OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
Provide the following information for the Senior/key personnel and
other significant contributors.
Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: Andres Vazquez-Torres, D.V.M., Ph.D.
USER NAME (credential, e.g., agency login): Vazquez-Torres
with baccalaureate or other initial professional education, such as nursing,
include postdoctoral training and residency training if applicable. Add/delete
rows as necessary.)
FIELD OF STUDY
of Córdoba, Córdoba, Spain
of Wisconsin, Madison, WI
of Wisconsin, Madison, WI
A. Personal Statement. The Vázquez-Torres’ lab
studies the molecular mechanisms by which redox active sensors of reactive
oxygen and nitrogen species regulate transcription of genes essential for
bacterial pathogenesis as well as the function of antioxidant and
antinitrosative defenses that protect intracellular pathogens against the
actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase
hemoproteins. The long-term goal of the Vazquez-Torres’ lab is to understand
how sensing of oxidative and nitrosative stress by redox-active bacterial
regulatory proteins promotes antioxidant and antinitrosative defenses,
antibiotic resistance, and pathogenicity. These investigations are conducted in
the clinically important pathogens Salmonella, and Burkholderia. The
basic mechanisms uncovered in these microorganisms are likely generalizable to
a variety of clinically important, phylogenetically diverse pathogenic
bacteria. The fundamental processes studied in our lab are leading to the
identification of new antibiotics against evolutionarily conserved bacterial
Honors, and Awards.
1987-1989: Intern, Department of Parasitology,
Veterinary School, University of Córdoba, Spain.
1989-1990: Visiting Scientist, National Wildlife
Health Research Center, Madison, WI.
1990-1991: Visiting Scientist, Department of Animal
Health and Biomedical Sciences, and Department of Poultry Sciences, University
1991-1996: Graduate Student, Laboratory of Edward
Balish, Ph.D.; Department of Animal Health and Biomedical Sciences; University
1996-2001: Post-Doctoral Fellow, Laboratory of Ferric
C. Fang, M.D.; Division of Infectious Diseases; University of Colorado Health
2001-2008: Assistant Professor, Department of
Microbiology; University of Colorado Health Sciences Center.
2005-present: Biomedical Sciences Program Faculty,
University of Colorado School of Medicine.
2005-present: Medical Scientist Training Program
Faculty, University of Colorado School of Medicine.
2008-2013: Associate Professor with Tenure;
Department of Microbiology; University of Colorado School of Medicine.
2010-present: Program Director of the
multi-departmental T32 pre-doctoral training grant to study Molecular
Pathogenesis of Infectious Diseases.
2012-present: Department of Veterans Affairs and the
Department of Defense Medical Research Service Non-Clinician Scientist
Intramural Career Program.
2012-present: University of Colorado School of
Medicine Molecular Biology Graduate Program.
2013-present: Professor with Tenure, Department of
Immunology and Microbiology, University of Colorado School of Medicine.
Memberships in NIH Study Sections. NIH Bacterial
Pathogenesis Study Section (2007-11); NIH T32 Microbiology and Infectious
Diseases (MID) (2015-2019).
Ad hoc Member Study Sections. NIH Bacteriology
and Mycology ZRG1 BM-1 (2003); NIH Innate Immunity and Inflammation (III)
(2005); NIH Host Interactions with Bacterial Pathogens (2007); Argentinean
National Agency for the Promotion of Science and Technology (2001-2005);
Wellcome Trust (2001-2004); the European Science Foundation (2009); INFB Merit
VA Study Section (2011-2015); NIH T32 Microbiology and Infectious Diseases
MID-B (2014); NIH Topics in Bacterial Pathogenesis IDM-B (2015).
Editorial Board Member for the journals Infection
and Immunity (since 2010) and Frontiers in Cellular Microbiology
Associate Editor for Scientific Reports (since
Ad hoc Reviewer for the Journals: Antioxidants
& Redox Signaling; Am J Physiol; Cell Host Microbe; Cell Microbiol; FEMS
Microbiol Letters; Free Radical Biol Med; Immunology; J Clin Microbiol; J Exp
Med; J Infect Dis; J Leuk Biol; mBio; Microbes Infect; Microbial Pathogenesis;
Microbiology; Mol Microbiol; Nitric Oxide; PLoS ONE; PLoS Pathogens; Traffic;
Society Memberships: American Society of
Microbiology; American Academy for the Advancement of Science; American Society
for Biochemistry and Molecular Biology.
