|Borna Mehrad, MD
Professor and Chief
Summary of Research
The tissue response to injury is a complex and evolutionarily ancient process that is fundamental to many diseases. As the organ of gas exchange, the lung epithelial barrier separating the body from the outside world has a large surface area (70m2 in an adult human) but is exceedingly thin (mean thickness 0.6μm). In the context of injury, this structure poses the unique challenge of balancing 3 competing demands: First, the host must ignore a constant barrage of innocuous particles, but accurately identify the occasional pathogen that arrive at the surface. Second, it has to mount a rapid and fierce, yet highly localized, inflammatory response to kill those pathogens but leave most of the surface area intact for gas exchange. Third, it has to repair the resulting damage but halt scar formation to minimize permanent loss of gas exchange surface. Although this seems like a tall order, the process works remarkably well most of the time; when it does not, the consequences are lung infection, inflammatory damage to the lung, or lung scarring — the key features of most lung diseases.
Areas of research in the lab include:
1. Fibrocytes in fibrotic lung disease: Interstitial lung diseases are a heterogeneous group of lung diseases defined by chronic and multifocal inflammation and fibrosis. We and others have identified a bone marrow-derived circulating cell, named fibrocyte, that homes to the lungs in these illnesses, differentiates into fibroblasts and myofibroblasts and contributes to tissue fibrosis. In translational projects in the laboratory and clinic, we are investigating these cells as potential biomarkers and therapeutic targets in human interstitial lung diseases.
2. Host defense mechanisms in invasive aspergillosis: Aspergillus species are among the most common environmental moulds and their airborne spores are inhaled daily by all humans. Despite this constant exposure, the vast majority of normal hosts clear the organism without developing any illness. Hosts with impaired immunity, however, can develop a life-threatening infection in the respiratory tract that can then disseminate to other organs. A long-standing area of investigation in our lab is the study of host defense mechanisms in a model of this infection in neutropenic animals.
3. Experimental therapy for Gram-negative bacterial infections: Aerobic Gram-negative bacilli are the most common causes of nosocomial infections and their treatment is enormously complicated by the progressive rise of antibiotic-resistance in hospitals. In recent work using a murine model of Gram-negative infection, we have identified an iron-regulatory hormone, hepcidin, that can be therapeutically harnessed to enhance defenses against these infections. Ongoing studies seek to develop this mechanism as a potential therapy for human infections.
Current Research Projects/Grants
- National Institutes of Health (U01EB024501), “Modular design of multiscale models, with an application to the innate immune response to fungal respiratory pathogens,” Borna Mehrad, Co-principle Investigator; 7/1/2017-06/30/2021.
- National Institutes of Health (R21AI117397), “Neutrophils and adaptive immunity against invasive aspergillosis,” Borna Mehrad, Principle Investigator; 4/1/15-3/31/18.
Completed Research Projects/Grants
- National Institutes of Health (R01HL098329), “Fibrocytes in human pulmonary fibrosis,” Borna Mehrad, Co-Principle Investigator; 3/1/11-1/31/16 (no-cost extension until 1/31/17).
- University of Virginia School of Medicine Transformative, Collaborative Science Pilot Grant. “Hyper-polarized xenon MRI as a biomarker in pulmonary fibrosis” Borna Mehrad, Co-Principle Investigator, 1/1/15-12/31/15.
- National Institutes of Health (R01HL098526), “Fibrocytes in the pathogenesis of sickle cell lung disease,” C. Edward Rose, Principle Investigator; Borna Mehrad, Co-Investigator; 9/5/2010-8/31/2014.
- National Institutes of Health (R01HL073848), “NK cells in host defense against invasive aspergillosis,” Borna Mehrad, Principal Investigator; 7/11/03-5/31/14.
- Barletta KE, Ley K, Mehrad B. Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol. 2012; 32(4):856-64. PMCID: PMC3353547
- Park SJ, Burdick MD, Mehrad B. Neutrophils mediate maturation and efflux of lung dendritic cells in response to Aspergillus germ tubes. Infect Immun. 2012; 80(5):1759-65. PMCID: PMC3347458
- Barletta KE, Cagnina RE, Burdick MD, Linden J, Mehrad B. Adenosine A2B receptor-deficiency promotes host defenses against Gram-negative bacterial pneumonia. Am J Respir Crit Care Med 2012; 186(10):1044-50. PMCID: PMC3530209
- Chen L, Zhang Z, Barletta KE, Burdick MD, Mehrad B. Heterogeneity of lung mononuclear phagocytes during pneumonia: contribution of chemokine receptors. Am J Physiol Lung Cell Mol Physiol 2013; 305(10):L702-11. PMCID: PMC3840272
- Trimble A, Gochuico BR, Markello TC, Fischer R, Gahl WA, Lee JK, Kim K, Burdick MD, Strieter RM, Mehrad B. Circulating fibrocytes as biomarker of prognosis in Hermansky-Pudlak syndrome. Am J Respir Crit Care Med. 2014; 190(12):1395-401. PMCID: PMC4299649
- Mehrad B, Clark NM, Zhanel GG, Lynch JP 3rd. Antimicrobial resistance in hospital-acquired Gram-negative bacterial infections. Chest 2015; 147(5):1413-21. PMCID: PMC4420185.
- Michels K, Nemeth E, Ganz T, Mehrad B. The role of hepcidin in host defense against infectious diseases. PLoS Pathogens 2015;11(8):e1004998. PMCID: PMC4546197
- Oremland M, Michels K, Bettina A, Lawrence C, Mehrad B, Laubenbacher R. Computational model of invasive aspergillosis in the lung. BMC Syst Biol. 2016; 10(1):34. doi: 10.1186/s12918-016-0275-2. PMCID: PMC4839115
- Keeley EC, Marinescu MA, Burdick MD, Strieter RM, Mehrad B. Circulating fibrocytes as predictors of adverse events in unstable angina. Transl Res 2016 ;172:73-83.e1. doi: 10.1016/j.trsl.2016.02.013. Epub 2016 Mar 8. PMCID: PMC4866880
- Bettina A, Zhang Z, Michels K, Cagnina RE, Vincent I, Burdick MD, Kadl A, Mehrad B. M-CSF mediates host defense during bacterial pneumonia by promoting the survival of lung and liver mononuclear phagocytes. J Immunol. 2016;196(12):5047-55. PMCID: PMC4893984
- Michels K, Zhang Z, Bettina A, Cagnina RE, Stefanova D, Burdick MD, Nemeth E, Ganz T, Mehrad B. 2017. Hepcidin-mediated iron sequestration is required for host defense against pneumonia. JCI Insight. 2017;2(6):e92002. PMCID: PMC5358492
- Mehrad B, Burdick MD, Wandersee NJ, Shahir KS, Zhang L, Simpson PM, Strieter RM, Field JJ. Circulating fibrocytes as biomarkers of impaired lung function in adults with sickle cell disease. Blood Adv 2017. In press.