Selvakumar Subbian, Ph.D.

The central theme of our research program is to understand the host response to microbial infections of humans, particularly bacterial and fungal diseases, using animal and in vitro models. We are well-recognized for research in tuberculosis, specifically for the rabbit model. In this area, one of the goals is to determine, characterize, understand and apply the molecular immunologic and metabolic determinants underlying the progression of Mycobacterium tuberculosis (Mtb) infection to active tuberculosis (TB) versus control of infection and establishment of latency (LTBI) (i.e, protective versus permissive host response) as well as reactivation of TB upon immune suppression.  Another aspect of our research involves exploring the efficacy of adjunctive immune modulation therapy as a host-directed intervention to improve current TB treatment modalities. For these studies, we have been primarily using our well-established animal models (rabbit, mouse, rat and guinea pig) of Mtb infection; each of these models recapitulates various pathophysiological aspects seen in patients with active and/or latent TB to various extents. In these models of TB, using cutting edge molecular technologies, such as single-molecule mRNA-FISH, fluorescent IHC-confocal microscopy, genome-wide transcriptomics and bioinformatics approaches, we have defined the intricate host-pathogen interactions at the site of infection and have identified several host immune markers and gene networks/pathways that can significantly contribute to the differential disease pathogenesis leading to active TB or latency. For the first time in literature, we have identified/reported several host immune markers and associated gene networks/pathways in the rabbit lungs that contribute to the differential outcome of Mtb infection (active TB and/or latency/reactivation). In pre-clinical animal models (mouse and rabbit) of pulmonary TB, we have established proof-of-concept for the beneficial effect of host directed therapy with a small molecule phosphodiesterase-4 (PDE4i) inhibitor in combination with anti-TB drugs; at present, this molecule is in human clinical trial.  Recently, we obtained an NIH award to explore the role of host metabolic changes (a.k.a. Warburg effect) associated with the immune response during Mtb infection. Our collaborators at PHRI include, Drs. Lanbo Shi, Yuri Bushkin, Sanjay Tyagi, Abraham Pinter, Christopher Vinnard, Jyothi Nagajyothi, Neeraj Chauhan, Marcela Rodriguez, Theresa Chang, Marila Gennaro, Veronique Dartois, David Perlin, Barry Kreiswirth, Chaoyang Xue, and Claudia Manca. We have also established collaborative tuberculosis research with reputed national and international researchers.

Other Research Activities

1. Understanding the host-pathogen interactions and determinants in non-tuberculosis mycobacteria (NTM), fungal and viral infection using in vitro and animal models
2. Exploring host directed therapeutics either as sole or adjunct to antibiotics to treat infectious diseases
3. Delineating host immune response and cells during microbial infections
4. Determining the host immune metabolism (Warburg effect) in microbial infections
5. Developing new and novel diagnostic tool and vaccine candidates for microbial diseases
6. Studying the role of adipose tissue and host lipid metabolism in the pathogenesis of microbial infections
7. Characterizing antibody response in TB pathogenesis and harnessing it for diagnosis/treatment
8. Understanding the drug induced toxicity and host immune modulation during TB
9. Deciphering the host metal ion homeostasis in TB pathogenesis
10. Exploring the host response to HIV-TB infection

View all on PubMed

Dusthackeer A, Balasubramanian M, Shanmugam G, Priya S, Nirmal CR, Sam Ebenezer R, Balasubramanian A, Mondal RK, Thiruvenkadam K, Hemanth Kumar AK, Ramachandran G, Subbian S (2019) Differential Culturability of Mycobacterium tuberculosis in Culture-Negative Sputum of Patients With Pulmonary Tuberculosis and in a Simulated Model of Dormancy. Frontiers in Microbiology 10.

Li J, Fu L, Wang G, Subbian S, Qin C, Zhao A Unmethylated CpG motif-containing genomic DNA fragment of Bacillus calmette-guerin promotes macrophage functions through TLR9-mediated activation of NF-κB and MAPKs signaling pathways. Innate Immunity 0: 1753425919879997. PMI: 31615313

Kumar R, Singh P, Kolloli A, Shi L, Bushkin Y, Tyagi S, Subbian S (2019) Immunometabolism of Phagocytes During Mycobacterium tuberculosis Infection. Front Mol Biosci 6: 105. PMI: 31681793

Shi L, Jiang Q, Bushkin Y, Subbian S, Tyagi S (2019) Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection. MBio 10. PMI: 30914513

Ayyappan JP, Vinnard C, Subbian S, Nagajyothi JF (2018) Effect of Mycobacterium tuberculosis infection on adipocyte physiology. Microbes Infect 20: 81-88. PMI: 29109018

Kurthkoti K, Amin H, Marakalala MJ, Ghanny S, Subbian S, Sakatos A, Livny J, Fortune SM, Berney M, Rodriguez GM (2017) The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas. MBio 8. PMI: 28811344

Kolloli A, Subbian S (2017) Host-Directed Therapeutic Strategies for Tuberculosis. Front Med (Lausanne) 4: 171. PMI: 29094039

