By: Ada Chong
November 2023
Rabindra Tirouvanziam’s research journey started in Paris, France where he studied biotechnology as a masters student and developmental biology as a PhD. His current research looks at understanding responses to pathological stress in humans. Dr. Tirouvanziam’s lab focuses primarily on the innate immune system – cells such as macrophages and granulocytes. Dr. Tirouvanziam says these cells are highly adaptable when recruited into a stressed tissue, and we are barely scratching the surface on what we can do with them therapeutically. His research team believes these cells can do a better job at responding to acute stressors like viral and bacterial infections with the help of novel therapeutics they are developing.
Dr. Tirouvanziam’s team has a program in cystic fibrosis (CF) in which they’re building on work he’s done in the past 15 years, demonstrating that chronic lung disease in CF patients is driven by an abnormal reprogramming of innate immune cells (resident macrophages and recruited neutrophils). In normal responses, blood neutrophils come when stress occurs to take care of the issue, rapidly die by apoptosis, and then the tissue goes back to its original state. In certain conditions, neutrophils can overstay their welcome and build a stable microenvironment resulting in chronic recruitment from blood and tissue reorganization. In CF, this leads to the tolerance/selection of opportunistic bacteria like Staph and Pseudomonas, which lost most of their virulence factors but remain in the lungs for years.
In addition to lung diseases (CF, COVID-19, TB), the Tirouvanziam Lab has collaborations across different departments at Emory, Georgia Tech and outside institutions exploring mechanisms of innate immunity in other human pathologies. For example, they’re partnering with colleagues at Winship to investigate “cold tumor” and in Radiology to investigate diabetic foot ulcers.
The first approach used in the Tirouvanziam lab consists in analyzing patient samples. For lung sampling, one method (called a lavage) involves putting a tube in a patient’s airways after sedation, so fluid can be injected and quickly retrieved to acquire secretions and cells. A less invasive method (sputum collection) consists of having patients cough up material from their lungs into a cup. Yet another method is to have the patients breathe in a tube (EBC collection) so the team can measure small molecules (metabolites, proteins). The second approach is to use engineered platforms that mimic lung exposure to stressors and the migration of innate immune cells into the stressed lung environment. For this, researchers in the lab purify blood cells and allow them to cross the lung barrier in their in vitro models, so they can adopt a lung-like set of functions. This method enables the mass-production of lung-conditioned cells in vitro that look like the ones retrieved from the patients’ lungs. This trick allows the lab to conduct extensive mechanistic studies of tissue responses to different stressors (for example, exposure to the CF lung fluid, or to influenza or corona viruses) and use this new knowledge to develop therapies. For example, this method was used in collaboration with the Schinazi lab to demonstrate efficacy of the immune modulator drug baricitinib in COVID-19. Another collaboration with the Schinazi Lab is targeting one novel pathway discovered in CF using computational and biological screening.
A top goal of the Tirouvanziam lab is to target the innate immune system in ways that have not been attempted so far. Currently, there are no immunomodulatory drugs that are efficient at modulating innate cells besides those attempting to block their entry into a stressed tissue, which often backfires. To fill this gap, Dr. Tirouvanziam wants to develop new classes of innate immune modulatory therapeutics (small molecule and regulatory RNAs), which will control their tissue reprogramming at will. He hopes to have the first trial of an innate immunotherapeutic drug tested in humans in the next five to ten years.
Another top goal of the Tirouvanziam Lab is to train the next generation of scientists to rethink mechanisms of innate immunity in human pathology. Dr. Tirouvanziam strives to recruit graduate students and postdocs from different areas of biomedical research (immunology, microbiology, pharmacology, biomedical engineering) in order to promote a diversity of perspectives. He’s particularly proud of the multi-national personnel in his lab. He says, “there’s a definite richness in a diverse workforce and we pride ourselves on that and use it to drive innovation.”