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Molecular Pathogenesis of Infectious Diseases

Training PhD candidates to investigate the fundamental mechanisms of microbial pathogenesis


National Institute of Allergies and Infectious Diseases
Molecular Pathogenesis of Infectious Diseases (MPID)
T32 Pre-doctoral Training Program
HIV/AIDS, tuberculosis, acute lower respiratory tract infections, and diarrheal infections are major causes of death, disability, and social and economic disruption for millions of people each year. In addition, emerging, re-emerging and previously unrecognized infections are threats to humans and animals worldwide. Understanding the molecular aspects of infectious diseases provides a rational basis for developing targeted new methods for the diagnosis, prevention, treatment and cure of current and emerging infectious diseases.

The goal of this interdepartmental NIAID MPID T32 training grant is to train PhD candidates to both investigate the mechanisms by which human microbial pathogens cause disease and discover novel therapeutic strategies against a variety of viral, bacterial, and protozoan pathogens. Our training grant provides pre-doctoral students from multiple graduate programs at the University of Colorado Anschutz Medical Campus (UCAMC) with opportunities to train in the molecular pathogenesis of diverse infectious diseases.

Trainees supported by this T32 grant have opportunities to investigate the molecular determinants that allow RNA viruses (e.g., human entroviruses, hepatitis C virus, HIV, reovirus, mosquito-transmitted alphaviruses such as chikungunya virus, Ross River virus, Mayaro virus, and Zika virus), DNA viruses (e.g., varicella zoster virus, human papillomavirus, and gammaherpesvirus), Gram-positive bacteria (e.g., Streptococcus pneumoniae, Group B streptococci, Staphylococcus aureus, Bacillus anthracis, Listeria monocytogenes, Enterococcus feacalis), Gram-negative bacteria (e.g., Salmonella enterica, E. coli, Pseudomonas aeruginosa, Francisella tularensis), Mycobacterium tuberculosis, and protozoan parasites (e.g., Plasmodium and Leishmania) to cause morbidity and mortality in humans worldwide. Our trainees have opportunities to perform structural and functional studies of viral, bacterial, and protozoan virulence factors, and to study the regulation of microbial gene transcription. Most investigations in the laboratories of training faculty provide opportunities of training in translational research, and many involve innate and acquired host responses to viral, bacterial, and protozoan microorganisms in mucosal surfaces, internal viscera, and the central nervous system. The efforts of our faculty to understand the microbiome and its impact on disease susceptibility and host defense provide a dynamic area of molecular pathogenesis with local access to high-throughput sequencing and data analysis. These research opportunities are carried out in the laboratories of 26 training grant faculty in 6 different departments.

Training Program Director. Dr. Vázquez-Torres received his DVM degree from the University of Córdoba, Spain in 1988, and his Ph.D. in Immunology from the Department of Animal Health and Biomedical Sciences at the University of Wisconsin-Madison in 1996. In 2013, he became Professor with Tenure in the Department of Immunology and Microbiology at the UCSOM. He also holds faculty positions in the BSP, MSTP, Molecular Biology, and Immunology Graduate Programs, and the VA Non-clinician Scientist Intramural Career Program.

Dr. Vázquez-Torres is an internationally recognized leader on the molecular biology and pathogenesis of intracellular microorganisms. His lab provides training opportunities to study redox active thiol-based sensors in bacterial resistance to the antimicrobial actions of host NADPH phagocyte oxidase and inducible nitric oxide synthase hemoproteins. This research is uncovering novel bacterial mechanisms of redox sensing, antioxidant and antinitrosative defense, antibiotic tolerance, metabolic adaptation, and virulence. Dr. Vázquez-Torres is the author of 83 research papers, book chapters, reviews and letters. Since 2001, uninterruptedly, the work in the Vázquez-Torres lab has been supported by the NIH and in the last 5 years by the VA. His research has been published in prestigious journals, including Nature, Nature Med, Science, Proceedings of the National Academy of Sciences, J. Exp. Med., Cell Reports, and journals of the American Society for Microbiology and the American Society for Biochemistry and Molecular Biology. In the last five years, he has given 30 invited seminars and lectures at universities, and national and international meetings.

Training Program Associate Director. Dr. K. Tyler has served as the Associate Director of this training grant since 2012. Dr. Tyler is Chair of the Department of Neurology and Co-Director of the Center for Neuroscience. He has graduate faculty appointments in Immunology, Microbiology, Neuroscience and the MSTP programs. He has a strong interest in medical and scientific graduate education, and has served as a mentor of multiple graduate students as well as MD and PhD fellows, including several recipients of F30, F31, K08, KL2 and VA Research Career Development Awards. He also has overall responsibility for the ACGME-accredited Neurology Residency Training Program (21 residents). The extensive experience of Dr. Tyler in directing large programs will continue to aid Dr. Vázquez-Torres in the administration of this T32.

