by the NIAID/PFGC to obtain DNA microarrays for studying Salmonella typhimurium pathogenesis under microgravity. Other research initiatives include developing a safe and efficacious DTaP vaccine and new targets to control inflammation in diseases such as IBD and atherosclerosis. Our more recent studies are on discovering new therapies against anthrax and to better understand the pathogenesis of another biological warfare agent Yersinia pestis, which causes plague.
Dr. Mark Estes' biodefense-related research investigates novel adjuvant materials in the development of safe and effect vaccines for threat agents. Two projects are ongoing at present. The first project is investigating a newly described cytokine which has potent activities related to enhancement of antigen-specific mucosal IgA responses. As the majority of infections occur via mucosal routes, including weaponized agents delivered by aerosol, enhancement of IgA responses is essential for strategies where the objective is to prevent pathogen entry or toxin binding. Delivery strategies are under investigation for anti-viral vaccines where neutralizing IgA is known to be effective. A second project is to investigate approaches to improving vaccine efficacy in males and females by modulating sex hormones to foster protective innate and adaptive immune responses. If vaccination against threat agents is advocated across the general population, hormonal status (e.g. pre menopausal, post menopausal, pregnant, HRT) may affect vaccine efficacy. Approaches are being developed to improve vaccine success in females of differing hormonal status against intracellular pathogens.
Dr. Charles Fulhorst's laboratory research is focused on (1) the pathogenesis of arenaviral and hantaviral infections in vivo, (2) immediate post-exposure prophylaxis against hantaviral and arenaviral infections, (3) therapy for the arenaviral hemorrhagic fevers and for hantavirus pulmonary syndrome, and (4) molecular methods for rapid, accurate diagnosis of arenaviral infections. Field studies are designed to understand the ecology and epidemiology of rodent-borne viral diseases and mechanisms of human infection and disease emergence.
Dr. David Gorenstein's research interests include NMR spectroscopy of biological macromolecules, computational biology, proteomics and drug design. He has been particularly interested in structure-based drug design targeting various viruses such as HIV, Hepatitis C and various arena-, flavi- and alphaviruses. He is a member of a collaborative group funded by Defense Advanced Research Projects Agency (DARPA/DoD), Defense Threat Reduction Agency (DTRA/DoD), NIAID and CDC, to develop antivirals and diagnostic methods targeting agents involved in bioterrorism threats. In this program as well as through support of his HIV NIAID grant, he has invented (patented as well as patents pending) new in vitro combinatorial selection and split synthesis (one bead one sequence) technologies for nucleic acid “thioaptamers” with monothiophosphate and dithiophosphate backbone chemistries. These thioaptamers have enhanced affinity towards proteins and represent novel technology utilized to develop thioaptamer proteomics chips.
Dr. Stephen Higgs' research focuses on interactions between mosquitoes and arboviruses. He works with a variety of viruses including yellow fever, West Nile, o'nyong nyong, and Sindbis. Biological, immunologic and molecular techniques are employed to identify viral dissemination in mosquitoes and to investigate the determinants of viral-vector specificities. A hamster model of yellow fever is being modified to demonstrate transmission dynamics of South American viruses by indigenous strains of vector mosquitoes. The influence of vector salivary components upon the vertebrate immune system is being examined to elucidate the effects that natural delivery has upon viral infection, establishment and disease development.
Dr. Gary Klimpel has initiated studies with regard to the human innate immune response to Tularemia. The overall goal of this research is to better understand the local and systemic immune response to these pathogens so that efficient immunotherapies and vaccines can be developed. Thus far, he has directed his efforts toward gaining a better understanding of how different cell populations of the human innate immune system respond to Francisella tularensis. He proposes the following hypotheses: Virulent Francisella tularensis and Francisella tularensis live vaccine strain (LVS) differ in how they interact with the innate immune response. LVS and virulent Francisella induce different innate immune responses with regard to the production of inflammatory cytokines and dendritic cell activation. A full understanding of how the innate immune response reacts to Francisella will be extremely important for not only developing a successful vaccine for this pathogen, but also for furthering our understanding of how this bacterium is recognized by the human immune response and the pathogenesis associated with these infections.