Tasker C, Subbian S, Gao P, Couret J, Levine C, Ghanny S, Soteropoulos P, Zhao X, Landau N, Lu W, Chang TL (2016) IFN-epsilon protects primary macrophages against HIV infection. JCI Insight 1: e88255. PMI: 27942584

Subbian S, Tsenova L, Holloway J, Peixoto B, O’Brien P, Dartois V, Khetani V, Zeldis JB, Kaplan G (2016) Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model. EBioMedicine 4: 104-114. PMI: 26981575

Shi L, Eugenin EA, Subbian S (2016) Immunometabolism in Tuberculosis. Front Immunol 7: 150. PMI: 27148269

Guerrini V, Subbian S, Santucci P, Canaan S, Gennaro ML, Pozzi G (2016) Experimental Evolution of Mycobacterium tuberculosis in Human Macrophages Results in Low-Frequency Mutations Not Associated with Selective Advantage. PLoS One 11: e0167989. PMI: 27959952

Dehnad A, Ravindran R, Subbian S, Khan IH (2016) Development of immune-biomarkers of pulmonary tuberculosis in a rabbit model. Tuberculosis (Edinb) 101: 1-7. PMI: 27865378

Subbian S, Tsenova L, Kim MJ, Wainwright HC, Visser A, Bandyopadhyay N, Bader JS, Karakousis PC, Murrmann GB, Bekker LG, Russell DG, Kaplan G (2015) Lesion-Specific Immune Response in Granulomas of Patients with Pulmonary Tuberculosis: A Pilot Study. PLoS One 10: e0132249. PMI: 26133981

Subbian S, Pandey R, Soteropoulos P, Rodriguez GM (2015) Vaccination with an Attenuated Ferritin Mutant Protects Mice against Virulent Mycobacterium tuberculosis. J Immunol Res 2015: 385402. PMI: 26339659

Tsenova L, O’Brien P, Holloway J, Peixoto B, Soteropoulos P, Fallows D, Kaplan G, Subbian S (2014) Etanercept exacerbates inflammation and pathology in a rabbit model of active pulmonary tuberculosis. J Interferon Cytokine Res 34: 716-726. PMI: 24831609

Liu TB, Subbian S, Pan W, Eugenin E, Xie J, Xue C (2014) Cryptococcus inositol utilization modulates the host protective immune response during brain infection. Cell Commun Signal 12: 51. PMI: 25201772

Subbian S, Bandyopadhyay N, Tsenova L, O’Brien P, Khetani V, Kushner NL, Peixoto B, Soteropoulos P, Bader JS, Karakousis PC, Fallows D, Kaplan G (2013) Early innate immunity determines outcome of Mycobacterium tuberculosis pulmonary infection in rabbits. Cell Commun Signal 11: 60. PMI: 23958185

Manca C, Koo MS, Peixoto B, Fallows D, Kaplan G, Subbian S (2013) Host targeted activity of pyrazinamide in Mycobacterium tuberculosis infection. PLoS One 8: e74082. PMI: 24015316

Subbian S, Tsenova L, O’Brien P, Yang G, Kushner NL, Parsons S, Peixoto B, Fallows D, Kaplan G (2012) Spontaneous latency in a rabbit model of pulmonary tuberculosis. Am J Pathol 181: 1711-1724. PMI: 22960076

Koo MS, Subbian S, Kaplan G (2012) Strain specific transcriptional response in Mycobacterium tuberculosis infected macrophages. Cell Commun Signal 10: 2. PMI: 22280836

Subbian S, Tsenova L, Yang G, O’Brien P, Parsons S, Peixoto B, Taylor L, Fallows D, Kaplan G (2011) Chronic pulmonary cavitary tuberculosis in rabbits: a failed host immune response. Open Biol 1: 110016. PMI: 22645653

Subbian S, Tsenova L, O’Brien P, Yang G, Koo MS, Peixoto B, Fallows D, Dartois V, Muller G, Kaplan G (2011) Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs. PLoS Pathog 7: e1002262. PMI: 21949656

Park B, Subbian S, El-Etr SH, Cirillo SL, Cirillo JD (2008) Use of gene dosage effects for a whole-genome screen to identify Mycobacterium marinum macrophage infection loci. Infect Immun 76: 3100-3115. PMI: 18443095

Dusthackeer A, Kumar V, Subbian S, Sivaramakrishnan G, Zhu G, Subramanyam B, Hassan S, Nagamaiah S, Chan J, Paranji Rama N (2008) Construction and evaluation of luciferase reporter phages for the detection of active and non-replicating tubercle bacilli. J Microbiol Methods 73: 18-25. PMI: 18272245

Subbian S, Narayanan S (2007) Identification and characterization of the regulatory elements of the inducible acetamidase operon from Mycobacterium smegmatis. Can J Microbiol 53: 599-606. PMI: 17668018

Subbian S, Mehta PK, Cirillo SL, Bermudez LE, Cirillo JD (2007) A Mycobacterium marinum mel2 mutant is defective for growth in macrophages that produce reactive oxygen and reactive nitrogen species. Infect Immun 75: 127-134. PMI: 17030568