PROGRAM FACULTY

The training faculty members of the MPID have affiliations in the Departments of Biochemistry and Molecular Genetics (Kieft), Biomedical Informatics and Personalized Medicine (Lozupone), Immunology and Microbiology (Barton, Doran, Duerkop, Horswill, Keestra-Gounder, Lenz, Morrison, Pyeon, Rochford, Schurr, van Dyk, Vazquez-Torres, and Voskuil), Medicine (Beckham, Colgan, Cota-Gomez, Janoff, Poeschla, Rosen, Santiago, and Schwartz), Neurology (Nagel and Tyler), and Pharmacology (Churchill) (Table 2). Training faculty members participate in this T32 as mentors, course lecturers, student advisors, and Dissertation Advisory Committee members. They also partake in biweekly seminars entitled “Infectious Diseases Journal Clubs,” and participate in career development workshops organized by the MPID training Program or the Graduate School-administered BEST Program.

Research Programs in the Laboratories of Training Faculty.

Our training grant emphasizes molecular aspects of
  1. bacterial pathogenesis (Drs. Churchill, Doran, Duerkop, Horswill, Janoff, Keestra-Gounder, Schurr, Vázquez-Torres and Voskuil);
  2. viral pathogenesis (Drs. Barton, Beckham, Cota-Gomez, Janoff, Kieft, Morrison, Nagel, Poeschla, Pyeon, Rochford, Rosen, Santiago, Tyler, and van Dyk);
  3. host responses to infection (Drs. Barton, Beckham, Colgan, Cota-Gomez, Janoff, Lenz, Morrison, Pyeon, Rosen, van Dyk, and Vázquez-Torres); and
  4. emerging infections (Beckham, Kieft, Morrison, and Tyler). In addition, the laboratories of Drs. Duerkop, Keestra-Gounder, Lozupone, Janoff, and Schwartz have strong emphasis on the molecular mechanisms by which the microbiome affects health and disease.

The research programs of our training faculty study various aspects of host-pathogen interactions, placing strong emphasis on innate immunity. For example, M. Keestra-Gounder studies how the cytosolic pattern recognition receptors NOD1 and NOD2 induce inflammation in response to type III secretion system effectors of Gram-negative pathogens and how insults of the endoplamic reticulum activate the unfolded protein response. L. Lenz investigates the mechanisms by which the Listeria p60 protein activates interferons and NLRP3 signaling in NK and dendritic cells, and his investigations are revealing how chromatin remodeling silences IFNγ receptor signaling in response to type I interferons. M. Santiago studies cell-intrinsic innate immune responses to nucleic acids of HIV-1 and positive strand RNA viruses, whereas E. Poeschla studies sensing of RNA species generated by RNA-dependent RNA polymerases by MDA5 and RIG-I. H. Rosen’s efforts capitalize on NK cell immunity to HCV in acute and chronic infection before and after antiviral therapy and following liver transplantation. S. Colgan is investigating the role enterocytes and neutrophils play in the development of gastrointestinal inflammation.

Bacterial pathogenesis is also represented among our training faculty. Investigations in the laboratories of K. Doran, M. Schurr, and A. Vazquez-Torres are revealing the importance of two-component regulatory systems in the pathogenesis of Group B Streptococci, Pseudomonas, and Salmonella. A. Horswill, M. Voskuil and A. Vazquez-Torres study the importance of anaerobic and aerobic metabolism in the pathogenesis of Staphylococci, Mycobacterium, Pseudomonas, and Salmonella. The laboratory of A. Horswill is also making important discoveries into the mechanics of peptide quorum-sensing signal production, cysteine proteases, secreted nucleases and extracellular DNA binding proteins as they relate to S. aureus biofilm development. The laboratories of A. Vazquez-Torres and M. Voskuil are interested in uncovering the effect that anaerobiosis and nitrosative stress have on respiratory systems and metabolism induces antibiotic tolerance and pathogenicity of M. tuberculosis, Burkholderia pseudomallei, E. coli and Salmonella.

The laboratories of D. Pyeon, L. van Dyk, and R. Rochford focus on the pathogenesis of DNA viruses such as papillomavirus, and herpesvirus. Our training faculty are using functional genomic analysis of patient tissue specimens from primary human cervical and head/neck tumors to reveal the role APOBEC3 plays in the evolution of papillomavirus in the human host. The laboratory of L. van Dyk is examining the role of gammaherpesvirus cyclin in acute lethal pneumonia, splenic plasma cell lymphoma, vessel disease and perivascular inflammation, pulmonary lymphoma with secondary central nervous system lymphoma, and pulmonary hypertension and fibrosis. She is also characterizing the importance of gammaherpesvirus miRNAs in the regulation of both virus and host gene expression.