Dr. Stanley Lemon's research focuses on the molecular virology and pathogenesis of hepatitis C. As Director of the NIAID-funded Hepatitis C Cooperative Research Center, Dr. Lemon oversees a range of research projects related to this disease. His laboratory is interested in defining the molecular mechanisms of viral RNA replication. On a broader scale, the laboratory is engaged in efforts to expand the repertoire of laboratory systems available for the study of HCV. This has included the development of transgenic mice that express the complete polyprotein of HCV and that have been shown to develop both hepatic steatosis and hepatocellular carcinoma, common complications of hepatitis C in humans. His laboratory interacts widely with a number of basic and clinical scientists at UTMB who share the desire to develop better ways to control this common and potentially life-threatening infection. Dr. Lemon is also PI of the National Biocontainment Lab proposal.
Dr. Shinji Makino's research focuses on Rift Valley fever virus (RVFV), which causes hemorrhagic fever that kills humans and decimates ruminants. There are no effective countermeasures against RVFV infection. Accordingly, now that bioterrorism has emerged as a real and recurring form of aggression, RVFV merits extensive study. For the development of countermeasures against RVFV-based bioterrorism, Dr. Makino's group studies the molecular genetics, virus-host cell interactions and pathogenesis of RVFV.
Dr. Peter Mason's research is focused on development of new methods to control acute viral diseases including foot-and-mouth disease (FMD) as well as the mosquito-borne flavivirus diseases, dengue and West Nile encephalitis (WNE). FMDV is a USDA select agent due to its ability to cause catastrophic economic losses, and dengue and WNV are category A and B pathogens. Vaccines exist for FMD, but not for dengue or WNE. There are no useful antiviral agents for treatment of any of these diseases. To develop new vaccines and antiviral agents, Dr. Mason is studying these pathogens at multiple levels, ranging from the replication of the RNA genomes to the genetic changes that accompany the appearance of new outbreak strains. Approaches include: 1) development of genetically engineered viruses and subgenomic replicons to evaluate the role of individual sequences in viral replication and pathogenicity, 2) animal models, and 3) detailed analyses of host-cell components, including the innate immune response, that are disrupted by viral infection or hijacked for viral replication. These approaches are designed to help identify new antivirals and vaccines that can aid in the control of these important emerging diseases and bioterrorism threat agents.
Dr. David Niesel's research investigates the genetic and molecular basis of virulence of Streptococcus pneumoniae, an important mediator of community acquired pneumonia and gram negative enteric pathogens, which mediate diarrheal disease syndromes. Current work is focused on investigating in vivo gene expression by these pathogens using recently developed animal models. Differences in gene expression are being discovered using differential display -PCR and DNA microarrays with products identified using database searching in a functional genomic approach. The laboratory also has projects evaluating surface expression of antigens using Salmonella and Mycobacterium bovis BCG as multivalent recombinant vaccine systems.
Dr. C.J. Peters. Most of the work in the laboratory focuses on either Biodefense Category A hemorrhagic fever agents or SARS. Dr. Peters is currently concentrating on Rift Valley fever (RVF) using two models. First, he is evaluating the ability of RVFV peptides expressed in HBc particles or alphavirus replicons expressing RVF G1 and G2 to induce neutralizing antibodies to the attenuated MP-12 RVF strain in mice. Later protection will be confirmed in the BSL4 suite with virulent virus. Second, he is examining another Phlebovirus as a model for RVF and looking at the role of different RNA segments and their coding products as the basis for differential virulence in hamsters. Other projects include evaluating the effects of virulent and attenuated Junin virus (Argentine hemorrhagic fever) on macrophages and dendritic cells, development of Lassa fever models, and selection of mutant cells resistant to SARS virus.
Dr. Johnny Peterson's research focuses on two major areas, the pathogenesis of bacterial enterotoxin-mediated intestinal infections (i.e. cholera, salmonellosis) and the development of therapeutics against the anthrax toxins. The research on cholera and other secretory diarrheal diseases focuses on the role of eicosanoids in intestinal secretion, as well as strategies for interrupting their formation. Experiments are in progress to develop novel antisecretory and anti-inflammatory compounds for improving the treatment of intestinal diseases. Compounds that inhibit the anthrax toxins also are being evaluated in in vitro and in vivo models. The molecular, genetic, and immunological approaches to these research projects will derive mechanistic information that will enable the development of therapeutic and prophylactic approaches for interrupting the pathogenesis of these infectious diseases.
