Focus:
Research in the Tirouvanziam Lab @ Emory includes patient- and model-based studies of lung diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), coronavirus disease of 2019 (COVID-19), flu, asthma, as well as other disease conditions, such as food allergy, malaria, tuberculosis, and cancer. Active areas of research in the laboratory include: (i) epigenetic and transcriptional reprogramming in tissue-recruited leukocytes; (ii) extracellular vesicle-mediated crosstalk in tissue immunity; (iii) predictive biomarkers of early CF airway disease; (iv) drug development for intractable human conditions leveraging new knowledge on tissue-recruited leukocytes.
Approach:
The laboratory emphasizes sample analysis from patients and animal models using direct, high-content analyses by flow / image cytometry / transcriptomics / proteomics (for cells), proteomics and metabolomics (for fluids) to study immunometabolic pathways and their relation to disease in vivo. We also develop custom, feature-rich in vitro systems for drug screening / testing. Finally, we are interested in identifying bettertargets for therapy and in identifying endpoints to improve immunometabolic monitoring at the clinic and at home.
Funding:
Current and past funding sources include the US National Institutes of Health (NIH R01 program), the US National Science Foundation (NSF EAGER program), the US CF Foundation (basic research and clinical trial award programs), the Defense Advanced Research Program Agency (DARPA THoR and PREPARE programs), the Australian National Health and Medical Research Council (NHMRC SYNERGY program), as well as industry contracts.
Collaborations:
Our laboratory has a strong ecosystem of partners. Near: Emory and Georgia Tech in Atlanta; University of North Carolina in Chapel Hill; University of Alabama in Birmingham. Far: Erasmus University in Rotterdam, The Netherlands; Telethon Kids Institute in Perth, Australia; Royal Children’s Hospital in Melbourne, Australia; Charité Hospital in Berlin, Germany; University of Reims, France.
Contributions to science
1. Development of a xenograft model of human lung development: Dr. Tirouvanziam’s work in the field of lung biology and CF started 20 years ago, with the development and experimental use of a xenograft model of human lung development. He was the primary scientist in charge of developing this model as a graduate student at CNRS-College de France in Paris [Refs. a, b] and continued to use it as a postdoctoral fellow at Stanford University in collaborative studies with his graduate laboratory [Refs. c, d]. This xenograft model offered a unique window into the ontogeny of airway mucosal immune structures [Ref. c], and human CF disease prior to any infection. Unexpectedly, this model revealed a primary defect in the regulation of neutrophilic inflammation in CF [Ref. d]. This seminal result pushed Dr. Tirouvanziam to investigate this defect in patients during his postdoctoral training (see below).
a. Tirouvanziam R, …, Chinet T. Bioelectric properties of human CF and non-CF fetal tracheal xenografts in SCID mice. Am J Physiol. 1998; 274:C875-82. PMID: 9575783
b. Tirouvanziam R, …, Puchelle E. Inflammation and infection in naive human CF airway grafts. Am J Respir Cell Mol Biol. 2000; 23(2):121-7. PMID: 10919974
c. Tirouvanziam R, …, Péault B. Primary inflammation in human CF small airways. Am J Physiol Lung Cell Mol Physiol. 2002;283:L445-51. PMID: 12114207
d. Tirouvanziam R, …, Péault B. Ex vivo development of functional human lymph node and bronchus-associated lymphoid tissue. Blood. 2002; 99:2483-9. PMID: 11895783
2. Patient-based studies of neutrophilic inflammation in cystic fibrosis: Based on results in the SCID-Hu model (see above), Dr. Tirouvanziam set out as a research fellow at Stanford to revisit the process of CF airway inflammation. To this end, he developed an approach for analysis of airway samples using high-content flow / image cytometry. This led him to show that a large fraction of CF airway neutrophils is alive and releases toxic effectors actively, driving lung destruction [Refs a, b]. This finding changed the paradigm of CF airway inflammation and opened key research avenues. Recent efforts yielded evidence for reprogramming of CF airway neutrophils [Refs c, d], which Dr. Tirouvanziam showed can be recapitulated in vitro in a transmigration model developed by his laboratory at Emory [Ref e].
a. Tirouvanziam R, …, Herzenberg LA. Profound functional and signaling changes in viable inflammatory neutrophils homing to CF airways. PNAS. 2008; 105:4335-9. PMCID: PMC2393742. PMID: 18334635
b. Makam M, …, Tirouvanziam R. Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into CF lungs. PNAS. 2009; 106:5779-83. PMCID: PMC2667067. PMID: 19293384
c. Laval J, …, Tirouvanziam R. Metabolic adaptation of neutrophils in CF airways involves distinct shifts in nutrient transporter expression. J Immunol. 2013; 190:6043-50. PMID: 23690474
d. Ingersoll SA, …, Tirouvanziam R. Mature cystic fibrosis airway neutrophils suppress T cell function: evidence for a role of arginase 1 but not programmed death-ligand 1. J Immunol. 2015; 194:5520-8. PMCID: PMC4433848. PMID: 25926674
e. Forrest OA, …, Tirouvanziam R. Pathological conditioning of human neutrophils recruited to the airway milieu in cystic fibrosis. J Leukoc Biol. 2018; 104:665-75. PMID: 29741792
3. Drug trials and biomarker studies in CF: Using the approach for rapid ex vivoprofiling of patient samples mentioned above, Dr. Tirouvanziam discovered a basic defect in redox regulation of CF blood neutrophils, culminating in a phase 2b clinical trial for a redox intervention [Ref. a]. These studies use optimized procedures for airway sample collection and analysis that his laboratory leverages for all our patient-based studies, including a study of the CFTR corrector ivacaftor [Ref. b]. The Tirouvanziam laboratory also expanded our studies to include fluid-based biomarkers of CF lung disease [Ref. c], now enabling multiscale studies in CF infants [Refs. d, e].