Committee Memberships: Advisory Committee, Boulder
3-D Lab, P01 project (2005); Steering Committee for the Rocky Mountain Research
Center of Excellence (2009-2014); Postdoctoral Association Committee,
University of Colorado School of Medicine (2008-2009); University of Colorado
School of Medicine Faculty Promotions and Tenure Committee (2010-2012); University
of Colorado School of Medicine Rules and Governance Committee (2012); External
Advisory Committee for the T32 Training Program in Comparative Medicine,
College of Veterinary Medicine, Cornell University (2014-present); Vice
Chancellor’s Advisory Committee University of Colorado Denver (2014-present).
Spanish Ministry of Science and Education Merit Fellowship (1983-1984).
F32 Individual National Research Service Award, Department
of Health and Human Services (1998-2001).
Schweppe Career Development Award from the Schweppe
Merck Irving S. Sigal Memorial 2004 Award by the American
Academy of Microbiology (2004).
Burroughs Wellcome Fund Investigators in Pathogenesis of
Infectious Diseases Award (2007).
Teaching Awards presented by the Sophomore Medical Class of the University of
Colorado School of Medicine in the academic years 2001-2, 2003-4, 2004-5, and
Teaching Award presented by University of Colorado Microbiology Graduate
students in 2005.
Fellow to the American Academy of Microbiology (2016).
C. contributions to science (Selected
from 84 original papers, review articles, book chapters, and letters).
Innate immune responses in the
gastrointestinal mucosa. Our investigations have contributed to a greater
understanding of mucosal immunology. We identified a critical role for nitric
oxide (NO) in resistance to mucosal candidiasis. NO produced in response to γδ T cell-generated IFNγ protects mice against gastric candidiasis. We were
the first to discover that lamina propria phagocytic cells sample microbes from
the gut lumen. The ability of dendritic cells to migrate to systemic sites
provides a route for extraintestinal dissemination of pathogenic microorganisms.
We now know that this mechanism of antigen sampling from mucosal surfaces is
exploited by phylogenetically diverse pathogens, including viruses and
bacteria, to gain access to host tissues.
J., A. Vazquez‑Torres, H.C. van der Heyde, T. Warner, R.D. Wagner,
& E. Balish. 1995. γ δ T cell‑induced nitric oxide
production enhances resistance to mucosal candidiasis. Nature Med. 1:
Jones-Carson, A.J. Bäumler, S. Falkow, R. Valdivia, W. Brown, M. Lee, R.
Berggren, W.T. Parks, & F.C. Fang. 1999. Extraintestinal dissemination of
Salmonella via CD18-expressing phagocytes. Nature 401:
Antimicrobial mechanisms of
mononuclear phagocytic cells. Since I was a student in graduate school at
the University of Wisconsin-Madison, I have investigated the mechanisms
underlying the potent antimicrobial activity of mononuclear phagocytic cells. I
have published seminal investigations on the precise reactive oxygen and
nitrogen species used by macrophages in their antimicrobial toolbox. IFNγ-activated
macrophages kill the opportunistic pathogen Candida albicans by
producing peroxynitrite, a product arising from the condensation of NO and
superoxide (O2.-). IFNγ-activated macrophages also
use a combination of reactive oxygen and nitrogen species in their
antimicrobial activity against the Gram-negative pathogen Salmonella
Typhimurium. However, the anti-Salmonella activity of the NADPH
phagocyte oxidase and iNOS is manifested in a sequential manner. An early respiratory
burst, which is dominated by the the enzymatic activity of NADPH phagocyte
oxidase, kills most intracellular Salmonella, whereas reactive nitrogen
species produced by iNOS exert late bacteriostatic activity against this
intracellular pathogen. The strong nitrosative chemistry that dominates late
phases of the innate response of macrophages against Salmonella stems
from reactive nitrogen species generated from acidified nitrite in the
phagosomal lumen, and N2O3 arising from the second order
reaction of NO with molecular oxygen.
Jones-Carson, & E. Balish. 1996. Peroxynitrite contributes to the
candidacidal activity of nitric oxide-producing macrophages. Infect. Immun.
Jones-Carson, P. Mastroeni, H. Ischiropoulous, & F.C. Fang. 2000.
Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide
synthase in experimental salmonellosis. I. Effects on microbial killing by
activated peritoneal macrophages. J. Exp. Med. 192: 227-236.
B.D., J.T. Myers, J. Jones-Carson, M. Husain, & A. Vazquez-Torres.
2008. N2O3 enhances the nitrosative potential of IFNγ-primed
macrophages in response to Salmonella. Immunobiology. 212:
759-69. Epub 2007 Dec 3.