Dr. Norbert Roberts' research addresses three important aspects of influenza that are relevant to biodefense: (1) the immunogenetic basis for resistance of the lymphocytes of certain individuals to infection by influenza virus, a phenotype that has mapped in association with homozygous expression of certain HLA determinants although not yet proven to be based on those HLA determinants; (2) the regulation of cells in the respiratory tract that effectively suppresses unwarranted and constant activation (and inflammation) in response to daily inhaled challenges yet allows and facilitates an appropriate immune response to a perceived threat such as influenza virus or another respiratory virus infection; and (3) the roles of lymphocyte infection, activation, and apoptosis in generation of an effective immune defense (assuring recovery) and immunity to re-infection versus aggressive pathology, and the roles of different virus gene products in inducing these responses.
Dr. Chiaho Shih. Hepatitis B virus (HBV) capsid protein can self-assemble into icosahedral VLP particles in E. coli. Dr. Shih has developed a highly efficient expression, assembly, and purification system for HBV capsid particles. Foreign epitopes, peptides, and proteins (as large as 22 kD) can be expressed at the tip of the particles' spike without affecting the protein folding, solubility, and stability. He has recently succeeded in engineering the HBV capsid expression vector and created a chimera containing a putative neutralizing epitope from Rift Valley fever virus. He is in the process of introducing more unknown or known protective epitopes from SARS and other viruses into this HBV VLP vector. Further investigation of its vaccination and protection potential will be studied using the animal model.
Dr. Robert Tesh studies the epidemiology and pathology of zoonotic viral diseases; a number of the latter diseases are caused by select agents, or by viruses considered to be bioterrorist threat agents. He is currently the P.I. of two large 7-year NIAID contracts dealing directly with select agents or diseases caused by them. The “U.S. Based Collaboration in Emerging Viral and Prion Diseases” consists of 7 distinct research projects dealing with the ecology and pathogenesis of a variety of emerging viral pathogens including Venezuelan equine encephalitis, West Nile, Rift Valley fever, yellow fever and monkeypox viruses, as well as viruses associated with hantavirus pulmonary syndrome, arenaviral hemorrhagic fever and SARS. Work on the various projects involves both field and laboratory studies. The “World Reference Center for Emerging Viruses and Arboviruses” provides the core support for the Reference Center. The intent of the contract is to learn more about the basic biology, virulence, and ecology of emerging viruses and arboviruses and to provide assistance to investigations of emerging or arthropod-borne virus outbreaks throughout the world. Another objective is to maintain the Reference Center's unique collection of emerging and arthropod-borne viruses, which are available to qualified investigators at no cost. Many of the viruses in the collection are select agents and are used by researchers working in the area of biodefense.
Dr. David Walker's research focuses on mechanisms of pathogenesis and immunity to arthropod-borne, obligately intracellular bacteria of the genera Rickettsia and Ehrlichia. Studies to elucidate the structure, adhesins for host cells, antigenic composition and characterization of T cell epitopes as well as cytokine-driven rickettsicidal activity are ongoing projects. The goals of these projects are the use of molecular methods and our genomes data to develop vaccines against typhus fever, a bioterror threat, and ehrlichiosis, an important emerging infectious disease. Other interests include the development of novel effective diagnostic methods for murine typhus, spotted fever rickettsioses and human monocytic ehrlichiosis, and the definition of the etiology, ecology, and epidemiology of rickettsioses and ehrlichioses in targeted tropical geographic regions.
Dr. Stanley Watowich is developing a phenomics program to rapidly identify and simultaneously validate novel targets for therapeutics against BWT pathogens. The technology identifies both host cell and pathogen targets, and discovers pathogen vulnerabilities that may be common to unrelated BWT pathogens. To demonstrate the efficacy, broad-based nature, and rapid throughput of this technology, he is identifying molecular targets that protect cells against Category A-C pathogens, including Bacillus anthracis, Venezuelan equine encephalitis, Rift Valley fever, West Nile, and yellow fever viruses. The large amount of data generated by this program will be filtered and prioritized, and target validation will initially focus on protective proteomes demonstrating broad antipathogen activity. Analysis of these proteomes will elucidate lead target pathways and mechanisms, from which comprehensive interconnected sets of targets will be identified. The program will deliver diverse, cell-resident proteome libraries, pathogen-resistant cells containing protective proteomes, functionally ranked and validated antipathogen target lists, and a comprehensive analysis of functional interactions within protective proteomes. Together with the new BSL-4 facility, the technology can be employed to rapidly identify validated targets for most BWT and emerging/reemerging pathogens.