a. Conrad C, …, Tirouvanziam R. Long-term treatment with oral NAC: affects lung function but not sputum inflammation in CF. A phase II randomized placebo-controlled trial. J Cyst Fibros. 2015; 14:219-27. PMID: 25228446
b. Bratcher PE, …, Tirouvanziam R*, Gaggar A*. Alterations in blood leukocytes of G551D-bearing CF patients undergoing treatment with ivacaftor. J Cyst Fibros. 2015; 15(1):67-73. PMCID: PMC456751. PMID: 25769931. *co-senior authors
c. Forrest OA, …, Tirouvanziam R. Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function. J Cyst Fibros. 2018; in press. PMID: 29937317
d. Chandler JC, …, Tirouvanziam R*$, Jones DP*, Janssens HM*. Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease. Eur Respir J. 2018; In press. PMID: 30190273. *co-senior authors, $corresponding author
e. Margaroli C, …, Tirouvanziam R. Elastase exocytosis by airway neutrophils associates with lung damage in cystic fibrosis children. Am J Respir Crit Care Med. 2018; in press. PMID: 30281324
4. Clinical trials and ancillary studies in chronic human conditions other than CF: The Tirouvanziam laboratory contributed to several studies in allergic disease [Ref. a], chronic obstructive pulmonary disease [Ref. b], transfusion reactions [Ref. c], asthma [Ref. d], as well as autism, and malaria. These efforts have reused the framework and know-how developed in CF studies to study other human conditions.
a. Gernez Y, Tirouvanziam R, …, Nadeau KC. Basophil CD203c levels are increased at baseline and can be used to monitor omalizumab treatment in nut allergy. Int Arch Allergy Immunol. 2011; 154:318-27. PMCID: PMC3214954. PMID: 2097523
b. Johnson K, …, Tirouvanziam R, Niewoehner DE. High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with COPD and chronic bronchitis: a randomized, placebo-controlled trial. Int J Chron Obstruct Pulmon Dis. 2016 Apr 21;11:799-807. PMID: 27143871
c. Fontaine MJ, …, Tirouvanziam R. Leukocyte and plasma activation profiles in chronically transfused patients with a history of allergic reactions. Transfusion. 2017; 57(11):2639-2648. PMID: 28880378
d. Grunwell JR, Stephenson ST, Tirouvanziam R, …, Fitzpatrick AM. Children with neutrophil-predominant severe asthma have pro-inflammatory neutrophils with enhanced survival and impaired clearance. J Allergy Clin Immunol Pract. 2018; In press. PMID: 30193935
5. Myeloid cell development / function in animal models: In parallel with translational studies, Dr. Tirouvanziam advanced basic knowledge on effector and regulatory subsets of myeloid cells in Drosophila [Ref. a], and mice [Refs b, c, d]. This work is currently expanded in non-human primate studies, and informs human studies.
a. Tirouvanziam R, Davidson CJ, Lipsick JS, Herzenberg LA. Fluorescence-activated cell sorting (FACS) of Drosophila hemocytes reveals important functional similarities to mammalian leukocytes. Proc Natl Acad Sci U S A. 2004; 101(9):2912-7. PMCID: PMC365719. PMID: 14976247
b. Lartey FM, Ahn GO, Shen B, Cord KT, Smith T, Chua JY, Rosenblum S, Liu H, James ML, Chernikova S, Lee SW, Pisani LJ, Tirouvanziam R, Chen JW, Palmer TD, Chin FT, Guzman R, Graves EE, Loo BW Jr. PET imaging of stroke-induced neuroinflammation in mice using Mol Imaging Biol. 2014; 16:109-17. PMCID: PMC4141125. PMID: 23836504
c. Napier RJ, Norris BA, Swimm A, Giver CR, Harris WA, Laval J, Napier BA, Patel G, Crump R, Peng Z, Bornmann W, Pulendran B, Buller RM, Weiss DS, Tirouvanziam R, Waller EK, Kalman D. Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity. PLoS Pathog. 2015; 11(3):e1004770. PMCID: PMC4379053. PMID: 25822986
d. Shin EY, Wang L, Zemskova M, Deppen J, Xu K, Strobel F, García AJ, Tirouvanziam R, Levit RD. Adenosine production by biomaterial-supported mesenchymal stromal cells reduces the innate inflammatory response in myocardial ischemia/reperfusion injury. J Am Heart Assoc. 2018;7(2). pii: e006949. PMID: 29331956