Molecular targets of
reactive species generated in the innate response. Despite the wide
range of biomolecules damaged by reactive species, very few bacterial molecular
targets have been identified. We have shown that cytochrome bd of the
electron transport chain is a preferred target of NO. Nitrosylation of terminal
cytochromes of the electron transport chain arrests replication, thereby
exerting bacteriostasis. NO congeners produced by macrophages also inhibit
transcription of the SPI2 type III secretion system. Cys203 in the
C-terminal dimerization domain of SsrB and PhoP/PhoQ signaling are the
molecular targets by which reactive nitrogen species inhibit SPI2
transcription. To the best of our knowledge, these studies were the first to
realize that, in addition to the classical phosphorylation signal, bacterial
response regulators can be modulated post-translationally by reactive oxygen
and nitrogen species.
B.D., T. Bourret, R. Gill, J. Jones-Carson, & A. Vazquez-Torres.
2005. Repression of SPI2 transcription by nitric oxide-producing, IFNγ-activated
macrophages promotes maturation of Salmonella phagosomes. J. Exp. Med.
M., J. Jones-Carson, M. Song, B.D. McCollister, T.J. Bourret, & A. Vazquez-Torres.
2010. Redox sensor SsrB Cys203 enhances Salmonella fitness
against nitric oxide generated in the host immune response to oral infection. Proc
Natl Acad Sci U.S.A. 107:14396-401. Epub 2010 Jul 26. Faculty of
1000, 13 Aug 2010. F1000.com/4765958
M., T.J. Bourret, B.D. McCollister, J. Laughlin, J. Jones-Carson, & A. Vazquez-Torres.
2008. Respiratory arrest evokes an NADH-dependent adaptive response to
oxidative stress. J. Biol. Chem. 283: 7682-9. Epub 2008 Jan 15.
M.A., T. Tapscott, L.F. Fitzsimmons, L. Liu, A.M. Reyes, S.J. Libby, M.
Trujillo, F.C. Fang, R. Radi, & A. Vázquez-Torres. 2016.
Redox-active sensing by bacterial DksA transcription factors is determined by
cysteine and zinc content. mBio. 7: e02161-15. doi:10.1128/mBio.02161.15.
Novel bacterial defense
mechanisms against reactive oxygen and nitrogen species. Our investigations
have demonstrated critical roles for glutathione, periplasmic superoxide
dismutase, and flavohemoprotein in the antioxidant and antinitrosative arsenal
of Salmonella. In addition to these traditional protective mechanisms, Salmonella
use a unique defense mechanism to avoid the effects of the NADPH phagocyte
oxidase. The type III secretion system encoded within the Salmonella
pathogenicity island-2 helps this facultative intracellular pathogen avoid
contact with vesicles containing the NADPH phagocyte oxidase. Our recent
investigations have demonstrated that expression of the SPI2 type III secretion
system is under post-translational control by thioredoxin, a conserved
antioxidant system preserved in all branches of life. To our surprise, the
canonical thiol-disulfide oxidoreductase activity of thioredoxin is dispensable
for regulation of SPI2 expression and antioxidant defense of Salmonella.
We have found that the antioxidant defense associated with this ancestral
protein is dependent on the interactions of thioredoxin with the flexible
linker joining receiver and effector domains of the SPI2 master regulator SsrB.
Because thioredoxins are ubiquitous in the bacterial kingdom, the
thiol-disulfide oxidoreductase-independent function discovered in our
investigations is likely to be a common post-translational mechanism governing
protein function. Our investigations have also shown that the global regulatory
metalloproteins Fur and FNR coordinate antioxidant and antinitrosative defenses
of Salmonella. We have also observed that the RNA polymerase regulatory
protein DksA, which is known to regulate the stringent response to nutritional
starvation, plays an unexpected and critical role as a sensor of oxidative and
nitrosative stress. In addition to playing structural roles critical for the
global metabolic adaptation to nutritional stress, we have discovered that
thiol groups of cysteine residues in DksA zinc finger help orchestrate
transcriptional responses to oxidative and nitrosative stress. Sensing of
reactive oxygen and nitrogen species by DksA is essential for Salmonella
Xu, J. Jones-Carson, D.W. Holden, S.M. Lucia, M. Dinauer, P. Mastroeni, &
F.C. Fang. 2000. Salmonella pathogenicity island 2-dependent evasion of
the phagocyte NADPH oxidase. Science. 287: 1655-8.
C.A., T.J. Bourret, M. Song, & A. Vazquez-Torres. 2010. Control of
redox balance by the stringent response regulatory protein promotes antioxidant
defenses of Salmonella. J. Biol. Chem. 285:
36785-93. Epub 2010 Sep 17.