Course requirements for Biodefense trainees
The BBSC contains three 16 week “foundation” courses (Biochemistry and Cell Biology offered in the fall term; and Molecular Biology and Genetics offered in the spring term) and a series of fifteen 5-week modules (offered in mixed order throughout the spring and summer terms) dispersed among four clusters of biomedical science (Cluster 1: “Cells, from outside to inside”, with three modules; Cluster II: “Cells to organs to systems”, with 5 modules; Cluster III: “Microbes, viruses and pathogenic mechanisms”, with three modules; and Cluster IV: “Molecular and cellular basis of disease”, with four modules). Unless students have taken equivalent courses previously, they take the three foundation courses plus a minimum of four modules, with at least one from each of the four clusters. The BBSC also includes a two-part course on ethics of scientific conduct.
The Biodefense training program core requirements will integrated into individual graduate program cores to assure that students avoid multiple sets of requirements, while providing the best preparation for careers in biodefense. Accordingly, the core course requirements will depend on the graduate program in which the trainee is registered. The following are the core courses required of all Biodefense trainees:
CORE COURSE REQUIREMENTS AND ELECTIVES FOR ALL BIODEFENSE PROGRAM TRAINEES
1. Biothreat agents and biodefense
2. Emerging and Tropical Diseases
3. Frontiers in Infectious Disease and Tropical Medicine Seminar Series
4. Research Rotations*
*Research rotations are treated as courses at UTMB. They are variable in duration (8 or 16 weeks) and credit hours depending on the graduate program.
ELECTIVES: Selection of electives will depend, in part, on the core course requirements of individual graduate programs but trainees are expected to do a minimum of 3 electives. The following list of electives are available:
1. Evolution of Infectious Disease
9. Molecular Biological Techniques
The trainees will have the opportunity select different career tracks. For example, a trainee interested in pathogenesis may select electives 1, 2, 3 and 4 and a trainee interested in molecular biology of BWT agents may select electives 7, 8, 9 and 12, while a trainee interested in immunology may select electives 10, 11 and 12.
Recruitment and Selection Process. Since 1999, entering students (representing 8 of the UTMB graduate programs) are enrolled as “generalists” in a First Year Basic Biomedical Sciences Curriculum (BBSC [see below]). Thus, this training program cannot directly recruit students, rather we encourage students to apply to UTMB Graduate School. As BBSC students are generalists and do not have to declare their graduate program until the end of the first year, we will generally not support first year graduate students. During the first term of year 1, each of the eight graduate programs participating in BBSC, plus the pre-doctoral training grants (including this one) have three hours allocated for “orientation” to meet with the entire BBSC class and inform them of opportunities in the respective programs. This will enables all first year students to become aware of this training program. The academic activities involved in year 1 are described in detail below. In terms of recruitment and selection, electronic and paper notices will sent to faculty and students (BBSC and advanced students) during the Spring term, informing them of competition for trainee slots with a deadline for applications in May. The following materials will be required for all trainee applications: A CV, undergraduate transcripts and GRE scores, UTMB Graduate School transcript, and letter of nomination from the faculty mentor plus his/her NIH biosketch. In addition, the student will submit a description of their research project in an abbreviated, 2 page NIH R01 format including specific aims, significance and background, preliminary studies, and research design and methods. Special attention will paid to a discussion of relevance to emerging and/or tropical diseases. Applicants for continued funding will be required to report progress made during the previous year. Preliminary data and references will be reported on additional pages. Selection of trainees will made by the Admissions and Recruitment Committee in May-July each year for the following academic year. Applications will be evaluated using an NIH-style scale of 1-5 for each of the following criteria: Academic credentials of the applicant (grades, GRE scores, recommendations etc.), demonstration of a aptitude for research (past research experience, publications and abstracts, etc.), quality of the research proposal, and relevance of the proposed research to biodefense. The Admissions and Recruitment Committee will review the extramural funding of potential mentors, and trainees will not be placed into unfunded laboratories.