Drs. J. Kieft, L. van Dyk, D. Beckham, and K. Tyler investigate how the structures of viral RNA molecules, RNA conformation dynamics, and RNA interactions with other macromolecules dictate biological function and disease. Fundamental knowledge is being gained on viral internal ribosome entry sites, viral tRNA-mimicking RNAs, self-associating phage RNAs, and non-coding RNAs in the pathogenesis of flaviviruses such as Zika and Dengue.
   
Translational Research Opportunities in the laboratories of Training Faculty. Most training faculty conduct some aspects of translational research. For example, based on the discoveries of our trainee J. Humann on the recognition of bacterial polypeptides by human NK cells, the Lenz lab has applied for a patent to develop anti-cancer therapeutics. Work in the laboratories of training faculty spans the spectrum of bacterial, virologic, parasitic and immunologic translational research. Selected examples of these studies include:
  1. the role of interferons human intestinal mucosa to regulate and potentially provide therapeutic approaches to control HIV infection (M. Santiago); 
  2. development of novel immunotherapies and diagnostic/prognostic tools for HPV-positive head/neck and cervical cancers (D. Pyeon);
  3. fundamental mechanisms of disease pathogenesis and therapeutic strategies with small molecules and vaccine candidates in pre-clinical animal models of Chikungunya- and Leishmania-induced disease (T. Morrison);
  4. identification and function of a novel conserved surface protein of Streptococcus pneumoniae isolates from infected patients to develop a broadly protective human vaccine (E. Janoff); 
  5. defining the genomics and transcriptomics of patients presenting with neuroinflammatory diseases in an effort to develop new diagnostic and prognostic assays for clinical care (D. Beckham);
  6. epidemiologic and molecular studies to define the contribution of malaria and EBV infections to the development of Burkitt's lymphoma in Kenyan children (R. Rochford);
  7. defining the relationship of group B streptococci (GBS) with the human vaginal microbiome and other vaginal opportunistic pathogens, as well as characterize the use of probiotics to control GBS vaginal colonization and thereby prevent its transmission to the neonate (K. Doran);
  8. develop novel antibiotics to the RNA polymerase regulatory protein DksA and defining activity against human clinical isolates of diverse Gram-negative, multidrug resistant bacteria (A. Vazquez-Torres); and
  9. use of novel deep-sequencing methods to identify the host and viral RNAs targeted by cellular endoribonucleases in every tissue and organ and to identify novel biomarkers of health and disease in liver biopsies in patients with hepatitis C infection (D. Barton, J. Hesselberth, H. Rosen). These translational opportunities are readily available to our trainees.

Genomic and systems biology opportunities in the laboratories of training faculty. Many of our training faculty employ genomic and systems biology approaches to understanding host or pathogen phenotypes as well as host/microbe interactions that occur in the context of infectious disease. For example, M. Voskuil and A. Vazquez-Torres have developed microarray methods for the study of bacterial pathogens and use whole genome sequencing, RNA and transposon library sequencing, and mass spectrometry metabolomic methods in their research of M. tuberculosis, B. pseudomallei, and Salmonella enterica pathogenesis. D. Schwartz integrates human gene expression (microarray and RNA-seq) and epigenetic (methylation) data to explore the onset of diseases influenced by environmental exposures, including lipopolysaccharide from Gram-negative bacteria. C. Lozupone has developed innovative DNA-based methodologies and analysis software for metagenomic surveys of microbial communities. B. Duerkop and C. Lozupone both use systems biology approaches to study host/microbe and microbe/microbe interactions [with a focus on bacteriophages (Duerkop) or bacteria (Lozupone)]. These are some of the excellent opportunities of training in genomic and systems biology available to our students.

Selection of Students for Support by the MPID Training Grant.

Each year the Steering Committee invites all training faculty to nominate outstanding graduate students in their labs who are working on projects relevant to the molecular pathogenesis of infectious diseases. Applications include the student's CV and academic record, a letter of nomination from the mentor, and a description of the student’s research project. The nominee must be a US citizen or permanent resident who has passed the Comprehensive Examination, has an excellent academic record, and is making excellent progress in the dissertation research project. The nominee must have taken a course in Ethics in Research. The Program Director of the T32 appoints a Selection Committee from among training grant faculty who have not nominated a candidate in that year. The Selection Committee recommends candidates for funding based on the qualifications of the student, the quality of the research, and commitment of the trainee to university leadership and service. Consideration is also given to the participation of the nominee in various aspects of graduate student life, including recruitment of new graduate students to Immunology, Molecular Biology, Microbiology, BSP, and MSTP Graduate Programs; the organization of journal clubs, annual graduate student retreats; scientific awards in national and international meetings; and leadership positions in institutional committees such as the Student Senate or the Graduate Student Council. Outstanding trainees will be considered for a second year of support. Productivity during the first year of support, scientific progress of the research project, quality of oral presentation in the T32 seminar series, and extracurricular activities will be considered for granting a second year of support. The Selection Committee will weigh the desirability of providing a second year of support for outstanding students versus the advantages of distributing the limited number of training positions among students mentored by multiple members of the training faculty.