C.A., T. Tapscott, M.A. Crawford, M. Husain, P.T, Doulias, S. Porwollik, L.
Liu, M. McClelland, H. Ischiropoulos, & A. Vázquez-Torres. 2014. The
4-Cysteine Zinc-Finger Motif of the RNA Polymerase Regulator DksA serves as a
Thiol Switch for Sensing Oxidative and Nitrosative Stress. Mol. Microbiol.
Epub 2013 Dec 20. doi: 10.1111/mmi.12498.
13. Song, M., J.S. Kim, L. Liu, M. Husain, & A. Vazquez-Torres.
2016. Antioxidant defense by thioredoxin can occur independently of canonical
thiol-disulfide oxidoreductase enzymatic activity. Cell Reports. 14:1-11.
Host cell inhibition of
microbial respiratory activity induces antibiotic tolerance. Despite the strong
antimicrobial activity that stems from the nitrosylation of terminal
cytochromes of the electron transport chain, diverse bacteria including Salmonella,
Burkholderia, and Pseudomonas use the signaling cascade arising
from the nitrosylation of terminal cytochromes to reprogram bacterial
metabolism, enhance antioxidant defenses, and tolerate antibiotics of clinical
relevance. Decreases in oxygen availability also induce antibiotic tolerance.
Cumulatively, our investigations indicate that adaptive responses of bacteria
to host factors promote resistance of pathogens to antibiotics.
B.D., M. Hoffman, M. Husain, & A. Vazquez-Torres. 2011. Nitric oxide protects bacteria from aminoglycosides by
blocking the energy-dependent phases of drug uptake. Antimicrob
Agents Chemother. 55: 2189–2196. [Epub 2011 Feb 22].
J., A.E. Zweifel, T. Tapscott, C. Austin, J.M. Brown, K.L. Jones, M.I. Voskuil,
& A. Vazquez-Torres. 2014. Nitric oxide from IFNγ-primed
macrophages modulates the antimicrobial activity of -lactams against
the intracellular pathogens Burkholderia pseudomallei and
nontyphoidal Salmonella. PLoS Neglected Tropical Diseases. *:
15. Hamad, M.A., C.R. Austin, A.L. Stewart, M. Higgins, A. Vazquez-Torres,
& M.I. Voskuil. 2011. Adaptation and antibiotic tolerance of anaerobic Burkholderia
pseudomallei. Antimicrob Agents Chemother. 55:3313-23. Epub
2011 May 2.
& A.J. Bäumler. 2016. Nitrate, nitrite and nitric oxide reductases: from
the last universal common ancestor to modern bacterial pathogens. Current
Opinion Microbiology. 29: 1-8.
For complete list of
publications on Pubmed see:
R01 AI5449 NIAID. (PI, A. Vazquez-Torres).
Title: “Analysis of intracellular host defenses in Salmonella
pathogenesis.” The major goal of this project is to identify the molecular
mechanisms underlying the reactive nitrogen species-mediated repression of Salmonella
pathogenicity island-2 transcription. Dr. Vazquez-Torres (PI) is responsible
for the overall management of the project and the training of postdoctoral
fellows, graduate students, and professional research assistant involved in
this project. Dates Approved: 9/30/03 – 05/30/19.
I01BX002073 VA-Merit Award.
(PI, A. Vazquez-Torres). Title: “Molecular
Analysis of Bacterial Adaptive Response to Host Reactive Species.” The goal
is to elucidate the molecular mechanisms by which the RNA polymerase-binding regulatory
protein DksA regulates bacterial adaptive responses to oxidative and
nitrosative stress. Dates Approved- 04/01/2013-03/30/2017.
Burroughs Wellcome Fund; Investigators in Pathogenesis of
Infectious Disease; (PI, A. Vazquez-Torres). Title:
“Effects of nitrosative stress on bacterial two component regulatory systems
in innate host defense.” The goal is to identify the molecular mechanisms
underlying the reactive nitrogen species-mediated inactivation of the PhoPQ
two-component regulatory system. Dates Approved- 7/1/2007 – 6/30/2017.
T32 AI052066 Predoctoral Training Grant. (PD, A. Vazquez-Torres). Title: “Molecular Pathogenesis of
Infectious Diseases.” The major goals of this pre-doctoral training grant
are 1) to educate Ph.D. students in the investigation of fundamental mechanisms
by which microbes cause infection, and 2) prepare our graduate students for scientific
leadership positions. Dates Approved- 09/30/2003-06/30/2018.