The primary goal of my translational research is to improve the understanding of environmental effects on human health and human immunity during infections such as with Mycobacterium tuberculosis (M.tb), the bacterium that causes TB. For the past 15 years my lab in collaboration with others has spearheaded research on human lung immune responses to M.tb. Our findings helped to establish the concept of compartmentalization of immune responses to the lungs in human pulmonary TB.
Recent studies from my lab with coinvestigators at the Environmental and Occupational Health Sciences Institute (EOHSI) in Piscataway, NJ and at the University of Southern California (USC), have shown that stimulation of peripheral blood mononuclear cells (PBMC) with diesel exhaust particles (DEP) alter cytokine production and toll-like receptor-mediated M.tb-specific cell activation pathways. DEP are major components of aerosolized urban ambient fine particulate matter (PM). We noted that the production of critical M.tb-induced pro-inflammatory cytokines such as IFN-gamma, TNF-alpha, IL-1 beta, and IL-6 was reduced in a DEP dose-dependent manner in PBMC. Furthermore, inhibition of expression of many NF-kB and IFN regulatory signaling pathway target genes was observed upon DEP stimulation in non-infected cells. This data suggests that DEP downregulate M.tb-induced cytokine and gene expression responses thus significantly compromising antimycobacterial host immune responses.
As the Principal Investigator on a newly funded NIEHS RO1 grant, my lab and I will now pursue a 5-year project to assess the effects of ambient air pollution exposure on human immunity against M.tb. Because the lungs are the primary portal of entry for inhaled aerosolized PM and M.tb, we will assess the effects of exposure to urban fine PM (<2.5 microns in size) on primary human lung (bronchoalveolar) and respiratory epithelial cells. The multidisciplinary project with coinvestigators from environmental sciences, toxicology, biostatistics, microbiology and immunology at academic institutions in the US, Canada and Mexico, will be performed at the National Institute for Respiratory Diseases in Mexico City (Co-PI Martha Torres) and at the School of Public Health in Piscataway, NJ. We will examine the impact of short-term and long-term exposure to ambient and indoor air pollution, and of the seasonal variability and physicochemical characteristics of PM2.5 from Mexico City on cellular toxicity, pro- and anti-inflammatory cytokine production, mRNA expression and M.tb uptake and growth control. Adult study participants in Mexico City and in Piscataway will be selected based on their M.tb-exposure status. This research project has major global environmental and global public health implications as both TB and air pollution cause large scale morbidity and mortality in disadvantaged and impoverished populations worldwide.
My lab also investigates the effects of consumer-derived and engineered nanoparticles (silver and carbon spheres, silver and carbon wires and nanotubes) and of DEP with and without fuel additives on human immunity in in vitro and in vivo studies. These NIEHS- and EPA-funded studies are performed in conjunction with investigators at the University of Southern California (PI: Junfeng (Jim) Zhang), The Imperial College in London (PIs: Fan Chung and Terry Tetley), Rutgers University, and EOHSI (Piscataway, NJ).